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Mapping and Profiling Lipid Distribution in a 3D Model of Breast Cancer Progression
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Cite this: ACS Cent. Sci. 2019, 5, 5, 768–780
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https://doi.org/10.1021/acscentsci.8b00932
Published April 19, 2019

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Abstract

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Aberrant lipid accumulation and marked changes in cellular lipid profiles are related to breast cancer metabolism and disease progression. In vitro, these phenomena are primarily studied using cells cultured in monolayers (2D). Here, we employ multicellular spheroids, generated using the MCF10A cell line series of increasing malignancy potential, to better recapitulate the 3D microenvironmental conditions that cells experience in vivo. Breast cancer cell lipid compositions were assessed in 2D and 3D culture models as a function of malignancy using liquid chromatography coupled with mass spectrometry. Further, the spatial distribution of lipids was examined using Raman chemical imaging and lipid staining. We show that with changes in the cellular microenvironment when moving from 2D to 3D cell cultures, total lipid amounts decrease significantly, while the ratio of acylglycerols to membrane lipids increases. This ratio increase could be associated with the formation of large lipid droplets (>10 μm) that are spatially evident throughout the spheroids but absent in 2D cultures. Additionally, we found a significant difference in lipid profiles between the more and less malignant spheroids, including changes that support de novo sphingolipid production and a reduction in ether-linked lipid fractions in the invasive spheroids. These differences in lipid profiles as a function of cell malignancy and microenvironment highlight the importance of coupled spatial and lipidomic studies to better understand the connections between lipid metabolism and cancer.

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Synopsis

The profiles and spatial distribution of lipids in breast cancer cells change as a function of culture dimensionality and malignancy potential, yielding insight into cancer-related lipid metabolism.

Introduction

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Cancer cell metabolism differs from normal cell metabolism in ways that support the biosynthetic, energy, and redox needs of tumors and enable cell proliferation and survival under stressful conditions such as nutrient limitation. (1) In such conditions, lipids can serve as an alternative energy source through lipogenesis (2,3) or through fatty acid scavenging. (4) Altered lipid metabolism is a hallmark of human cancer and may promote proliferation by providing the energy and the membrane building blocks for rapid growth. (5−7) Many cancer cells store excess lipids in intracellular lipid droplets, organelles involved in lipid storage, transport, and signaling that differ in composition, size, and distribution depending on the cells or tissue in which they are found. (8,9) Recent advances in imaging and analytical techniques such as Raman microscopy and mass-spectrometry-based lipidomics (10−12) provide opportunities for obtaining high resolution spatial maps of lipid distribution within tissues coupled with detailed lipid composition profiles. (13,14) Here, we apply these techniques to assess lipid accumulation and spatial distribution and compare the global lipid profiles in human breast cancer cell lines as a function of cell culture dimensionality (2D vs 3D) and malignancy potential.
Currently, in vitro models that employ lipid mapping (15) and profiling (16) to study the relationships between breast cancer progression and lipid production use 2D cell cultures on substrates such as polystyrene. In contrast, in a solid tumor, regions of cellular viability, in which cells proliferate and interact in all directions, often transition to diffusion-limited inner regions of hypoxia and cell death. With varying nutrient availability, abnormal metabolic demands, and a continuing need for energy to drive cancer cell proliferation, three-dimensional tumor growth is dependent in part on lipid metabolism. (17,18) The complex 3D microenvironmental conditions to which cells are exposed in vivo such as cell–cell and cell–extracellular matrix interactions can be better mimicked by 3D cell cultures compared to 2D cultures. (19,20) For example, 3D multicellular spheroids have been shown to recapitulate some in vivo cancer behaviors, including cell death (21) and tumor progression (22) pathways. In other work, we have used 3D multicellular spheroids of human breast cancer cell lines of varying malignancy to study the formation of breast microcalcifications. (23) Much like ductal breast cancer, the spheroids develop necrotic cores with spatially distinct viable cell and hypoxic areas. In addition, gene expression changes induced by conditions affecting metabolism are differentially regulated in 2D vs 3D cultures. (24) Thus, cells cultured in 3D spheroids provide a biologically more relevant model for exploring lipid distribution in a three-dimensional microenvironment with variable access to nutrients and oxygen as well as exposure to metabolites.
The power of emerging lipid characterization techniques such as Raman microscopy and mass spectrometry-based lipidomics to provide both spatial mapping and molecular identification of lipids has been demonstrated in systems ranging from single-celled algae (10,14) to myelin distribution in brain tissue. (13) In cancer research, these techniques have shown differences in lipid profiles among human breast cancer subtypes as well as between breast cancer and normal cells (15,16,25−30) though, for the latter, these in vitro experiments were carried out in 2D cultures. It remains unclear, however, the extent to which changes in tissue dimensionality that may be mimicked with 3D culture models can affect lipid profiles and spatial distribution. Although spatial differences in lipid accumulation may be key to tumorigenesis, (26,31) they are rarely assessed with micrometer-scale resolution due to a shortage of methodologies allowing for this analysis. Furthermore, systems harboring multiple cellular environments such as necrotic and viable cell regions necessitate the use of techniques that venture beyond the bulk. Raman microscopy is one such technique that enables spatially mapping a multitude of chemical signatures (at submicrometer resolution (32)) in biological materials without staining or significant sample preprocessing. (33,34) At high enough concentrations, different types of lipids can be readily detected and distinguished, as well as proteins (generally and, in some cases, specifically), cells, extracellular matrix components, sugars, and other chemical species. The information gained by coupling Raman microscopy with lipidomics has the potential to offer a view of biological lipid profiles encompassing both the physical distribution of lipids and the diversity of lipid species.
The aim of this study is to understand the effect of cell culture dimensionality on lipid metabolism and spatial distribution by using breast cancer cell lines of a tumor progression series of nonmalignant, precancer, and invasive cells. We employed ultrahigh performance liquid chromatography coupled with state-of-the-art mass spectrometry (LCMS) to analyze lipid production in both traditional 2D cell cultures and 3D multicellular spheroids. Histological staining and Raman mapping are used in conjunction with LCMS to detail changes in the spatial distribution of local lipid accumulation as a function of malignancy and dimensionality. These experiments are designed to provide insights into the relationships among lipid profiles, both spatial and compositional, and cell microenvironment and malignancy potential.

Results

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We represented tumor progression in our model by using the nonmalignant human breast epithelial cell line MCF10A (35) and two additional cell lines that were derived from the parent MCF10A to exhibit higher malignancy potential: the “precancer” MCF10DCIS.com cell line (36,37) and the “invasive” MCF10CA1a cell line. (38) Each of the three cell lines was cultured using two different methods: as 2D cell monolayers and as multicellular spheroids (3D).

Spatial Distribution of Lipids Depends on the Dimensionality (2D vs 3D) and Malignancy Potential of the Cells

Using hydrophobic Oil-Red-O staining of the cell monolayers and of cryosections from the spheroids, the nonpolar lipid distribution was observed for the different malignancy potentials and culture dimensionalities. In both 2D and 3D cultures, the nonmalignant breast epithelial cells had low lipid content (Figure 1a, d, g, j). In 2D, the majority of the lipid droplets in the precancer and invasive cells had diameters smaller than 2 μm (Figure 1b, c, e, f). When moving to 3D, the overall amount of lipid staining decreased compared to 2D, and the nonmalignant spheroids presented small patches of lipids that were not observed in 2D culture (Figure 1g). In the malignant 3D spheroids, increased staining was observed in the spheroid cores, which contain necrotic and apoptotic cells. In this region, distinguishable lipid bodies had diameters (<1 μm) smaller than those found in 2D (see magnified field of view in Supporting Figure S1). Additionally in 3D, large lipid droplets (with diameters larger than 10 μm), with size and number varying from spheroid to spheroid, were present throughout the sections and were more abundant in the invasive spheroids (Figure 1h, i, k, l).

Figure 1

Figure 1. Relation between lipid amounts and the malignancy potential of breast cancer cells in 2D and 3D. Oil-Red-O lipid staining of cell lines from the MCF10A-based breast cancer progression series cultured in 2D (a–f) and as multicellular spheroids (g–l). (a, d, g, j) Nonmalignant MCF10A cells; (b, e, h, k) precancer MCF10DCIS.com cells; (c, f, i, l) invasive MCF10CA1a cells. Lipids are stained red, and cell nuclei are stained purple. Arrows: lipid droplet aggregates close to cell nuclei. For a high resolution version of Figure 1 see Supporting Data.

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Lipid Profiling of Precancer and Invasive Cells in 2D and 3D Culture

Oil-Red-O staining is a nonspecific stain for any neutral lipid and, as such, does not provide any information about how the lipid species are changing as a function of culture dimensionality and malignancy potential. We hypothesize that the complex interactions present in 3D cultures, as well as the malignancy potential, affect the lipid profiles. To test this hypothesis, we characterized the lipid profiles of the precancer and invasive cells cultured both in 2D and 3D using ultrahigh performance liquid chromatography coupled with electrospray ionization mass spectrometry in positive mode (referred to as LCMS for short). Because the nonmalignant cells presented very small amounts of Oil-Red-O staining, which were hardly detectable compared to the more malignant cells, their lipid profiles were not studied by LCMS.

Lipid Amounts and Profiles Differ Significantly Depending on Dimensionality

From LCMS, a total of 660 unique lipid species were detected (Figure 2 and Supporting Figure S2). The lipid amounts and profiles of both the precancer and invasive cells changed when moving from 2D cultures to 3D multicellular spheroids (Supporting Table S1). Overall, cells cultured in 3D had substantially less total lipid than those in 2D (3–6 × 107 normal peak area/μg protein in 3D and 2–4 × 109 normal peak area/μg protein in 2D) (Supporting Figure S3, Table S1). Hierarchical cluster analysis performed on lipids identified in 2D and 3D cultures of precancer and invasive cells by LCMS shows clear differences between the two groups (Figure 2a, Supporting Figure S2, and Supporting Table S1). Across conditions, membrane lipids (i.e., glycerophospholipids) make up the highest fraction of lipid type, followed by either sphingomyelins in 2D or neutral glycerolipids (i.e., acylglycerols) in 3D (Figures 2b and S2). Broadly, the lipid profiles of 3D cultures show larger variation than those of the 2D cultures both across biological replicates and between malignancies, possibly due to the more complex microenvironmental conditions and signaling cues that the cells are exposed to in 3D culture and consequential changes in tumor cell heterogeneity.

Figure 2

Figure 2. Lipid profiles in 2D and 3D culture of precancer and invasive cells detected using LCMS. (a) Heatmap showing the clustering of lipid species in 2D and 3D cultures of MCF10DCIS.com (precancer) and MCF10CA1a cells (invasive). Color bar indicates the scaled distance from the row mean of the normalized transformed data. For assessment of the variation within each group, the biological replicates for each condition are shown. For the 2D samples, each group consists of three biological replicates, and for the 3D samples, each group consists of four biological replicates. Lipid classes are color coded as indicated. Coenzyme Q10 is shown in white. To the right, representative example lipid structures of the color-coded lipid classes in part a are shown. (b) Lipid class distribution in precancer and invasive 2D and 3D cultures as detected with LCMS, calculated from areas in LCMS normalized per microgram of protein in the sample and presented as a fraction of total lipids in the sample. Error bars are the standard error of the mean. 34 Cs = summed acyl chain and sphingoid base chain lengths of 34 carbons. See Supporting Figure S2 for a version of this figure with individual lipid identifiers associated with the heat map.

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Neutral Glycerolipids Are Significantly Increased in 3D Compared to 2D

On further inspection of the cluster analysis (Figure 2a), there are clear differences in lipid populations between 2D and 3D cultures: the relative amounts of certain lipid classes, saturations, and number of carbons differ (Supporting Table S1). In the 3D cultures as compared to 2D, neutral lipids make up significantly more of the total lipid composition (Figure 2b). Neutral lipids, including triradylglycerols (TGs, majority triacylglycerols with minor contributions from ether linked species), are proportionally higher in 3D than in 2D and higher in the invasive cells than in the precancer cells. In 2D, TGs account for <2% of the total detected lipid population, whereas in 3D they make up on average 13 ± 5% of lipids in precancer and 18 ± 4% in invasive. It is likely that it is these neutral lipids that are evident in the Oil-Red-O staining. Similarly, <2% of total lipids are diacylglycerols (DAGs) and monoacylglycerols (MAGs) in 2D, yet in 3D, they make up 9 ± 4 and 14 ± 3% of lipids detected in precancer and invasive cells, respectively.

Alkyl and Alkenyl Ether Lipid Fractions Are Significantly Increased in 3D

Out of total lipids, cells cultured in 2D contain a higher percentage of both phosphatidylethanolamine (PE) and phosphatidylcholine (PC) relative to the same cells cultured in 3D (Figure 2b). The fraction of ether-linked, as opposed to ester-linked, PCs and PEs, however, differs depending on culture dimensionality and cell malignancy. The largest difference arises in PEs that contain an alk-1-enyl ether linkage (P-PEs, i.e., plasmalogens and plasmenyl). The percentage of PEs that are P-PE is substantially higher in 3D compared to 2D and differs strongly between malignancies (∼30% in 2D independent of malignancy, 52 ± 1.5 and 68 ± 0.95% in 3D invasive and precancer, see Supporting Table S1). The percentage of alkyl ether PEs (O-PEs, i.e., plasmanyl) in 3D is also higher when compared to that in 2D. Alkyl ether linked PCs (O-PCs) make up 5–20% of PCs, and P-PCs make up 5–10% of PCs, depending on the group. Percentages of both types of PC ethers were highest in 2D and 3D precancer and lowest in 3D invasive.

Sphingomyelin and Lysophosphatidylcholine Show Differences between 2D and 3D Based on Number of Carbons

Sphingomyelin (SM) fractions are similar for the 2D precancer and invasive cells and for the 3D invasive spheroids (∼6–8%) with a decrease in the precancer spheroids (∼3%). The fraction of sphingomyelins consisting of <34 carbons is increased in 3D. There is an increase in lysophosphatidylcholine (LPC) amount in 3D, and the makeup of LPCs differs significantly depending on chain length (Supporting Table S1).

Lipid Profiles Differ between Precancer and Invasive in 3D Spheroids

In breast cancer, both lipid quantity and the expression of fatty acid synthase increase with malignancy, (39−43) motivating us to further compare lipid profiles between precancer and invasive cell lines. The lipid profile difference between cells of varied malignancy potentials is more profound within 3D samples compared to 2D samples (Figure 2). Given that spheroids more closely model tumor microenvironmental conditions in vivo, (19−22) we performed further analysis of the LCMS data for the 3D spheroids as a function of tumor cell malignancy (Figure 3).

Figure 3

Figure 3. Heat map showing clustering of the 25 lipid species with the most significant changes, selected by t-test, across 3D cultures of MCF10DCIS.com (precancer) and MCF10CA1a (invasive) cells as detected with LCMS. Each group consists of four biological replicates. So(d18:0) = sphinganine. Color bar indicates the scaled distance from the row mean of the normalized transformed data.

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The precancer spheroids contain more lipids than the invasive spheroids (Supporting Figure S3, Figure 2b) and differ considerably in their lipid profiles; there is an increase in the percentage of acylglycerols and SMs in the invasive spheroids and an increase in PCs in the precancer spheroids (Figure 2b). A heat map showing the clustered top 25 lipids with the most significant changes across spheroid malignancies is shown in Figure 3. Almost all are membrane lipids. The species increased in the invasive spheroids include polyunsaturated PCs (diacyl), SMs with ≤34 carbons, one DAG species, and sphinganine. In the precancer spheroids, O-PCs and P-PCs are the species most significantly increased. Additional increased species include a P-PE, a PC (monounsaturated), and two very long chain LPCs (>26 carbons). In addition, between the 3D spheroids, more LPCs were detected in invasive, though the fraction of LPCs with chain lengths >26 carbons was larger in precancer spheroids.

Mapping Spatial Distribution of Lipids and Other ECM Components in 3D Spheroids Using Raman Microscopy

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While the LCMS cluster analysis of precancer versus invasive spheroids shows that the lipid amount and profiles vary significantly (Figure 3), the Oil-Red-O staining suggests that there is also a change in neutral lipid distribution between these two cell lines (Figure 1). Cross-polarized light microscopy images of unwashed sections of spheroids show that some lipid-containing areas in the spheroids have strong birefringence, suggesting an anisotropic molecular ordering (Figure 4a–d). Raman microscopy was used to map the spatial distribution of chemical species, including lipids, proteins, and glycogen, within the precancer and invasive spheroids (Figure 4e–g). The Raman maps can provide insight into how the biochemical differences revealed by the lipidomics analysis are spatially distributed within the spheroids.

Figure 4

Figure 4. Characterization of the lipid droplets formed in 3D multicellular spheroids of malignant cell lines. (a, b, e) Precancer spheroid cross sections. (c, d, g) Invasive spheroid cross sections. Asterisks show the necrotic core. (a, c) Oil-Red-O lipid staining showing lipid accumulation in the necrotic core area of the spheroids as well as lipid droplets in the invasive spheroid (arrows). (b, d) Cross-polarized light images of the spheroid cross sections showing birefringence (arrows in part d point at the same areas as in part c). (e, g) Overlaid spatial distribution maps of key basis spectra resultant from NMF multivariate analysis of Raman mapping. (f) Corresponding NMF basis spectra (precancer: black, invasive: gray). The precancer overlay map (e) shows an increase in lipid content toward the spheroid center, while the invasive overlay map confirms the birefringent  regions are lipid-rich droplets (cyan). Arrows indicate the same bodies as in parts c and d.

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An unsupervised multivariate approach, non-negative matrix factorization (NMF), was employed to reduce each hyperspectral Raman map into a basis set consisting of chemically meaningful, separable spectral signatures (i.e., basis spectra). Each basis spectrum has a corresponding heat map, in which the value of each pixel is the calculated contribution of the given basis spectrum, effectively showing the relative spatial distributions of each basis. This unsupervised method was validated using a supervised peak area-based approach to ensure that basis maps and basis spectra are comparable to results obtained from standard univariate analysis (Supporting Figures S4–S8, Supporting Table S2). Figure 4e and g show overlaid false-colored maps of the most spatially and spectrally clear biological bases (substrate signatures and spatially or spectrally noisy signatures are not shown). For the precancer and invasive spheroids, similar emergent biological bases (Figure 4f) are mapped to reveal spatial distributions of chemical species: lipid-rich (cyan, a lipid-dominated spectral signature characterized by a strong lipid peak at 2850 cm–1, among others), protein–lipid (blue, a combination of protein and lipid signatures in which protein was increased compared to the lipid-rich signature), cellular (yellow, a combination of protein and DNA signatures), and glycogen (red).

Raman Mapping Localizes Multiple Signatures: Lipids, Proteins, Cells, Glycogen, and Cytochrome c

The Raman overlay images provide a sensitive, chemically rich landscape of the precancer (Figure 4e) and invasive (Figure 4g) spheroid sections. Cellular signatures (yellow) are clear amidst a backdrop of the ubiquitous protein–lipid signature (blue). The morphologies and positions of cell signatures in the Raman maps correspond almost exactly to the stained cell nuclei processed afterward on the same samples (Figure 4a and c), although fewer cells are observed in the Raman maps compared to staining, most likely due to focal limitations of Raman microscopy. In the invasive spheroid, a strong signature for the polysaccharide glycogen is evident throughout the section. Additionally, a cytochrome c basis is present and appears associated with many of the lipid bodies (Supporting Figure S4) as well as cells, which could suggest local apoptosis. (44) Peaks associated with cytochrome c are present in precancer spectra as well but they did not emerge as independent bases by NMF for the sample shown in Figure 4 (Supporting Figure S7). Raman maps taken of a separate precancer spheroid produced clear glycogen and cytochrome c basis spectra.

Raman Mapping Shows That Lipid Droplets Are Consistent with Unsaturated Acylglycerols

The spatial distribution of the lipid-rich signature differs markedly between the malignancies. In precancer (Figure 4e), there is a gradual increase from periphery to core that is not easily discernible in the Oil-Red-O image from the same section (Figure 4a) though is consistent with results shown in Figure 1. In the invasive spheroid section (Figure 4g), the lipid-rich basis appears amidst cells but is additionally concentrated in large bodies or droplets, consistent with the Oil-Red-O staining and polarized light images (Figure 4c, d). The birefringent areas, which are indicative of molecular order, are colocalized with locally distinct lipid–protein Raman signatures. The lipid-rich basis spectrum represents a mixture of lipids (with protein contributions as well), and the spectral features from both malignancy potentials are consistent with unsaturated acylglycerols in the liquid state (Supporting Table S2). (45) There is a notable lack of substantial peaks in the 700–760 cm–1 range, ruling out the otherwise spectrally similar lipids phosphatidylcholine and phosphatidylethanolamine as well as cholesterol or cholesterol esters (in agreement with the LCMS findings) as large contributors to these spectra (Supporting Table S2).

Raman Mapping of a Clinical Sample Shows Spatially Distinct Distribution of Lipids within DCIS

To validate the potential relevance of our in vitro findings with a clinical sample, confocal Raman mapping was performed on a human duct presenting comedo-type ductal carcinoma in situ (DCIS, a precancer) (Figure 5). A hematoxylin and eosin stained cryo-section of the specimen (H&E, Figure 5a) shows the general morphology of the analyzed tissue. The duct is filled with both living cancer cells and a large necrotic region. From Raman, the localization and distribution of multiple chemical species is evident (Figure 5b). Using a partially supervised component analysis approach, collagen, cellular, protein, and lipid signatures are clearly distinguished (Figure 5, and Supporting Figure S9). The ECM-rich tissue surrounding the duct contains abundant collagen consistent with the presence of stromal fibroblasts, while a DNA-rich protein signature (cellular, likely nuclei) is primarily located to the right side of the duct, as in the H&E image. Cellular features become cross-sectionally smaller and disappear completely within the protein-rich necrotic region. Two major noncollagenous protein signatures are present: one that appears more associated with cellular signatures and includes cytochrome c and a second that appears more associated with necrosis. The lipid component lacks any distinguishing peaks associated with membrane lipids and is consistent with a saturated neutral lipid signature that includes cholesterol ester (Supporting Table S2). This neutral lipid signature is more prevalent in the necrotic region of the duct compared to the viable cell areas and is often concentrated within domains with diameters larger than 2 μm (Figure 5b), consistent with features found in precancer and invasive spheroids (Figures 1 and 4).

Figure 5

Figure 5. Spatial characterization of DCIS (precancer) from human tissue. (a) H&E stained cryo-section showing the duct cross section containing cells (purple), necrosis (dark pink and purple), and surrounding stromal tissue (pink). (b) Confocal Raman mapping and component analysis of a serial section from the same duct in part a, showing the spatial distribution of the tissue components. Lipids, cyan; collagen, green; protein/cytochrome c, magenta; noncollagenous proteins, blue; cells, yellow. A distinct lipid signature consistent with neutral lipids, including cholesterol ester(s), is observed in the necrotic regions and occurs in spatially discrete domains (arrow). (c) The corresponding Raman component spectra for the Raman map in part b.

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Discussion

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We used a series of MCF10A-based cell lines to study the individual and combined effects of breast cancer malignancy and culture dimensionality on lipid spatial distribution (Raman microscopy) and global lipid profiles (LCMS). The cells were cultured in multicellular spheroids (3D) to mimic breast cancer microenvironmental conditions more closely than cells traditionally cultured on polystyrene substrates. The total amount of lipid decreased significantly when moving from 2D to 3D culture, though larger lipid droplets were observed in 3D regardless of malignancy. In 3D spheroid cultures, in addition to malignancy-dependent changes in lipid profiles, spatial distribution of lipids was both malignancy and microenvironment-dependent. Spheroids cultured using the invasive cell line showed relative increases in neutral lipids (DAGs and TGs), sphingolipids, and sphingoid bases (sphingomyelin, dihydroceramide, sphinganine, and sphingosine), while PCs and ether-linked lipid fractions decreased compared to precancer spheroid cultures. Taken together, these differences suggest that malignancy potential, together with culture dimensionality and thus microenvironmental conditions, can have a significant impact on lipid biogenesis in cancer with potential implications for lipid biophysics, signaling, and metabolism (Figure 6). Below, we discuss the differences in lipid profiles and spatial distribution and their potential biological implications going from the macroscale (cell culture dimensionality) to the microscale (the formation of large lipid droplets, microenvironment-dependent lipid distribution within the spheroids), and finally to the molecular scale (malignancy- and dimensionality-dependent changes in sphingolipids and ether-linked lipid levels).

Figure 6

Figure 6. A scheme describing the effects of dimensionality (top left) and the cell malignancy potential (bottom left) on lipid species amounts in the MCF10A breast cancer in vitro model. Lipid-rich areas (red) are observed in the necrotic core with decreasing amounts toward the spheroid periphery alongside large lipid droplets at the periphery. The observed increase in the ratio of neutral to membrane lipid species in 3D versus 2D may be related to large lipid droplet formation through TG synthesis and/or lipid droplet coalescence (top right). The observed increase in sphingolipid species in invasive versus precancer spheroids could be due to enhancement of the de novo sphingolipid synthesis pathway (bottom right, adapted from Ogretmen (46)). Species of lipids increased out of total lipids in 3D invasive spheroids are underlined. CoA = coenzyme A, SPT = serine palmitoyltransferase, KDSR = 3-ketosphinganine reductase, CERS = (dihydro)ceramide synthases, DES = dihydroceramide desaturase, SMS = sphingomyelin synthase, CDase = ceramidases.

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Cell Culture Dimensionality Affects Lipid Production and Distribution

When moving from 2D to 3D cultures, total lipids decreased, and lipid spatial distributions differed. Even though it is now relatively well-established that culture dimensionality affects the phenotype of cancer cells at multiple levels, including their transcriptome and proteome, (47,48) it remains largely unclear what effect(s) 3D microenvironmental conditions have on the lipidome of cancer cells. Two-dimensional cultures, where cells effectively grow as a monolayer with equal access to nutrients from the media, including carbon sources required for lipid synthesis, contain substantially more lipids compared to 3D, as qualitatively seen by the increased density and intensity of staining in Oil-Red-O (Figure 1) and quantitatively demonstrated by the lipid profiling (Supporting Figure S3). Furthermore, the LCMS lipid profiles in 2D, though different between malignancies, are well-conserved across biological replicates.
In the 3D spheroids, the reduction in lipid amounts may be related to alterations in cell metabolism due to changes in cell–microenvironment interactions (e.g., cell–cell and cell–extracellular matrix interactions) and/or because the supply of carbon sources for biosynthetic pathways is subject to diffusion-limited transport, much like in tumors in vivo. Importantly, both metabolism and nutrient diffusion are interdependent because differences in oxygen and nutrient transport can directly influence the cellular microenvironment and vice versa. Collectively, these changes may affect the cells’ ability to synthesize lipids, which could potentially contribute to the observed reduction in total lipids in 3D. While the increased amount of total lipids found in 2D could be accounted for by the presence of a large number of small lipid droplets (Figure 1, often hundreds of lipid droplets per cell), differences in plasma membrane or organelle membranes could also exist. In addition, spheroid cultures may have lower proliferation rates than in 2D (49) and hence may exhibit a decreased demand for energy and/or biosynthetic building blocks contained in stored lipid droplets.

Lipid Composition and Distribution in Multicellular Spheroids May Relate to Energy Storage in Nutrient Deprived Conditions

In the spheroids, multiple cellular niches coexist due to nutrient and oxygen diffusion limits (23) (e.g., necrotic, apoptotic, and viable cell areas; high and low nutrient levels). As revealed by Oil-Red-O staining and Raman microscopy, lipid spatial distribution appears to depend on the specific microenvironmental conditions, with lipids mostly localized in the spheroid core and in large birefringent droplets, which are more common in the invasive spheroids (Figures 1 and 4). When the spatial distribution of lipids in the spheroids is compared to a clinical sample, we observe that in both the spheroids and the human tissue sample, neutral lipids are concentrated in spatially distinct domains with diameters >2 μm. In the spheroids, at least two lipid droplet and/or body populations exist: diffuse signatures where lipid bodies or droplets are very small and Raman mapping cannot resolve them (<1 μm), and large (10s of micrometers), birefringent concentrations of lipids that appear in close proximity to cell nuclei and do not necessarily occur within the spheroid core. While these concentrated regions could be accumulations of smaller droplets similar to what is seen for some cells in 2D, their appearance is consistent with larger droplets.
Lipid droplets are known to be composed primarily of neutral lipids such as TGs or cholesterol esters as well as proteins encapsulated by a glycerophospholipid monolayer. (50−54) From the lipidomics in this study, the fraction of detected neutral lipids requiring storage in lipid droplets (TGs and DAGs) is significantly higher in 3D and also substantially more variable among 3D biological replicates. Lipid spectra obtained by Raman mapping of the large lipid domains in the 3D spheroid sections lack peaks associated with cholesterol esters. These lipid spectra are consistent with unsaturated TGs and DAGs, and in contrast to the DCIS clinical sample, which contains a signature of saturated cholesterol esters. In spheroids, the absence of cholesterol or cholesterol esters is consistent with the LCMS results. The increase in DAGs and TGs is most likely associated with the formation and coalescence of lipid droplets. The increase could also suggest that cells within spheroids are structurally able to accommodate large volume droplets, unlike 2D cultures that are essentially a cell monolayer. Further, the sporadic presence of larger droplets within the spheroid sections could explain both the pronounced relative increase in neutral lipids from 2D to 3D compared to membrane lipids, as well as the higher variability of TG and DAG amounts between replicates within the same group. The formation of the larger lipid droplets in 3D is also consistent with a decrease in membrane lipids compared to neutral lipids and increased de novo triglyceride synthesis, where the necessary enzymes are localized to the droplet monolayer (52) (Figure 6, top right).
In other systems, it was shown that cancer cells can use lipids stored in neighboring adipocytes to fuel their own growth (55,56) or use lipid droplets as a reservoir of lipid building blocks for new membrane formation. (57) The increase in lipid accumulation and formation of larger lipid droplets in central regions of both the spheroids and the clinical DCIS sample may be related to the development of cellular stress or hypoxia in these areas. Indeed, Raman microscopy of central regions of spheroids also identified glycogen, which increases in cancer cells exposed to hypoxia. (58−60) Furthermore, cytochrome c signatures are evident in both spheroids and the clinical sample, suggesting that cells may be undergoing apoptosis, possibly due to environmental stresses. (61) Taken together, these observations could be related to cancer cells’ adaptive energy storage in conditions of limited exogenous nutrients and oxygen. (62)

Sphingolipid de Novo Synthesis Is Upregulated in Invasive Cells

De novo sphingolipid synthesis is related to cellular lipid homeostasis and to the regulation of cell processes associated with disease conditions. (63) The sphingolipid profile of the invasive spheroids is markedly different from that of precancer spheroids and is consistent with activation of the de novo sphingolipid synthesis metabolic pathway (Figure 6). Species involved in the one-way de novo biosynthesis of sphingolipids, including sphinganine and dihydroceramides, are increased in invasive spheroids (Figure 6) as well as possible downstream products: sphingosine, ceramides, and sphingomyelins. Interestingly, conversion of ceramide to sphingomyelin entails removal of a PC headgroup to yield DAGs, (46) which are also increased in invasive spheroids, though DAGs can be produced via numerous pathways. (64) Further evidence of de novo synthesis comes from work that shows the invasive cell line used here, MCF10CA1a, has substantially increased expression levels of the gene C3orf57 compared to the parent cell line. (65) C3orf57, currently known as serine palmitoyltransferase small subunit B (SPTSSB), is a protein involved in the first committed step of sphingolipid metabolism. (66)
The apparent sphingolipid de novo synthesis in invasive spheroids raises the question: is upregulation of sphingolipid biosynthesis connected to invasiveness and/or cell survival pathways? Elevated sphinganine has been reported in endometrial cancer tissue (67) and was thought to be associated with de novo sphingolipid synthesis. Many sphingolipid species have been found to influence tumor progression through cell death and survival signaling depending on their ratios in membrane lipid rafts. (68) Sphingoid bases such as sphingosine and its derivatives, which are increased in the invasive spheroids, can also impact the cell cycle and apoptosis. (69) Finally, ceramides, which are increased in invasive spheroids, are thought to mediate cell death and tumor suppression. Ceramides are known to be elevated in response to cellular stress have been found to play important context-dependent roles in cancer cell death and survival pathways. (46)

Ether Lipid Fractions Depend on Both Malignancy and Dimensionality

Dysregulation of ether lipids has been implicated in a number of diseases, including cancer, (70,71) and inhibition of ether lipid synthesis may have anticancer effects, (72) but their exact roles remain elusive. When looking at our results, the differences in ether lipid content as a function of culture dimensionality and malignancy, particularly plasmalogens, are striking. At least two interesting trends are observed: (1) a drastic increase in P-PE fraction in 3D compared to 2D and (2) a less-drastic, but still substantial, difference in P-PE fraction in invasive versus precancer that only emerges in 3D. Physiologically, different tissues have varying but characteristic ether lipid fractions. In humans, the percentage of PEs that are P-PEs, for example, is as high as 84% in white matter brain tissue and as low as 8% in the liver. (73) Here, in 2D, both invasive and precancer cell lines maintain a P-PE/PE fraction of ∼30%. However, in 3D, this fraction increases up to 52% for invasive (about the level of heart) (73) and 68% for precancer (as high as human neutrophils) (Supporting Table S1). The dimensional disparity is as large as the difference between a liver and a kidney cell. Although they make up a significant portion of cell membranes and clearly impact lipid metabolism, roles of ether PCs and PEs are not fully understood. (73,74) Whether the increase in ether PE fractions in 3D is related to cellular stress within the spheroids and/or metabolic or biophysical changes in 3D is unknown.
The differences among ether lipids in general between precancer and invasive spheroids are also considerable. Fourteen of the 25 most significantly different lipid species across malignancies are ether lipids (Figure 3), primarily O- and P-PCs. P-PEs are also substantially decreased in invasive spheroids, and almost all other ether lipid types are also relatively decreased. Our data suggest a malignancy-dependent shift in the ether lipid balance in general through either enhancement of biosynthetic pathways that produce ether lipids or reduction of consumptive pathways. The large change in P-PE fractions between malignancies, which only occurs when cells are cultured as spheroids, suggests a complexity of function that has yet to be explored.
Taken together, our results present many interesting new research directions regarding lipid metabolism and distribution in cancer. Future studies will be aimed at identifying differences in lipid metabolism that could be responsible for the changes in lipid composition and distribution detected in this work. Such studies could include analysis of expression levels and localization of key de novo lipid synthesis proteins, including TG synthesis enzymes, to inform lipid droplet formation mechanisms and enzymes involved in sphingolipid synthesis to determine how regulation of these lipids impact cancer cell stress and survival. Lipids, including sphingolipids, DAGs, and polyunsaturated PCs, take part in many important signaling pathways (17) and affect membrane sensing by proteins. (75,76) To examine whether differences in the amounts of these lipid species between the precancer and invasive spheroids are indeed related to cancer signaling, further studies are required. Finally, Raman mapping of a clinical sample shows that the spatial distribution of neutral lipids within precancer ducts varies depending on the local tissue components with an increase in necrotic regions, similar to the observations in the spheroid model. Much like in the spheroid model, neutral lipid domains are formed within the duct and appear accumulated in the necrotic region. To further establish the clinical relevance of the 3D spheroid model to human breast tumors, analogous studies, combining Raman microscopy and advanced lipidomic techniques, will be performed using patient samples. (77) Through such studies, we will explore the functional impact of the observed differences in lipid profile on tumor progression.
To conclude, by combining the spatial resolution of Raman mapping with the chemical resolution of liquid chromatography mass spectrometry lipidomics, we show that lipid accumulation, profiles, and spatial distribution depend on breast cancer cell culture dimensionality and malignancy potential. Lipidomics revealed that there are significant changes in 3D spheroids versus 2D monolayer culturing dimensions. While the inherent metabolic differences between the cell lines themselves likely play a large part, the marked changes in lipid profiles between 2D and 3D could be attributed to several factors. These factors include the existence of multiple microenvironments in 3D with varying states of lipid accumulation and possibly lipid metabolism, the formation of large lipid droplets to house an increased supply of neutral lipids as an energy source, and alterations in the plasma membrane composition, all of which are interconnected. Lipid profiles between precancer and invasive cells cultured as 3D spheroids were also significantly different. Specifically, these differences suggest enhancement of the de novo sphingolipid metabolic pathway in the invasive spheroids. Additionally, lipid species that are less well understood, including ether PCs and PEs and very long chain LPCs, were decreased in the invasive spheroids compared to precancer spheroids. This work highlights the power of correlative analysis techniques to study tumor microenvironments and reveal qualitative and quantitative differences of breast-cancer-associated lipid profiles in different culture models. As our ability to resolve and identify unique lipid species improves, further combinations of lipidomics and Raman mapping could lead to new insights surrounding the complex network of functional imbalances that supports and enables cancer cell survival, growth, and metastasis.

Supporting Information

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The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acscentsci.8b00932.

  • Methods, LCMS and lipid staining data, Raman analysis information, NMF and NMF validations (PDF)

  • High Resolution Figure 1 and Metaboanalyst Download (ZIP)

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Author Information

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  • Corresponding Author
    • Lara A. Estroff - Department of Materials Science and Engineering, Cornell University, Ithaca, New York 14850, United States;  Kavli Institute at Cornell for Nanoscale Science, Ithaca, New York 14850, United States;  Orcidhttp://orcid.org/0000-0002-7658-1265;  Email: [email protected]
  • Authors
    • Netta Vidavsky - Department of Materials Science and Engineering, Cornell University, Ithaca, New York 14850, United States;  Orcidhttp://orcid.org/0000-0001-5516-6460
    • Jennie A. M. R. Kunitake - Department of Materials Science and Engineering, Cornell University, Ithaca, New York 14850, United States;  Orcidhttp://orcid.org/0000-0002-7061-3211
    • Maria Elena Diaz-Rubio - Metabolomics Facility, Institute of Biotechnology, Cornell University, Ithaca, New York 14850, United States;  Orcidhttp://orcid.org/0000-0003-3570-1774
    • Aaron E. Chiou - Nancy E. and Peter C. Meinig School of Biomedical Engineering, Cornell University, Ithaca, New York 14850, United States;  Orcidhttp://orcid.org/0000-0002-3762-9385
    • Hyun-Chae Loh - Department of Civil and Environmental Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States;  Orcidhttp://orcid.org/0000-0001-6026-3433
    • Sheng Zhang - Metabolomics Facility, Institute of Biotechnology, Cornell University, Ithaca, New York 14850, United States
  • Author Contributions

    N.V. and J.A.M.R.K. contributed equally.

  • Notes
    The authors declare no competing financial interest.

Acknowledgments

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We thank Drs. Clifford A. Hudis, Neil M. Iyengar, and Monica Morrow of the Memorial Sloan Kettering Cancer Center for providing the human sample and Dr. Daniel Sudilovsky of the Department of Pathology and Laboratory Medicine, Cayuga Medical Center at Ithaca for his pathological expertise. We thank Dr. Lynn M. Johnson from Cornell Statistical Consulting Unit for her help with statistical analysis, Prof. Elizabeth Johnson for lipid pathways discussion, Janille Maragh for assistance with Raman setup, and Dr. Minjee Kang and Dr. Neta Varsano for helpful discussions. We thank the Animal Health Diagnostic Center for help with staining, the Cornell College of Veterinary Medicine for the use of Scanscope, the Bonassar lab for the use of cross-polarized microscope, and the Schaffer-Nishimura lab for use of the cryotome. We thank WITec and Tavis Ezell for kindly allowing access to the WITec Suite FIVE software, Project FIVE Plus. Research reported in this publication was supported by the Center on the Physics of Cancer Metabolism through Award 1-U54-CA210184 and by the Human Science Frontiers Program (RGP0016/2017). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. This work made use of the Cornell Center for Materials Research Shared Facilities, which are supported through the NSF MRSEC program (DMR-1719875). Additional imaging data were acquired through the Cornell University Biotechnology Resource Center with NIH 1-S10-OD012287 funding. N.V. acknowledges funding from The Israeli Council for Higher Education and Ben-Gurion University. A.E.C. acknowledges funding from the National Institutes of Health through Award F31-CA228448.

Lipid Abbreviations: Neutral Lipids

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MAG

monoacylglycerol

DAG

diacylglycerol

TG

triradylglcerol (includes triacylglycerol, alkyldiacylglycerol, and alkenyldiacylglycerol)

Sphingolipids

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So

sphingosine/sphinganine

Cer

ceramide (also includes dihydroceramide, hexosylceramide, and dihexosylceramide)

SM

sphingomyelin

Glycerophospholipids

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PE

Phosphatidylethanolamine

PC

Phosphatidylcholine

(O−)

alkyl ether

(P-)

alkenyl ether

PI

Phosphatidylinositol

PS

Phosphatidylserine

PG

Phosphatidylglycerol

LPC

Lysophosphatidylcholine (also includes alkyl ether LPCs, alkenyl ether LPCs)

Prenol Lipids

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CoQ

coenzyme Q10

References

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    We have studied live non-malignant (MCF10A), mildly malignant (MCF7) and malignant (MDA-MB-231) breast cancer cells and human breast cancer tissue. We demonstrate the first application of Raman imaging and spectroscopy in diagnosing the role of lipid droplets in cell line cultures that closely mimic an in vivo environment of various stages in human breast cancer tissue. We have analyzed the compn. of the lipid droplets in non-malignant and malignant human breast epithelial cell lines and discussed the potential of lipid droplets as a prognostic marker in breast cancer. To identify any difference in the lipid droplet-assocd. biochem. and to correlate it with different stages of breast cancer, the PCA method was employed. The chem. compn. of lipids and proteins, both in the cell line models and in human breast tissue has been analyzed. The paper shows the alterations in lipid metab. that have been reported in cancer, at both the cellular and tissue levels, and discusses how they contribute to the different aspects of tumorigenesis.
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  16. 16
    Dória, M. L.; Cotrim, C. Z.; Simões, C.; Macedo, B.; Domingues, P.; Domingues, M. R.; Helguero, L. A. Lipidomic Analysis of Phospholipids from Human Mammary Epithelial and Breast Cancer Cell Lines. J. Cell. Physiol. 2013, 228 (2), 457– 468,  DOI: 10.1002/jcp.24152
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    16
    Lipidomic analysis of phospholipids from human mammary epithelial and breast cancer cell lines
    Doria, M. Luisa; Cotrim, Candida Z.; Simoes, Claudia; Macedo, Barbara; Domingues, Pedro; Domingues, M. Rosario; Helguero, Luisa A.
    Journal of Cellular Physiology (2013), 228 (2), 457-468CODEN: JCLLAX; ISSN:0021-9541. (Wiley-Blackwell)
    Alterations of phospholipid (PL) profiles have been assocd. to disease and specific lipids may be involved in the onset and evolution of cancer; yet, anal. of PL profiles using mass spectrometry (MS) in breast cancer cells is a novel approach. Previously, we reported a lipidomic anal. of PLs from mouse mammary epithelial and breast cancer cells using off-line thin layer chromatog. (TLC)-MS, where several changes in PL profile were found to be assocd. with the degree of malignancy of cells. In the present study, lipidomic anal. has been extended to human mammary epithelial cells and breast cancer cell lines (MCF10A, T47-D, and MDA-MB-231), using TLC-MS, validated by hydrophilic interaction liq. chromatog.-MS. Differences in phosphatidylethanolamine (PE) content relative to total amt. of PLs was highest in non-malignant cells while phosphatidic acid was present with highest relative abundance in metastatic cells. In addn., the following differences in PL mol. species assocd. to cancer phenotype, metastatic potential, and cell morphol. were found: higher levels of alkylacyl PCs and phosphatidylinositol (PI; 22:5/18:0) were detected in migratory cells, epithelial cells had less unsatd. fatty acyl chains and shorter aliph. tails in PE and sphingomyelin classes, while PI (18:0/18:1) was lowest in non-malignant cells compared to cancer cells. To date, information about PL changes in cancer progression is scarce, therefore results presented in this work will be useful as a starting point to define possible PLs with prospective as biomarkers and disclose metabolic pathways with potential for cancer therapy.
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  17. 17
    Baumann, J.; Sevinsky, C.; Conklin, D. S. Lipid Biology of Breast Cancer. Biochim. Biophys. Acta, Mol. Cell Biol. Lipids 2013, 1831 (10), 1509– 1517,  DOI: 10.1016/j.bbalip.2013.03.011
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    17
    Lipid biology of breast cancer
    Baumann, Jan; Sevinsky, Christopher; Conklin, Douglas S.
    Biochimica et Biophysica Acta, Molecular and Cell Biology of Lipids (2013), 1831 (10), 1509-1517CODEN: BBMLFG; ISSN:1388-1981. (Elsevier B. V.)
    A review. Alterations in lipid metab. have been reported in many types of cancer. Lipids have been implicated in the regulation of proliferation, differentiation, apoptosis, inflammation, autophagy, motility and membrane homeostasis. It is required that their biosynthesis is tightly regulated to ensure homeostasis and to prevent unnecessary energy expenditure. This review focuses on the emerging understanding of the role of lipids and lipogenic pathway regulation in breast cancer, including parallels drawn from the study of metabolic disease models, and suggestions on how these findings can potentially be exploited to promote gains in HER2/neu-pos. breast cancer research. This article is part of a Special Issue entitled Lipid Metab. in Cancer.
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  18. 18
    Liu, Q.; Luo, Q.; Halim, A.; Song, G. Targeting Lipid Metabolism of Cancer Cells: A Promising Therapeutic Strategy for Cancer. Cancer Lett. 2017, 401, 39– 45,  DOI: 10.1016/j.canlet.2017.05.002
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    Targeting lipid metabolism of cancer cells: A promising therapeutic strategy for cancer
    Liu, Qiuping; Luo, Qing; Halim, Alexander; Song, Guanbin
    Cancer Letters (New York, NY, United States) (2017), 401 (), 39-45CODEN: CALEDQ; ISSN:0304-3835. (Elsevier)
    One of the most important metabolic hallmarks of cancer cells is deregulation of lipid metab. In addn., enhancing de novo fatty acid (FA) synthesis, increasing lipid uptake and lipolysis have also been considered as means of FA acquisition in cancer cells. FAs are involved in various aspects of tumorigenesis and tumor progression. Therefore, targeting lipid metab. is a promising therapeutic strategy for human cancer. Recent studies have shown that reprogramming lipid metab. plays important roles in providing energy, macromols. for membrane synthesis, and lipid signals during cancer progression. Moreover, accumulation of lipid droplets in cancer cells acts as a pivotal adaptive response to harmful conditions. Here, we provide a brief review of the crucial roles of FA metab. in cancer development, and place emphasis on FA origin, utilization and storage in cancer cells. Understanding the regulation of lipid metab. in cancer cells has important implications for exploring a new therapeutic strategy for management and treatment of cancer.
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  19. 19
    Infanger, D. W.; Lynch, M. E.; Fischbach, C. Engineered Culture Models for Studies of Tumor-Microenvironment Interactions. Annu. Rev. Biomed. Eng. 2013, 15 (1), 29– 53,  DOI: 10.1146/annurev-bioeng-071811-150028
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    19
    Engineered culture models for studies of tumor-microenvironment interactions
    Infanger, David W.; Lynch, Maureen E.; Fischbach, Claudia
    Annual Review of Biomedical Engineering (2013), 15 (), 29-53CODEN: ARBEF7; ISSN:1523-9829. (Annual Reviews)
    A review. Heterogeneous microenvironmental conditions play crit. roles in cancer pathogenesis and therapy resistance and arise from changes in tissue dimensionality, cell-extracellular matrix (ECM) interactions, sol. factor signaling, oxygen as well as metabolic gradients, and exogenous biomech. cues. Traditional cell culture approaches are restricted in their ability to mimic this complexity with physiol. relevance, offering only partial explanation as to why novel therapeutic compds. are frequently efficacious in vitro but disappoint in preclin. and clin. studies. In an effort to overcome these limitations, phys. sciences-based strategies were employed to model specific aspects of the cancer microenvironment. Although these strategies offer promise to reveal the contributions of microenvironmental parameters on tumor initiation, progression, and therapy resistance, they, too, frequently suffer from limitations. This review highlights physicochem. and biol. key features of the tumor microenvironment, critically discusses advantages and limitations of current engineering strategies, and provides a perspective on future opportunities for engineered tumor models.
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    Fischbach, C.; Chen, R.; Matsumoto, T.; Schmelzle, T.; Brugge, J. S.; Polverini, P. J.; Mooney, D. J. Engineering Tumors with 3D Scaffolds. Nat. Methods 2007, 4 (10), 855– 860,  DOI: 10.1038/nmeth1085
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    Engineering tumors with 3D scaffolds
    Fischbach, Claudia; Chen, Ruth; Matsumoto, Takuya; Schmelzle, Tobias; Brugge, Joan S.; Polverini, Peter J.; Mooney, David J.
    Nature Methods (2007), 4 (10), 855-860CODEN: NMAEA3; ISSN:1548-7091. (Nature Publishing Group)
    Microenvironmental conditions control tumorigenesis and biomimetic culture systems that allow for in vitro and in vivo tumor modeling may greatly aid studies of cancer cells' dependency on these conditions. The authors engineered 3-dimensional (3D) human tumor models using carcinoma cells in polymeric scaffolds that recreated microenvironmental characteristics representative of tumors in vivo. Strikingly, the angiogenic characteristics of tumor cells were dramatically altered upon 3D culture within this system, and corresponded much more closely to tumors formed in vivo. Cells in this model were also less sensitive to chemotherapy and yielded tumors with enhanced malignant potential. The authors assessed the broad relevance of these findings with 3D culture of other tumor cell lines in this same model, comparison with std. 3D Matrigel culture and in vivo expts. This new biomimetic model may provide a broadly applicable 3D culture system to study the effect of microenvironmental conditions on tumor malignancy in vitro and in vivo.
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  21. 21
    Shekhar, M. P. V.V.; Tait, L.; Pauley, R. J.; Wu, G. S.; Santner, S. J.; Nangia-Makker, P.; Shekhar, V.; Nassar, H.; Visscher, D. W.; Heppner, G. H. Comedo-Ductal Carcinoma in Situ: A Paradoxical Role for Programmed Cell Death. Cancer Biol. Ther. 2008, 7 (11), 1774– 1782,  DOI: 10.4161/cbt.7.11.6781
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    21
    Comedo-ductal carcinoma in situ: a paradoxical role for programmed cell death
    Shekhar, Malathy P. V.; Tait, Larry; Pauley, Robert J.; Wu, Gen Sheng; Santner, Steven J.; Nangia-Makker, Pratima; Shekhar, Varun; Nassar, Hind; Visscher, Daniel W.; Heppner, Gloria H.; Miller, Fred R.
    Cancer Biology & Therapy (2008), 7 (11), 1774-1782CODEN: CBTAAO; ISSN:1538-4047. (Landes Bioscience)
    Comedo-DCIS is a histol. subtype of preinvasive breast neoplasia that is characterized by prominent apoptotic cell death and has greater malignant potential than other DCIS subtypes. We investigated the mechanisms of apoptosis in comedo-DCIS and its role in conversion of comedo-DCIS to invasive cancer. Clin. comedo-DCIS excisions and the MCF10DCIS.com human breast cancer model which produces lesions resembling comedo-DCIS were analyzed. Apoptotic luminal and myoepithelial cells were identified by TUNEL and reactivity to cleaved PARP antibody and cell death assessed by Western blotting, Mitocapture and immunohistochem. assays. MCF10DCIS.com cells undergo spontaneous apoptosis in vitro, both in monolayers and multicellular spheroids; it is assocd. with increased mitochondrial membrane permeability, increase in Bax/Bcl-2 ratio and occurs via caspase-9-dependent p53-independent pathway. This suggests that apoptosis is stromal-independent and that the cells are programmed to undergo apoptosis. Immunostaining with cleaved PARP antibody showed that myoepithelial apoptosis occurs before lesions progress to comedo-DCIS in both clin. comedo-DCIS and in vivo MCF10DCIS.com lesions. Intense staining for MMP-2, MMP-3, MMP-9 and MMP-11 was obsd. in the stroma and epithelia of solid DCIS lesions prior to conversion to comedo-DCIS in clin. and MCF10DCIS.com lesions. Gelatin zymog. showed higher MMP-2 levels in lysates and conditioned media of MCF10DCIS.com cells undergoing apoptosis. These data suggest that signals arising from the outside (microenvironmental) and inside (internal genetic alterations) of the duct act in concert to trigger apoptosis of myoepithelial and luminal epithelial cells. Our findings implicate spontaneous apoptosis in both the etiol. and progression of comedo-DCIS. It is possible that spontaneous apoptosis facilitates elimination of cells thus permitting expansion and malignant transformation of cancer cells that are resistant to spontaneous apoptosis.
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  22. 22
    McElwee, J. L.; Mohanan, S.; Griffith, O. L.; Breuer, H. C.; Anguish, L. J.; Cherrington, B. D.; Palmer, A. M.; Howe, L. R.; Subramanian, V.; Causey, C. P.; Identification of PADI2 as a Potential Breast Cancer Biomarker and Therapeutic Target. BMC Cancer 2012.  DOI: 10.1186/1471-2407-12-500 .
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    Vidavsky, N.; Kunitake, J. A.; Chiou, A. E.; Northrup, P. A.; Porri, T. J.; Ling, L.; Fischbach, C.; Estroff, L. A. Studying Biomineralization Pathways in a 3D Culture Model of Breast Cancer Microcalcifications. Biomaterials 2018, 179, 71– 82,  DOI: 10.1016/j.biomaterials.2018.06.030
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    DelNero, P.; Lane, M.; Verbridge, S. S.; Kwee, B.; Kermani, P.; Hempstead, B.; Stroock, A.; Fischbach, C. 3D Culture Broadly Regulates Tumor Cell Hypoxia Response and Angiogenesis via Pro-Inflammatory Pathways. Biomaterials 2015, 55, 110– 118,  DOI: 10.1016/j.biomaterials.2015.03.035
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    3D culture broadly regulates tumor cell hypoxia response and angiogenesis via pro-inflammatory pathways
    DelNero, Peter; Lane, Maureen; Verbridge, Scott S.; Kwee, Brian; Kermani, Pouneh; Hempstead, Barbara; Stroock, Abraham; Fischbach, Claudia
    Biomaterials (2015), 55 (), 110-118CODEN: BIMADU; ISSN:0142-9612. (Elsevier Ltd.)
    Oxygen status and tissue dimensionality are crit. determinants of tumor angiogenesis, a hallmark of cancer and an enduring target for therapeutic intervention. However, it is unclear how these microenvironmental conditions interact to promote neovascularization, due in part to a lack of comprehensive, unbiased data sets describing tumor cell gene expression as a function of oxygen levels within three-dimensional (3D) culture. Here, we utilized alginate-based, oxygen-controlled 3D tumor models to study the interdependence of culture context and the hypoxia response. Microarray gene expression anal. of tumor cells cultured in 2D vs. 3D under ambient or hypoxic conditions revealed striking interdependence between culture dimensionality and hypoxia response, which was mediated in part by pro-inflammatory signaling pathways. In particular, interleukin-8 (IL-8) emerged as a major player in the microenvironmental regulation of the hypoxia program. Notably, this interaction between dimensionality and oxygen status via IL-8 increased angiogenic sprouting in a 3D endothelial invasion assay. Taken together, our data suggest that pro-inflammatory pathways are crit. regulators of tumor hypoxia response within 3D environments that ultimately impact tumor angiogenesis, potentially providing important therapeutic targets. Furthermore, these results highlight the importance of pathol. relevant tissue culture models to study the complex phys. and chem. processes by which the cancer microenvironment mediates new vessel formation.
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  25. 25
    Kang, H. S.; Lee, S. C.; Park, Y. S.; Jeon, Y. E.; Lee, J. H.; Jung, S. Y.; Park, I. H.; Jang, S. H.; Park, H. M.; Yoo, C. W. Protein and Lipid MALDI Profiles Classify Breast Cancers According to the Intrinsic Subtype. BMC Cancer 2011, 11 (1), 465,  DOI: 10.1186/1471-2407-11-465
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    Kawashima, M.; Iwamoto, N.; Kawaguchi-Sakita, N.; Sugimoto, M.; Ueno, T.; Mikami, Y.; Terasawa, K.; Sato, T. A.; Tanaka, K.; Shimizu, K. High-Resolution Imaging Mass Spectrometry Reveals Detailed Spatial Distribution of Phosphatidylinositols in Human Breast Cancer. Cancer Sci. 2013, 104 (10), 1372– 1379,  DOI: 10.1111/cas.12229
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    High-resolution imaging mass spectrometry reveals detailed spatial distribution of phosphatidylinositols in human breast cancer
    Kawashima, Masahiro; Iwamoto, Noriko; Kawaguchi-Sakita, Nobuko; Sugimoto, Masahiro; Ueno, Takayuki; Mikami, Yoshiki; Terasawa, Kazuya; Sato, Taka-Aki; Tanaka, Koichi; Shimizu, Kazuharu; Toi, Masakazu
    Cancer Science (2013), 104 (10), 1372-1379CODEN: CSACCM; ISSN:1349-7006. (Wiley-Blackwell)
    High-resoln. matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI IMS) is an emerging application for lipid research that provides a comprehensive and detailed spatial distribution of ionized mols. Recent lipidomic approach has identified several phospholipids and phosphatidylinositols (PIs) are accumulated in breast cancer tissues and are therefore novel biomarker candidates. Because their distribution and significance remain unclear, we investigated the precise spatial distribution of PIs in human breast cancer tissues using high-resoln. MALDI IMS. We evaluated tissues from nine human breast cancers and one normal mammary gland by neg. ion MALDI IMS at a resoln. of 10 μm. We detected 10 PIs with different fatty acid compns., and their proportions were remarkably variable in the malignant epithelial regions. High-resoln. imaging enabled us to discriminate cancer cell clusters from the adjacent stromal tissue within epithelial regions; moreover, this technique revealed that several PIs were specifically localized to cancer cell clusters. These PIs were heterogeneously distributed within cancer cell clusters, allowing us to identify two different populations of cancer cells that predominantly expressed either PI(18:0/18:1) or PI(18:0/20:3). Tracing the expression level of PIs during cancer cell progression suggested that the latter population is assocd. with the invasion. Our study documents a novel model for phospholipid anal. of breast cancer tissues by using high-resoln. MALDI IMS and identifies candidate PIs that can describe a specific phenotype of cancer cells.
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    Angerer, T. B.; Magnusson, Y.; Landberg, G.; Fletcher, J. S. Lipid Heterogeneity Resulting from Fatty Acid Processing in the Human Breast Cancer Microenvironment Identified by GCIB-ToF-SIMS Imaging. Anal. Chem. 2016, 88 (23), 11946– 11954,  DOI: 10.1021/acs.analchem.6b03884
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    27
    Lipid Heterogeneity Resulting from Fatty Acid Processing in the Human Breast Cancer Microenvironment Identified by GCIB-ToF-SIMS Imaging
    Angerer, Tina B.; Magnusson, Ylva; Landberg, Goeran; Fletcher, John S.
    Analytical Chemistry (Washington, DC, United States) (2016), 88 (23), 11946-11954CODEN: ANCHAM; ISSN:0003-2700. (American Chemical Society)
    Breast cancer is an umbrella term used to describe a collection of different diseases with broad inter- and intra-tumor heterogeneity. Understanding this variation is crit. in order to develop, and precisely prescribe, new treatments. Changes in the lipid metab. of cancerous cells can provide important indications as to the metabolic state of the cells but are difficult to investigate with conventional histol. methods. Due to the introduction of new higher energy (40 kV) gas cluster ion beams (GCIBs) time-of-flight secondary ion mass spectrometry (ToF-SIMS) imaging is now capable of providing information on the distribution of hundreds of mol. species simultaneously on a cellular to sub-cellular scale. GCIB-ToF-SIMS was used to elucidate changes in lipid compn. in 9 breast cancer biopsy samples. Improved mol. signal generation by the GCIB produced location specific information that revealed elevated levels of essential lipids to be related to inflammatory cells in the stroma while cancerous areas are dominated by non-essential fatty acids and a variety of phosphatidylinositol species with further in-tumor variety arising from decreased desaturase activity. These changes in lipid compn. due to different enzyme activity are seemingly independent of oxygen availability and can be linked to favorable cell membrane properties for either proliferation/invasion or drug resistance/survival.
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    Cífková, E.; Holčapek, M.; Lísa, M.; Vrána, D.; Melichar, B.; Študent, V. Lipidomic Differentiation between Human Kidney Tumors and Surrounding Normal Tissues Using HILIC-HPLC/ESI-MS and Multivariate Data Analysis. J. Chromatogr. B: Anal. Technol. Biomed. Life Sci. 2015, 1000, 14– 21,  DOI: 10.1016/j.jchromb.2015.07.011
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    28
    Lipidomic differentiation between human kidney tumors and surrounding normal tissues using HILIC-HPLC/ESI-MS and multivariate data analysis
    Cifkova, Eva; Holcapek, Michal; Lisa, Miroslav; Vrana, David; Melichar, Bohuslav; Student, Vladimir
    Journal of Chromatography B: Analytical Technologies in the Biomedical and Life Sciences (2015), 1000 (), 14-21CODEN: JCBAAI; ISSN:1570-0232. (Elsevier B.V.)
    The characterization of differences among polar lipid classes in tumors and surrounding normal tissues of 20 kidney cancer patients is performed by hydrophilic interaction liq. chromatog. (HILIC) coupled to electrospray ionization mass spectrometry (ESI-MS). The detailed anal. of identified lipid classes using relative abundances of characteristic ions in neg.- and pos.-ion modes is used for the detn. of more than 120 individual lipid species contg. attached fatty acyls of different chain length and double bond no. Lipid species are described using relative abundances, providing a better visualization of lipidomic differences between tumor and normal tissues. The multivariate data anal. methods using unsupervised principal component anal. (PCA) and supervised orthogonal partial least square (OPLS) are used for the characterization of statistically significant differences in identified lipid species. Ten most significant up- and down-regulated lipids in OPLS score plots are also displayed by box plots. A notable increase of relative abundances of lipids contg. four and more double bonds is detected in tumor compared to normal tissues.
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  29. 29
    Hilvo, M.; Denkert, C.; Lehtinen, L.; Muller, B.; Brockmoller, S.; Seppanen-Laakso, T.; Budczies, J.; Bucher, E.; Yetukuri, L.; Castillo, S. Novel Theranostic Opportunities Offered by Characterization of Altered Membrane Lipid Metabolism in Breast Cancer Progression. Cancer Res. 2011, 71 (9), 3236– 3245,  DOI: 10.1158/0008-5472.CAN-10-3894
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    Perrotti, F.; Rosa, C.; Cicalini, I.; Sacchetta, P.; Del Boccio, P.; Genovesi, D.; Pieragostino, D. Advances in Lipidomics for Cancer Biomarkers Discovery. Int. J. Mol. Sci. 2016, 17 (12), 1992,  DOI: 10.3390/ijms17121992
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    Advances in lipidomics for cancer biomarkers discovery
    Perrotti, Francesca; Rosa, Consuelo; Cicalini, Ilaria; Sacchetta, Paolo; Del Boccio, Piero; Genovesi, Domenico; Pieragostino, Damiana
    International Journal of Molecular Sciences (2016), 17 (12), 1992/1-1992/26CODEN: IJMCFK; ISSN:1422-0067. (MDPI AG)
    Lipids play crit. functions in cellular survival, proliferation, interaction and death, since they are involved in chem.-energy storage, cellular signaling, cell membranes, and cell-cell interactions. These cellular processes are strongly related to carcinogenesis pathways, particularly to transformation, progression, and metastasis, suggesting the bioactive lipids are mediators of a no. of oncogenic processes. The current review gives a synopsis of a lipidomic approach in tumor characterization; we provide an overview on potential lipid biomarkers in the oncol. field and on the principal lipidomic methodologies applied. The novel lipidomic biomarkers are reviewed in an effort to underline their role in diagnosis, in prognostic characterization and in prediction of therapeutic outcomes. A lipidomic investigation through mass spectrometry highlights new insights on mol. mechanisms underlying cancer disease. This new understanding will promote clin. applications in drug discovery and personalized therapy.
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    Chughtai, K.; Jiang, L.; Greenwood, T. R.; Glunde, K.; Heeren, R. M. A. Mass Spectrometry Images Acylcarnitines, Phosphatidylcholines, and Sphingomyelin in MDA-MB-231 Breast Tumor Models. J. Lipid Res. 2013, 54 (2), 333– 344,  DOI: 10.1194/jlr.M027961
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    31
    Mass spectrometry images acylcarnitines, phosphatidylcholines, and sphingomyelin in MDA-MB-231 breast tumor models
    Chughtai, Kamila; Lu, Jiang; Greenwood, Tiffany R.; Glunde, Kristine; Heeren, Ron M. A.
    Journal of Lipid Research (2013), 54 (2), 333-344CODEN: JLPRAW; ISSN:0022-2275. (American Society for Biochemistry and Molecular Biology, Inc.)
    The lipid compns. of different breast tumor microenvironments are largely unknown due to limitations in lipid imaging techniques. Imaging lipid distributions would enhance our understanding of processes occurring inside growing tumors, such as cancer cell proliferation, invasion, and metastasis. Recent developments in MALDI mass spectrometry imaging (MSI) enable rapid and specific detection of lipids directly from thin tissue sections. In this study, we performed multimodal imaging of acylcarnitines, phosphatidylcholines (PC), a lysophosphatidylcholine (LPC), and a sphingomyelin (SM) from different microenvironments of breast tumor xenograft models, which carried tdTomato red fluorescent protein as a hypoxia-response element-driven reporter gene. The MSI mol. lipid images revealed spatially heterogeneous lipid distributions within tumor tissue. Four of the most-abundant lipid species, namely PC(16:0/16:0), PC(16:0/18:1), PC(18:1/18:1), and PC(18:0/18:1), were localized in viable tumor regions, whereas LPC(16:0/0:0) was detected in necrotic tumor regions. We identified a heterogeneous distribution of palmitoylcarnitine, stearoylcarnitine, PC(16:0/22:1), and SM(d18:1/16:0) sodium adduct, which colocalized primarily with hypoxic tumor regions. For the first time, we have applied a multimodal imaging approach that has combined optical imaging and MALDI-MSI with ion mobility sepn. to spatially localize and structurally identify acylcarnitines and a variety of lipid species present in breast tumor xenograft models.
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    Confocal Raman Microscopy; Dieing, T., Hollricher, O., Toporski, J., Eds.; Springer Berlin Heidelberg: Berlin, Heidelberg, 2011.
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    Butler, H. J.; Ashton, L.; Bird, B.; Cinque, G.; Curtis, K.; Dorney, J.; Esmonde-White, K.; Fullwood, N. J.; Gardner, B.; Martin-Hirsch, P. L. Using Raman Spectroscopy to Characterize Biological Materials. Nat. Protoc. 2016, 11 (4), 664– 687,  DOI: 10.1038/nprot.2016.036
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    Using Raman spectroscopy to characterize biological materials
    Butler, Holly J.; Ashton, Lorna; Bird, Benjamin; Cinque, Gianfelice; Curtis, Kelly; Dorney, Jennifer; Esmonde-White, Karen; Fullwood, Nigel J.; Gardner, Benjamin; Martin-Hirsch, Pierre L.; Walsh, Michael J.; McAinsh, Martin R.; Stone, Nicholas; Martin, Francis L.
    Nature Protocols (2016), 11 (4), 664-687CODEN: NPARDW; ISSN:1750-2799. (Nature Publishing Group)
    Raman spectroscopy can be used to measure the chem. compn. of a sample, which can in turn be used to ext. biol. information. Many materials have characteristic Raman spectra, which means that Raman spectroscopy has proven to be an effective anal. approach in geol., semiconductor, materials and polymer science fields. The application of Raman spectroscopy and microscopy within biol. is rapidly increasing because it can provide chem. and compositional information, but it does not typically suffer from interference from water mols. Anal. does not conventionally require extensive sample prepn.; biochem. and structural information can usually be obtained without labeling. In this protocol, we aim to standardize and bring together multiple exptl. approaches from key leaders in the field for obtaining Raman spectra using a microspectrometer. As examples of the range of biol. samples that can be analyzed, we provide instructions for acquiring Raman spectra, maps and images for fresh plant tissue, formalin-fixed and fresh frozen mammalian tissue, fixed cells and biofluids. We explore a robust approach for sample prepn., instrumentation, acquisition parameters and data processing. By using this approach, we expect that a typical Raman expt. can be performed by a nonspecialist user to generate high-quality data for biol. materials anal.
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    Talari, A. C. S.; Movasaghi, Z.; Rehman, S.; Rehman, I. U. Raman Spectroscopy of Biological Tissues. Appl. Spectrosc. Rev. 2015, 50 (1), 46– 111,  DOI: 10.1080/05704928.2014.923902
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    Raman Spectroscopy of Biological Tissues
    Talari, Abdullah Chandra Sekhar; Movasaghi, Zanyar; Rehman, Shazza; Rehman, Ihtesham ur
    Applied Spectroscopy Reviews (2015), 50 (1), 46-111CODEN: APSRBB; ISSN:0570-4928. (Taylor & Francis, Inc.)
    A review. We previously published a comprehensive review paper reviewing the Raman spectroscopy of biol. mols. This research area has expanded rapidly, which warranted an update to the existing review paper by adding the recently reported studies in literature. This article reviews some of the recent advances of Raman spectroscopy in relation to biomedical applications starting from natural tissues to cancer biol. Raman spectroscopy, an optical mol. detective, is a vibrational spectroscopic technique that has potential not only in cancer diagnosis but also in understanding progression of the disease. This article summarizes some of the most widely obsd. peak frequencies and their assignments. The aim of this review is to develop a database of mol. fingerprints, which will facilitate researchers in identifying the chem. structure of the biol. tissues including most of the significant peaks reported both in the normal and cancerous tissues. It has covered a variety of Raman approaches and its quant. and qual. biochem. information. In addn., it covers the use of Raman spectroscopy to analyze a variety of different malignancies including breast, brain, cervical, gastrointestinal, lung, oral, and skin cancer. Multivariate anal. approaches used in these studies have also been covered.
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  35. 35
    Soule, H. D.; Maloney, T. M.; Wolman, S. R.; Peterson, W. D.; Brenz, R.; McGrath, C. M.; Russo, J.; Pauley, R. J.; Jones, R. F.; Brooks, S. C. Isolation and Characterization of a Spontaneously Immortalized Human Breast Epithelial Cell Line, MCF-10. Cancer Res. 1990, 50 (18), 6075– 6086
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    Isolation and characterization of a spontaneously immortalized human breast epithelial cell line, MCF-10
    Soule, Herbert D.; Maloney, Terry M.; Wolman, Sandra R.; Peterson, Ward D., Jr.; Brenz, Richard, Jr.; McGrath, Charles M.; Russo, Jose; Pauley, Robert J.; Jones, Richard F.; Brooks, S. C.
    Cancer Research (1990), 50 (18), 6075-86CODEN: CNREA8; ISSN:0008-5472.
    Two sublines of a breast epithelial cell culture, MCF-10, derived from human fibrocystic mammary tissue exhibit immortality after extended cultivation in low calcium concns. (0.03-0.06 mM) and floating transfers in low calcium (MCF-10F), or by trypsin-Versene passages in the customary (normal) calcium levels, 1.05 mM (MCF-10A). Both sublines have been maintained as sep. entities after 2.3 yr (849 days) in vitro and at present have been in culture for longer than 4 yr. MCF-10 has the characteristics of normal breast epithelium by the following criteria: (a) lack of tumorigenicity in nude mice; (b) three-dimensional growth in collagen; (c) growth in culture that is controlled by hormones and growth factors; (d) lack of anchorage-independent growth; and (e) dome formation in confluent cultures. Cytogenetic anal. prior to immortalization showed normal diploid cells; although later passages showed minimal rearrangement and near-diploidy, the immortal cells were not karyotypically normal. The emergence of an immortal culture in normal calcium media was not an inherent characteristic of the original tissue from which MCF-10 was derived since reactivated cryo-preserved cells from cultures grown for 0.3 to 1.2 yr in low calcium were incapable of sustained growth in normal calcium.
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    Miller, F. R.; Santner, S. J.; Tait, L.; Dawson, P. J. MCF10DCIS.Com Xenograft Model of Human Comedo Ductal Carcinoma in Situ. J. Natl. Cancer Inst. 2000, 92 (14), 1185– 1186,  DOI: 10.1093/jnci/92.14.1185a
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    MCF10DCIS.com xenograft model of human comedo ductal carcinoma in situ
    Miller F R; Santner S J; Tait L; Dawson P J
    Journal of the National Cancer Institute (2000), 92 (14), 1185-6 ISSN:0027-8874.
    There is no expanded citation for this reference.
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    Barnabas, N.; Cohen, D. Phenotypic and Molecular Characterization of MCF10DCIS and SUM Breast Cancer Cell Lines. Int. J. Breast Cancer 2013, 2013, 872743,  DOI: 10.1155/2013/872743
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    Phenotypic and Molecular Characterization of MCF10DCIS and SUM Breast Cancer Cell Lines
    Barnabas Nandita; Cohen Dalia
    International journal of breast cancer (2013), 2013 (), 872743 ISSN:2090-3170.
    We reviewed the phenotypic and molecular characteristics of MCF10DCIS.com and the SUM cell lines based on numerous studies performed over the years. The major signaling pathways that give rise to the phenotype of these cells may serve as a good resource of information when researchers in drug discovery and development use these cells to identify novel targets and biomarkers. Major signaling pathways and mutations affecting the coding sequence are also described providing important information when using these cells as a model in a variety of studies.
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    Santner, S. J.; Dawson, P. J.; Tait, L.; Soule, H. D.; Eliason, J.; Mohamed, A. N.; Wolman, S. R.; Heppner, G. H.; Miller, F. R. Malignant MCF10CA1 Cell Lines Derived from Premalignant Human Breast Epithelial MCF10AT Cells. Breast Cancer Res. Treat. 2001, 65 (2), 101– 110,  DOI: 10.1023/A:1006461422273
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    Malignant MCF10CA1 cell lines derived from premalignant human breast epithelial MCF10AT cells
    Santner S J; Dawson P J; Tait L; Soule H D; Eliason J; Mohamed A N; Wolman S R; Heppner G H; Miller F R
    Breast cancer research and treatment (2001), 65 (2), 101-10 ISSN:0167-6806.
    The MCF10 series of cell lines was derived from benign breast tissue from a woman with fibrocystic disease. The MCF10 human breast epithelial model system consists of mortal MCF10M and MCF10MS (mortal cells grown in serum-free and serum-containing media, respectively), immortalized but otherwise normal MCF10F and MCF10A lines (free-floating versus growth as attached cells), transformed MCF10AneoT cells transfected with T24 Ha-ras, and premalignant MCF10AT cells with potential for neoplastic progression. The MCF10AT, derived from xenograft-passaged MCF10-AneoT cells, generates carcinomas in approximately 25% of xenografts. We now report the derivation of fully malignant MCF10CA1 lines that complete the spectrum of progression from relatively normal breast epithelial cells to breast cancer cells capable of metastasis. MCF10CA1 lines display histologic variations ranging from undifferentiated carcinomas, sometimes with focal squamous differentiation, to well-differentiated adenocarcinomas. At least two metastasize to the lung following injection of cells into the tail vein; one line grows very rapidly in the lung, with animals moribund within 4 weeks, whereas the other requires 15 weeks to reach the same endpoint. In addition to variations in efficiency of tumor production, the MCF10CA1 lines show differences in morphology in culture, anchorage-independent growth, karyotype, and immunocytochemistry profiles. The MCF10 model provides a unique tool for the investigation of molecular changes during progression of human breast neoplasia and the generation of tumor heterogeneity on a common genetic background.
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    Alo, P. L.; Visca, P.; Marci, A.; Mangoni, A.; Botti, C.; Di Tondo, U. Expression of Fatty Acid Synthase (FAS) as a Predictor of Recurrence in Stage I Breast Carcinoma Patients. Cancer 1996, 77 (3), 474– 482,  DOI: 10.1002/(SICI)1097-0142(19960201)77:3<474::AID-CNCR8>3.0.CO;2-K
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    Expression of fatty acid synthase (FAS) as a predictor of recurrence in stage I breast carcinoma patients
    Alo, Piero L.; Visca, Paolo; Marci, Adele; Mangoni, Antonella; Botti, Claudio; Di Tondo, Ugo
    Cancer (New York) (1996), 77 (3), 474-82CODEN: CANCAR; ISSN:0008-543X. (Wiley-Liss)
    Fatty acid synthase (FAS) is a mol. found in tumor cells from breast carcinomas of patients whose prognosis is very poor. Recently, this mol. has been identified as the key enzyme in fatty acid biosynthesis. This study was done to test the strength of FAS as a prognostic indicator for disease free survival (DFS) and overall survival (OS). Clin. records, histol. features, immunohistochem. expression of cathepsin D and c-erbB-2, and estrogen and progesterone receptor status of 110 Stage I breast carcinoma patients were all assocd. with FAS by a chi-square test. The patterns of DFS and OS were estd. over a ten-year follow-up period using the Kaplan-Meier method. Univariate and multivariate anal. were evaluated using a log logistic regression model. Multivariate regression anal. was based on the Cox proportional hazard model. To detect FAS, cathepsin D and c-erbB-2 expression as well as estrogen and progesterone receptor status, the authors used the unlabeled immunoperoxidase technique on formalin fixed, paraffin embedded tissue. FAS was significantly assocd. with a higher risk of recurrence because it predicted both DFS and OS when evaluated as a continuous variable and DFS when evaluated with other prognostic markers. Peritumoral lymphatic vessel invasion was the other most significant independent predictor for DFS and OS. FAS is a reliable prognostic marker to predict DFS and OS in patients with early breast cancer.
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    Milgraum, L. Z.; Witters, L. A.; Pasternack, G. R.; Kuhajda, F. P. Enzymes of the Fatty Acid Synthesis Pathway Are Highly Expressed in in Situ Breast Carcinoma. Clin. Cancer Res. 1997, 3 (11), 2115– 2120
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    Enzymes of the fatty acid synthesis pathway are highly expressed in in situ breast carcinoma
    Milgraum, Lea Z.; Witters, Lee A.; Pasternack, Gary R.; Kuhajda, Francis P.
    Clinical Cancer Research (1997), 3 (11), 2115-2120CODEN: CCREF4; ISSN:1078-0432. (American Association for Cancer Research)
    Expression of high levels of fatty acid synthase (FAS), an important enzyme in fatty acid synthesis, has been identified in a wide variety of human carcinomas. In breast and prostate carcinoma, FAS expression appears to be assocd. with aggressive disease. Recent biochem. studies have demonstrated that FAS expression in cancer cells connotes activation of the entire fatty acid synthesis pathway leading to the prodn. of palmitic acid. Here, we explore the immunohistochem. expression of FAS and human acetyl-CoA carboxylase (HACC), the rate-limiting enzyme in fatty acid synthesis, in breast cancer progression from histol. normal breast through the development of in situ duct and lobular carcinoma to infiltrating carcinoma. Both FAS and the Mr 275,000 isoform of HACC are expressed in a small subset of cells in normal breast lobules and terminal ducts. Upon development of either in situ duct or lobular carcinoma, FAS and both isoforms of HACC are expressed at higher levels and in a majority of the cells. These findings suggest that expression of the enzymes of fatty acid synthesis are frequently altered early in the progression of human breast carcinoma.
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    Menendez, J. A.; Lupu, R. Fatty Acid Synthase and the Lipogenic Phenotype in Cancer Pathogenesis. Nat. Rev. Cancer 2007, 7 (10), 763– 777,  DOI: 10.1038/nrc2222
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    Fatty acid synthase and the lipogenic phenotype in cancer pathogenesis
    Menendez, Javier A.; Lupu, Ruth
    Nature Reviews Cancer (2007), 7 (10), 763-777CODEN: NRCAC4; ISSN:1474-175X. (Nature Publishing Group)
    A review. Fatty acid synthase (FASN) catalyzes the synthesis of fatty acids, and this synthetic pathway is upregulated in many tumors. How might FASN and increased lipogenesis be involved in cancer, and is FASN a valid therapeutic target. There is a renewed interest in the ultimate role of fatty acid synthase (FASN) - a key lipogenic enzyme catalyzing the terminal steps in the de novo biogenesis of fatty acids - in cancer pathogenesis. Tumor-assocd. FASN, by conferring growth and survival advantages rather than functioning as an anabolic energy-storage pathway, appears to necessarily accompany the natural history of most human cancers. A recent identification of cross-talk between FASN and well-established cancer-controlling networks begins to delineate the oncogenic nature of FASN-driven lipogenesis. FASN, a nearly-universal druggable target in many human carcinomas and their precursor lesions, offers new therapeutic opportunities for metabolically treating and preventing cancer.
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    Ghosh, C.; Nandi, S.; Bhattacharyya, K. Probing Micro-Environment of Lipid Droplets in a Live Breast Cell: MCF7 and MCF10A. Chem. Phys. Lett. 2017, 670, 27– 31,  DOI: 10.1016/j.cplett.2016.12.068
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    Probing micro-environment of lipid droplets in a live breast cell: MCF7 and MCF10A
    Ghosh, Catherine; Nandi, Somen; Bhattacharyya, Kankan
    Chemical Physics Letters (2017), 670 (), 27-31CODEN: CHPLBC; ISSN:0009-2614. (Elsevier B.V.)
    Local environment of the lipid droplets inside the breast cancer cells, MCF7 and in non-malignant breast cells, MCF10A is monitored using time-resolved confocal microscopy. For this study, a coumarin-based dye C153 has been used. The local polarity and the solvation dynamics indicate that a cytoplasmic lipid droplet is less polar and displays slower solvation dynamics compared to the cytosol. Significant differences in terms of no. of lipid droplets, polarity and solvation dynamics are obsd. between the cancer cell (MCF7) and its non-malignant cell (MCF10A).
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    Wilmanski, T.; Buhman, K.; Donkin, S. S.; Burgess, J. R.; Teegarden, D. 1α,25-Dihydroxyvitamin D Inhibits de Novo Fatty Acid Synthesis and Lipid Accumulation in Metastatic Breast Cancer Cells through down-Regulation of Pyruvate Carboxylase. J. Nutr. Biochem. 2017, 40, 194– 200,  DOI: 10.1016/j.jnutbio.2016.11.006
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    1α,25-dihydroxyvitamin D inhibits de novo fatty acid synthesis and lipid accumulation in metastatic breast cancer cells through down-regulation of pyruvate carboxylase
    Wilmanski, Tomasz; Buhman, Kimberly; Donkin, Shawn S.; Burgess, John R.; Teegarden, Dorothy
    Journal of Nutritional Biochemistry (2017), 40 (), 194-200CODEN: JNBIEL; ISSN:0955-2863. (Elsevier)
    Both increased de novo fatty acid synthesis and higher neutral lipid accumulation are a common phenotype obsd. in aggressive breast cancer cells, making lipid metab. a promising target for breast cancer prevention. In the present studies, we demonstrate a novel effect of the active metabolite of vitamin D, 1α,25-dihydroxyvitamin D (1,25(OH)2D) on lipid metab. in malignant breast epithelial cells. Treatment of MCF10CA1a breast epithelial cells with 1,25(OH)2D (10 nM) for 5 and 7 days decreased the level of triacylglycerol, the most abundant form of neutral lipids, by 20%(±3.9) and 50%(±5.9), resp. In addn., 1,25(OH)2D treatment for 5 days decreased palmitate synthesis from glucose, the major fatty acid synthesized de novo (48% ± 5.5 relative to vehicle). We have further identified the anaplerotic enzyme pyruvate carboxylase (PC) as a target of 1,25(OH)2D-mediated regulation and hypothesized that 1,25(OH)2D regulates breast cancer cell lipid metab. through inhibition of PC. PC mRNA expression was down-regulated with 1,25(OH)2D treatment at 2 (73% ± 6 relative to vehicle) and 5 (56% ± 8 relative to vehicle) days. Decrease in mRNA abundance corresponded with a decrease in PC protein expression at 5 days of treatment (54% ± 12 relative to vehicle). Constitutive overexpression of PC in MCF10CA1a cells using a pCMV6-PC plasmid inhibited the effect of 1,25(OH)2D on both TAG accumulation and de novo palmitate synthesis from glucose. Together, these studies demonstrate a novel mechanism through which 1,25(OH)2D regulates lipid metab. in malignant breast epithelial cells.
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    Liu, X.; Kim, C. N.; Yang, J.; Jemmerson, R.; Wang, X. Induction of Apoptotic Program in Cell-Free Extracts: Requirement for DATP and Cytochrome C. Cell 1996, 86 (1), 147– 157,  DOI: 10.1016/S0092-8674(00)80085-9
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    Induction of apoptotic program in cell-free extracts: requirement for dATP and cytochrome c
    Liu, Xuesong; Kim, Caryn Naekyung; Yang, Jie; Jemmerson, Ronald; Wang, Xiaodong
    Cell (Cambridge, Massachusetts) (1996), 86 (1), 147-157CODEN: CELLB5; ISSN:0092-8674. (Cell Press)
    A cell-free system based on cytosols of normally growing cells was established that reproduces aspects of the apoptotic program in vitro. The apoptotic program was initiated by the addn. of dATP. Fractionation of cytosol yielded a 15-kDa protein that was required for in vitro apoptosis. The absorption spectrum and protein sequence revealed that this protein is cytochrome c. Elimination of cytochrome c from cytosol by immunodepletion, or inclusion of sucrose to stabilize mitochondria during cytosol prepn., diminished the apoptotic activity. Adding cytochrome c back to the cytochrome c-depleted exts. restored their apoptotic activity. Cells undergoing apoptosis in vivo showed increased release of cytochrome c to their cytosol, suggesting that mitochondria may function in apoptosis by releasing cytochrome c.
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    Rygula, A.; Majzner, K.; Marzec, K. M.; Kaczor, A.; Pilarczyk, M.; Baranska, M. Raman Spectroscopy of Proteins: A Review. J. Raman Spectrosc. 2013, 44 (8), 1061– 1076,  DOI: 10.1002/jrs.4335
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    Raman spectroscopy of proteins: a review
    Rygula, A.; Majzner, K.; Marzec, K. M.; Kaczor, A.; Pilarczyk, M.; Baranska, M.
    Journal of Raman Spectroscopy (2013), 44 (8), 1061-1076CODEN: JRSPAF; ISSN:0377-0486. (John Wiley & Sons Ltd.)
    A review. In this work, 26 proteins of different structure, function and properties are investigated by Raman spectroscopy with 488, 532 and 1064 nm laser lines. The excitation lines were chosen in NIR and Vis range as the most common and to show the difference due to normal and resonance effect, sometimes accompanied by the fluorescence. The selected proteins were divided, according to the Structural Classification of Proteins, into four classes according to their secondary structure, i.e. α-helical (α), β-sheet (β), mixed structures (α/β, α + β, s) and others. For all compds., FT-Raman and two Vis spectra are presented along with the detailed band assignment. To the best of our knowledge, this is the first review showing the potential of Raman spectroscopy for the measurement and anal. of such a large collection of individual proteins. This work can serve as a comprehensive vibrational spectra library, based on our and previous Raman measurements. Copyright © 2013 John Wiley & Sons, Ltd.
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    Ogretmen, B. Sphingolipid Metabolism in Cancer Signalling and Therapy. Nat. Rev. Cancer 2017, 18 (1), 33– 50,  DOI: 10.1038/nrc.2017.96
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    Kenny, P. A.; Lee, G. Y.; Myers, C. A.; Neve, R. M.; Semeiks, J. R.; Spellman, P. T.; Lorenz, K.; Lee, E. H.; Barcellos-Hoff, M. H.; Petersen, O. W. The Morphologies of Breast Cancer Cell Lines in Three-Dimensional Assays Correlate with Their Profiles of Gene Expression. Mol. Oncol. 2007, 1 (1), 84– 96,  DOI: 10.1016/j.molonc.2007.02.004
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    The morphologies of breast cancer cell lines in three-dimensional assays correlate with their profiles of gene expression
    Kenny, Paraic A.; Lee, Genee Y.; Myers, Connie A.; Neve, Richard M.; Semeiks, Jeremy R.; Spellman, Paul T.; Lorenz, Katrin; Lee, Eva H.; Barcellos-Hoff, Mary Helen; Petersen, Ole W.; Gray, Joe W.; Bissell, Mina J.
    Molecular Oncology (2007), 1 (1), 84-96CODEN: MOONC3; ISSN:1574-7891. (Elsevier B.V.)
    3D cell cultures are rapidly becoming the method of choice for the physiol. relevant modeling of many aspects of non-malignant and malignant cell behavior ex vivo. Nevertheless, only a limited no. of distinct cell types have been evaluated in this assay to date. Here we report the first large scale comparison of the transcriptional profiles and 3D cell culture phenotypes of a substantial panel of human breast cancer cell lines. Each cell line adopts a colony morphol. of one of four main classes in 3D culture. These morphologies reflect, at least in part, the underlying gene expression profile and protein expression patterns of the cell lines, and distinct morphologies were also assocd. with tumor cell invasiveness and with cell lines originating from metastases. We further demonstrate that consistent differences in genes encoding signal transduction proteins emerge when even tumor cells are cultured in 3D microenvironments.
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    Nath, S.; Devi, G. R. Three-Dimensional Culture Systems in Cancer Research: Focus on Tumor Spheroid Model. Pharmacol. Ther. 2016, 163, 94– 108,  DOI: 10.1016/j.pharmthera.2016.03.013
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    Three-dimensional culture systems in cancer research: Focus on tumor spheroid model
    Nath, Sritama; Devi, Gayathri R.
    Pharmacology & Therapeutics (2016), 163 (), 94-108CODEN: PHTHDT; ISSN:0163-7258. (Elsevier)
    Cancer cells propagated in three-dimensional (3D) culture systems exhibit physiol. relevant cell-cell and cell-matrix interactions, gene expression and signaling pathway profiles, heterogeneity and structural complexity that reflect in vivo tumors. In recent years, development of various 3D models has improved the study of host-tumor interaction and use of high-throughput screening platforms for anti-cancer drug discovery and development. This review attempts to summarize the various 3D culture systems, with an emphasis on the most well characterized and widely applied model - multicellular tumor spheroids. This review also highlights the various techniques to generate tumor spheroids, methods to characterize them, and its applicability in cancer research.
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    Edmondson, R.; Broglie, J. J.; Adcock, A. F.; Yang, L. Three-Dimensional Cell Culture Systems and Their Applications in Drug Discovery and Cell-Based Biosensors. Assay Drug Dev. Technol. 2014, 12 (4), 207– 218,  DOI: 10.1089/adt.2014.573
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    Three-Dimensional Cell Culture Systems and Their Applications in Drug Discovery and Cell-Based Biosensors
    Edmondson, Rasheena; Broglie, Jessica Jenkins; Adcock, Audrey F.; Yang, Liju
    Assay and Drug Development Technologies (2014), 12 (4), 207-218CODEN: ADDTAR; ISSN:1540-658X. (Mary Ann Liebert, Inc.)
    A review. Three-dimensional (3D) cell culture systems have gained increasing interest in drug discovery and tissue engineering due to their evident advantages in providing more physiol. relevant information and more predictive data for in vivo tests. In this review, we discuss the characteristics of 3D cell culture systems in comparison to the two-dimensional (2D) monolayer culture, focusing on cell growth conditions, cell proliferation, population, and gene and protein expression profiles. The innovations and development in 3D culture systems for drug discovery over the past 5 years are also reviewed in the article, emphasizing the cellular response to different classes of anticancer drugs, focusing particularly on similarities and differences between 3D and 2D models across the field. The progression and advancement in the application of 3D cell cultures in cell-based biosensors is another focal point of this review.
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    Tauchi-Sato, K.; Ozeki, S.; Houjou, T.; Taguchi, R.; Fujimoto, T. The Surface of Lipid Droplets Is a Phospholipid Monolayer with a Unique Fatty Acid Composition. J. Biol. Chem. 2002, 277 (46), 44507– 44512,  DOI: 10.1074/jbc.M207712200
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    The Surface of Lipid Droplets Is a Phospholipid Monolayer with a Unique Fatty Acid Composition
    Tauchi-Sato, Kumi; Ozeki, Shintaro; Houjou, Toshiaki; Taguchi, Ryo; Fujimoto, Toyoshi
    Journal of Biological Chemistry (2002), 277 (46), 44507-44512CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)
    We found that caveolin-2 is targeted to the surface of lipid droplets (Fujimoto, T., Kogo, H., Ishiguro, K., Tauchi, K., and Nomura, R. (2001) J. Cell Biol. 152, 1079-1085) and hypothesized that the lipid droplet surface is a kind of membrane. To elucidate the characteristics of the lipid droplet surface, we isolated lipid droplets from HepG2 cells and analyzed them by cryoelectron microscopy and by mass spectrometry. By use of cryoelectron microscopy at the stage temp. of 4.2 K, the lipid droplet surface was obsd. as a single line without any fixation or staining, indicating the presence of a single layer of phospholipids. This result appeared consistent with the hypothesis that the lipid droplet surface is derived from the cytoplasmic leaflet of the endoplasmic reticulum membrane and may be continuous to it. However, mass spectrometry revealed that the fatty acid compn. of phosphatidylcholine and lysophosphatidylcholine in lipid droplets is different from that of the rough endoplasmic reticulum. The ample presence of free cholesterol in lipid droplets also suggests that their surface is differentiated from the bulk endoplasmic reticulum membrane. On the other hand, although caveolin-2β and adipose differentiation-related protein, both localizing in lipid droplets, were enriched in the low d. floating fraction, the fatty acid compn. of the fraction was distinct from lipid droplets. Collectively, the result indicates that the lipid droplet surface is a hemi-membrane or a phospholipid monolayer contg. cholesterol but is compositionally different from the endoplasmic reticulum membrane or the sphingolipid/cholesterol-rich microdomain.
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    Penno, A.; Hackenbroich, G.; Thiele, C. Phospholipids and Lipid Droplets. Biochim. Biophys. Acta, Mol. Cell Biol. Lipids 2013, 1831 (3), 589– 594,  DOI: 10.1016/j.bbalip.2012.12.001
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    Phospholipids and lipid droplets
    Penno, Anke; Hackenbroich, Gregor; Thiele, Christoph
    Biochimica et Biophysica Acta, Molecular and Cell Biology of Lipids (2013), 1831 (3), 589-594CODEN: BBMLFG; ISSN:1388-1981. (Elsevier B. V.)
    A review. Lipid droplets are ubiquitous cellular organelles that allow cells to store large amts. of neutral lipids for membrane synthesis and energy supply in times of starvation. Compared to other cellular organelles, lipid droplets are structurally unique as they are made of a hydrophobic core of neutral lipids and are sepd. to the cytosol only by a surrounding phospholipid monolayer. This phospholipid monolayer consists of over a hundred different phospholipid mol. species of which phosphatidylcholine is the most abundant lipid class. However, lipid droplets lack some indispensable activities of the phosphatidylcholine biogenic pathways suggesting that they partially depend on other organelles for phosphatidylcholine synthesis. Here, the authors discuss very recent data on the compn., origin, transport and function of the phospholipid monolayer with a particular emphasis on the phosphatidylcholine metab. on and for lipid droplets. In addn., we highlight two very important quant. aspects: (i) The amt. of phospholipid required for lipid droplet monolayer expansion is remarkably small and (ii) to maintain the invariably round shape of lipid droplets, a cell must have a highly sensitive but so far unknown mechanism that regulates the ratio of phospholipid to neutral lipid in lipid droplets. This article is part of a Special Issue entitled Phospholipids and Phospholipid Metab.
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    Wilfling, F.; Wang, H.; Haas, J. T.; Krahmer, N.; Gould, T. J.; Uchida, A.; Cheng, J.-X.; Graham, M.; Christiano, R.; Fröhlich, F. Triacylglycerol Synthesis Enzymes Mediate Lipid Droplet Growth by Relocalizing from the ER to Lipid Droplets. Dev. Cell 2013, 24 (4), 384– 399,  DOI: 10.1016/j.devcel.2013.01.013
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    Triacylglycerol Synthesis Enzymes Mediate Lipid Droplet Growth by Relocalizing from the ER to Lipid Droplets
    Wilfling, Florian; Wang, Huajin; Haas, Joel T.; Krahmer, Natalie; Gould, Travis J.; Uchida, Aki; Cheng, Ji-Xin; Graham, Morven; Christiano, Romain; Frohlich, Florian; Liu, Xinran; Buhman, Kimberly K.; Coleman, Rosalind A.; Bewersdorf, Joerg; Farese, Robert V.; Walther, Tobias C.
    Developmental Cell (2013), 24 (4), 384-399CODEN: DCEEBE; ISSN:1534-5807. (Cell Press)
    Lipid droplets (LDs) store metabolic energy and membrane lipid precursors. With excess metabolic energy, cells synthesize triacylglycerol (TG) and form LDs that grow dramatically. It is unclear how TG synthesis relates to LD formation and growth. Here, we identify two LD subpopulations: smaller LDs of relatively const. size, and LDs that grow larger. The latter population contains isoenzymes for each step of TG synthesis. Glycerol-3-phosphate acyltransferase 4 (GPAT4), which catalyzes the first and rate-limiting step, relocalizes from the endoplasmic reticulum (ER) to a subset of forming LDs, where it becomes stably assocd. ER-to-LD targeting of GPAT4 and other LD-localized TG synthesis isoenzymes is required for LD growth. Key features of GPAT4 ER-to-LD targeting and function in LD growth are conserved between Drosophila and mammalian cells. Our results explain how TG synthesis is coupled with LD growth and identify two distinct LD subpopulations based on their capacity for localized TG synthesis.
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    Mouritsen, O. G.; Bagatolli, L. A. Life-as a Matter of Fat, 2nd ed.; Springer-Verlag: Heidelberg, 2005.
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    Walther, T. C.; Farese, R. V. The Life of Lipid Droplets. Biochim. Biophys. Acta, Mol. Cell Biol. Lipids 2009, 1791 (6), 459– 466,  DOI: 10.1016/j.bbalip.2008.10.009
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    The life of lipid droplets
    Walther, Tobias C.; Farese, Robert V.
    Biochimica et Biophysica Acta, Molecular and Cell Biology of Lipids (2009), 1791 (6), 459-466CODEN: BBMLFG; ISSN:1388-1981. (Elsevier B. V.)
    A review. Lipid droplets are the least characterized of cellular organelles. Long considered simple lipid storage depots, these dynamic and remarkable organelles have recently been implicated in many biol. processes, and investigators are only now beginning to gain insights into their fascinating lives in cells. Here, the authors examine what is known of the life of lipid droplets. The authors review emerging data concerning their cellular biol. and present their thoughts on some of the most salient questions for investigation.
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    Nieman, K. M.; Kenny, H. A.; Penicka, C. V.; Ladanyi, A.; Buell-Gutbrod, R.; Zillhardt, M. R.; Romero, I. L.; Carey, M. S.; Mills, G. B.; Hotamisligil, G. S. Adipocytes Promote Ovarian Cancer Metastasis and Provide Energy for Rapid Tumor Growth. Nat. Med. 2011, 17, 1498– 1503,  DOI: 10.1038/nm.2492
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    Adipocytes promote ovarian cancer metastasis and provide energy for rapid tumor growth
    Nieman, Kristin M.; Kenny, Hilary A.; Penicka, Carla V.; Ladanyi, Andras; Buell-Gutbrod, Rebecca; Zillhardt, Marion R.; Romero, Iris L.; Carey, Mark S.; Mills, Gordon B.; Hotamisligil, Goekhan S.; Yamada, S. Diane; Peter, Marcus E.; Gwin, Katja; Lengyel, Ernst
    Nature Medicine (New York, NY, United States) (2011), 17 (11), 1498-1503CODEN: NAMEFI; ISSN:1078-8956. (Nature Publishing Group)
    Intra-abdominal tumors, such as ovarian cancer, have a clear predilection for metastasis to the omentum, an organ primarily composed of adipocytes. Currently, it is unclear why tumor cells preferentially home to and proliferate in the omentum, yet omental metastases typically represent the largest tumor in the abdominal cavities of women with ovarian cancer. We show here that primary human omental adipocytes promote homing, migration and invasion of ovarian cancer cells, and that adipokines including interleukin-8 (IL-8) mediate these activities. Adipocyte-ovarian cancer cell coculture led to the direct transfer of lipids from adipocytes to ovarian cancer cells and promoted in vitro and in vivo tumor growth. Furthermore, coculture induced lipolysis in adipocytes and β-oxidn. in cancer cells, suggesting adipocytes act as an energy source for the cancer cells. A protein array identified upregulation of fatty acid-binding protein 4 (FABP4, also known as aP2) in omental metastases as compared to primary ovarian tumors, and FABP4 expression was detected in ovarian cancer cells at the adipocyte-tumor cell interface. FABP4 deficiency substantially impaired metastatic tumor growth in mice, indicating that FABP4 has a key role in ovarian cancer metastasis. These data indicate adipocytes provide fatty acids for rapid tumor growth, identifying lipid metab. and transport as new targets for the treatment of cancers where adipocytes are a major component of the microenvironment.
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    Nieman, K. M.; Romero, I. L.; Van Houten, B.; Lengyel, E. Adipose Tissue and Adipocytes Support Tumorigenesis and Metastasis. Biochim. Biophys. Acta, Mol. Cell Biol. Lipids 2013, 1831 (10), 1533– 1541,  DOI: 10.1016/j.bbalip.2013.02.010
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    56
    Adipose tissue and adipocytes support tumorigenesis and metastasis
    Nieman, Kristin M.; Romero, Iris L.; Van Houten, Bennett; Lengyel, Ernst
    Biochimica et Biophysica Acta, Molecular and Cell Biology of Lipids (2013), 1831 (10), 1533-1541CODEN: BBMLFG; ISSN:1388-1981. (Elsevier B. V.)
    A review. Adipose tissue influences tumor development in two major ways. First, obese individuals have a higher risk of developing certain cancers (endometrial, esophageal, and renal cell cancer). However, the risk of developing other cancers (melanoma, rectal, and ovarian) is not altered by body mass. In obesity, hypertrophied adipose tissue depots are characterized by a state of low grade inflammation. In this activated state, adipocytes and inflammatory cells secrete adipokines and cytokines which are known to promote tumor development. In addn., the adipocyte mediated conversion of androgens to estrogen specifically contributes to the development of endometrial cancer, which shows the greatest relative risk (6.3-fold) increase between lean and obese individuals. Second, many tumor types (gastric, breast, colon, renal, and ovarian) grow in the anatomical vicinity of adipose tissue. During their interaction with cancer cells, adipocytes dedifferentiate into pre-adipocytes or are reprogrammed into cancer-assocd. adipocytes (CAA). CAA secrete adipokines which stimulate the adhesion, migration, and invasion of tumor cells. Cancer cells and CAA also engage in a dynamic exchange of metabolites. Specifically, CAA release fatty acids through lipolysis which are then transferred to cancer cells and used for energy prodn. through β-oxidn. The abundant availability of lipids from adipocytes in the tumor microenvironment, supports tumor progression and uncontrolled growth. Given that adipocytes are a major source of adipokines and energy for the cancer cell, understanding the mechanisms of metabolic symbiosis between cancer cells and adipocytes, should reveal new therapeutic possibilities. This article is part of a Special Issue entitled Lipid Metab. in Cancer.
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    Thiam, A. R.; Farese, R. V.; Walther, T. C. The Biophysics and Cell Biology of Lipid Droplets. Nat. Rev. Mol. Cell Biol. 2013, 14 (12), 775– 786,  DOI: 10.1038/nrm3699
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    The biophysics and cell biology of lipid droplets
    Thiam, Abdou Rachid; Farese, Robert V., Jr.; Walther, Tobias C.
    Nature Reviews Molecular Cell Biology (2013), 14 (12), 775-786CODEN: NRMCBP; ISSN:1471-0072. (Nature Publishing Group)
    A review. Lipid droplets are intracellular organelles that are found in most cells, where they have fundamental roles in metab. They function prominently in storing oil-based reserves of metabolic energy and components of membrane lipids. Lipid droplets are the dispersed phase of an oil-in-water emulsion in the aq. cytosol of cells, and the importance of basic biophys. principles of emulsions for lipid droplet biol. is now being appreciated. Because of their unique architecture, with an interface between the dispersed oil phase and the aq. cytosol, specific mechanisms underlie their formation, growth and shrinkage. Such mechanisms enable cells to use emulsified oil when the demands for metabolic energy or membrane synthesis change. The regulation of the compn. of the phospholipid surfactants at the surface of lipid droplets is crucial for lipid droplet homeostasis and protein targeting to their surfaces.
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    Pelletier, J.; Bellot, G.; Gounon, P.; Lacas-Gervais, S.; Pouysségur, J.; Mazure, N. M. Glycogen Synthesis Is Induced in Hypoxia by the Hypoxia-Inducible Factor and Promotes Cancer Cell Survival. Front. Oncol. 2012, 2, 18,  DOI: 10.3389/fonc.2012.00018
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    Glycogen Synthesis is Induced in Hypoxia by the Hypoxia-Inducible Factor and Promotes Cancer Cell Survival
    Pelletier Joffrey; Bellot Gregory; Gounon Pierre; Lacas-Gervais Sandra; Pouyssegur Jacques; Mazure Nathalie M
    Frontiers in oncology (2012), 2 (), 18 ISSN:.
    The hypoxia-inducible factor 1 (HIF-1), in addition to genetic and epigenetic changes, is largely responsible for alterations in cell metabolism in hypoxic tumor cells. This transcription factor not only favors cell proliferation through the metabolic shift from oxidative phosphorylation to glycolysis and lactic acid production but also stimulates nutrient supply by mediating adaptive survival mechanisms. In this study we showed that glycogen synthesis is enhanced in non-cancer and cancer cells when exposed to hypoxia, resulting in a large increase in glycogen stores. Furthermore, we demonstrated that the mRNA and protein levels of the first enzyme of glycogenesis, phosphoglucomutase1 (PGM1), were increased in hypoxia. We showed that induction of glycogen storage as well as PGM1 expression were dependent on HIF-1 and HIF-2. We established that hypoxia-induced glycogen stores are rapidly mobilized in cells that are starved of glucose. Glycogenolysis allows these "hypoxia-preconditioned" cells to confront and survive glucose deprivation. In contrast normoxic control cells exhibit a high rate of cell death following glucose removal. These findings point to the important role of hypoxia and HIF in inducing mechanisms of rapid adaptation and survival in response to a decrease in oxygen tension. We propose that a decrease in pO(2) acts as an "alarm" that prepares the cells to face subsequent nutrient depletion and to survive.
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    Pescador, N.; Villar, D.; Cifuentes, D.; Garcia-Rocha, M.; Ortiz-Barahona, A.; Vazquez, S.; Ordoñez, A.; Cuevas, Y.; Saez-Morales, D.; Garcia-Bermejo, M. L. Hypoxia Promotes Glycogen Accumulation through Hypoxia Inducible Factor (HIF)-Mediated Induction of Glycogen Synthase 1. PLoS One 2010, 5 (3), e9644  DOI: 10.1371/journal.pone.0009644
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    Favaro, E.; Bensaad, K.; Chong, M. G.; Tennant, D. A.; Ferguson, D. J. P.; Snell, C.; Steers, G.; Turley, H.; Li, J.-L.; Günther, U. L. Glucose Utilization via Glycogen Phosphorylase Sustains Proliferation and Prevents Premature Senescence in Cancer Cells. Cell Metab. 2012, 16 (6), 751– 764,  DOI: 10.1016/j.cmet.2012.10.017
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    Glucose Utilization via Glycogen Phosphorylase Sustains Proliferation and Prevents Premature Senescence in Cancer Cells
    Favaro, Elena; Bensaad, Karim; Chong, Mei G.; Tennant, Daniel A.; Ferguson, David J. P.; Snell, Cameron; Steers, Graham; Turley, Helen; Li, Ji-Liang; Guenther, Ulrich L.; Buffa, Francesca M.; McIntyre, Alan; Harris, Adrian L.
    Cell Metabolism (2012), 16 (6), 751-764CODEN: CMEEB5; ISSN:1550-4131. (Elsevier Inc.)
    Metabolic reprogramming of cancer cells provides energy and multiple intermediates crit. for cell growth. Hypoxia in tumors represents a hostile environment that can encourage these transformations. We report that glycogen metab. is upregulated in tumors in vivo and in cancer cells in vitro in response to hypoxia. In vitro, hypoxia induced an early accumulation of glycogen, followed by a gradual decline. Concordantly, glycogen synthase (GYS1) showed a rapid induction, followed by a later increase of glycogen phosphorylase (PYGL). PYGL depletion and the consequent glycogen accumulation led to increased reactive oxygen species (ROS) levels that contributed to a p53-dependent induction of senescence and markedly impaired tumorigenesis in vivo. Metabolic analyses indicated that glycogen degrdn. by PYGL is important for the optimal function of the pentose phosphate pathway. Thus, glycogen metab. is a key pathway induced by hypoxia, necessary for optimal glucose utilization, which represents a targetable mechanism of metabolic adaptation.
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    Okada, M.; Smith, N. I.; Palonpon, A. F.; Endo, H.; Kawata, S.; Sodeoka, M.; Fujita, K. Label-Free Raman Observation of Cytochrome c Dynamics during Apoptosis. Proc. Natl. Acad. Sci. U. S. A. 2012, 109 (1), 28– 32,  DOI: 10.1073/pnas.1107524108
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    Label-free Raman observation of cytochrome c dynamics during apoptosis
    Okada, Masaya; Smith, Nicholas Isaac; Palonpon, Almar Flotildes; Endo, Hiromi; Kawata, Satoshi; Sodeoka, Mikiko; Fujita, Katsumasa
    Proceedings of the National Academy of Sciences of the United States of America (2012), 109 (1), 28-32, S28/1-S28/2CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
    We performed label-free observation of mol. dynamics in apoptotic cells by Raman microscopy. Dynamic changes in cytochrome c distribution at the Raman band of 750 cm-1 were obsd. after adding an apoptosis inducer to the cells. The comparison of mitochondria fluorescence images and Raman images of cytochrome c confirmed that changes in cytochrome c distribution can be distinguished as release of cytochrome c from mitochondria. Our observation also revealed that the redox state of cytochrome c was maintained during the release from the mitochondria. Monitoring mitochondrial membrane potential with JC-1 dye confirmed that the obsd. cytochrome c release was assocd. with apoptosis.
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    Vazquez, A.; Kamphorst, J. J.; Markert, E. K.; Schug, Z. T.; Tardito, S.; Gottlieb, E. Cancer Metabolism at a Glance. J. Cell Sci. 2016, 129 (18), 3367– 3373,  DOI: 10.1242/jcs.181016
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    Cancer metabolism at a glance
    Vazquez, Alexei; Kamphorst, Jurre J.; Markert, Elke K.; Schug, Zachary T.; Tardito, Saverio; Gottlieb, Eyal
    Journal of Cell Science (2016), 129 (18), 3367-3373CODEN: JNCSAI; ISSN:0021-9533. (Company of Biologists Ltd.)
    A defining hallmark of cancer is uncontrolled cell proliferation. This is initiated once cells have accumulated alterations in signaling pathways that control metab. and proliferation, wherein the metabolic alterations provide the energetic and anabolic demands of enhanced cell proliferation. How these metabolic requirements are satisfied depends, in part, on the tumor microenvironment, which dets. the availability of nutrients and oxygen. In this Cell Science at a Glance paper and the accompanying poster, we summarize our current understanding of cancer metab., emphasizing pathways of nutrient utilization and metab. that either appear or have been proven essential for cancer cells. We also review how this knowledge has contributed to the development of anticancer therapies that target cancer metab.
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    Worgall, T. S. Sphingolipids: Major Regulators of Lipid Metabolism. Curr. Opin. Clin. Nutr. Metab. Care 2007, 10 (2), 149– 155,  DOI: 10.1097/MCO.0b013e328028fda3
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    Sphingolipids: major regulators of lipid metabolism
    Worgall, Tilla S.
    Current Opinion in Clinical Nutrition and Metabolic Care (2007), 10 (2), 149-155CODEN: COCMF3; ISSN:1363-1950. (Lippincott Williams & Wilkins)
    A review. Emerging data strongly suggest a role of sphingolipid synthesis in the regulation of transcription factors and regulatory proteins that control cellular lipid homeostasis.
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    Eichmann, T. O.; Lass, A. DAG Tales: The Multiple Faces of Diacylglycerol—stereochemistry, Metabolism, and Signaling. Cell. Mol. Life Sci. 2015, 72 (20), 3931– 3952,  DOI: 10.1007/s00018-015-1982-3
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    DAG tales: the multiple faces of diacylglycerol-stereochemistry, metabolism, and signaling
    Eichmann, Thomas Oliver; Lass, Achim
    Cellular and Molecular Life Sciences (2015), 72 (20), 3931-3952CODEN: CMLSFI; ISSN:1420-682X. (Birkhaeuser Basel)
    The neutral lipids diacylglycerols (DAGs) are involved in a plethora of metabolic pathways. They function as components of cellular membranes, as building blocks for glycero(phospho)lipids, and as lipid second messengers. Considering their central role in multiple metabolic processes and signaling pathways, cellular DAG levels require a tight regulation to ensure a const. and controlled availability. Interestingly, DAG species are versatile in their chem. structure. Besides the different fatty acid species esterified to the glycerol backbone, DAGs can occur in three different stereo/regioisoforms, each with unique biol. properties. Recent scientific advances have revealed that DAG metabolizing enzymes generate and distinguish different DAG isoforms, and that only one DAG isoform holds signaling properties. Herein, we review the current knowledge of DAG stereochem. and their impact on cellular metab. and signaling. Further, we describe intracellular DAG turnover and its stereochem. in a 3-pool model to illustrate the spatial and stereochem. sepn. and hereby the diversity of cellular DAG metab.
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    Kadota, M.; Yang, H. H.; Gomez, B.; Sato, M.; Clifford, R. J.; Meerzaman, D.; Dunn, B. K.; Wakefield, L. M.; Lee, M. P. Delineating Genetic Alterations for Tumor Progression in the MCF10A Series of Breast Cancer Cell Lines. PLoS One 2010, 5 (2), e9201  DOI: 10.1371/journal.pone.0009201
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    Han, G.; Gupta, S. D.; Gable, K.; Niranjanakumari, S.; Moitra, P.; Eichler, F.; Brown, R. H.; Harmon, J. M.; Dunn, T. M. Identification of Small Subunits of Mammalian Serine Palmitoyltransferase That Confer Distinct Acyl-CoA Substrate Specificities. Proc. Natl. Acad. Sci. U. S. A. 2009, 106 (20), 8186– 8191,  DOI: 10.1073/pnas.0811269106
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    Knapp, P.; Baranowski, M.; Knapp, M.; Zabielski, P.; Błachnio-Zabielska, A. U.; Górski, J. Altered Sphingolipid Metabolism in Human Endometrial Cancer. Prostaglandins Other Lipid Mediators 2010, 92 (1–4), 62– 66,  DOI: 10.1016/j.prostaglandins.2010.03.002
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    Altered sphingolipid metabolism in human endometrial cancer
    Knapp, Pawel; Baranowski, Marcin; Knapp, Malgorzata; Zabielski, Piotr; Blachnio-Zabielska, Agnieszka U.; Gorski, Jan
    Prostaglandins & Other Lipid Mediators (2010), 92 (1-4), 62-66CODEN: POLMFL; ISSN:1098-8823. (Elsevier)
    There is a growing body of evidence indicating that bioactive sphingolipids play a key role in cancer development, progression and metastasis. However, sphingolipid metab. in malignant tumors is poorly investigated. Therefore, the aim of the present study was to examine the content of selected intermediates of ceramide metab. and the activity of key enzymes of ceramide de novo synthesis and sphingosine-1-phosphate (S1P) prodn. in the endometrial cancer. The specimens of cancer tissue and healthy endometrium were obtained from women undergoing surgery because of the cancer (n = 23) and because of myomas (n = 18), resp. The content of sphinganine, dihydroceramide, ceramide, sphingosine and S1P was measured using high pressure liq. chromatog. The activity of the enzymes was detd. using radioactive substrates. It has been found that the content of each examd. sphingolipid was markedly elevated in the cancer tissue compared with the healthy endometrium. Namely, sphinganine, sphingosine and dihydroceramide by 3-4.6-fold, ceramide and S1P by 1.9- and 1.6-fold, resp. Interestingly, the ratio of S1P to ceramide remained stable. The activity of serine palmitoyltransferase and sphingosine kinase 1 was increased by 2.3- and 2.6-fold, resp. We conclude that endometrial carcinoma is characterized by profound changes in sphingolipid metab. that likely contribute to its progression and chemoresistance.
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    Patra, S. K. Dissecting Lipid Raft Facilitated Cell Signaling Pathways in Cancer. Biochim. Biophys. Acta, Rev. Cancer 2008, 1785 (2), 182– 206,  DOI: 10.1016/j.bbcan.2007.11.002
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    Dissecting lipid raft facilitated cell signaling pathways in cancer
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  • Abstract

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    Figure 1

    Figure 1. Relation between lipid amounts and the malignancy potential of breast cancer cells in 2D and 3D. Oil-Red-O lipid staining of cell lines from the MCF10A-based breast cancer progression series cultured in 2D (a–f) and as multicellular spheroids (g–l). (a, d, g, j) Nonmalignant MCF10A cells; (b, e, h, k) precancer MCF10DCIS.com cells; (c, f, i, l) invasive MCF10CA1a cells. Lipids are stained red, and cell nuclei are stained purple. Arrows: lipid droplet aggregates close to cell nuclei. For a high resolution version of Figure 1 see Supporting Data.

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    Figure 2

    Figure 2. Lipid profiles in 2D and 3D culture of precancer and invasive cells detected using LCMS. (a) Heatmap showing the clustering of lipid species in 2D and 3D cultures of MCF10DCIS.com (precancer) and MCF10CA1a cells (invasive). Color bar indicates the scaled distance from the row mean of the normalized transformed data. For assessment of the variation within each group, the biological replicates for each condition are shown. For the 2D samples, each group consists of three biological replicates, and for the 3D samples, each group consists of four biological replicates. Lipid classes are color coded as indicated. Coenzyme Q10 is shown in white. To the right, representative example lipid structures of the color-coded lipid classes in part a are shown. (b) Lipid class distribution in precancer and invasive 2D and 3D cultures as detected with LCMS, calculated from areas in LCMS normalized per microgram of protein in the sample and presented as a fraction of total lipids in the sample. Error bars are the standard error of the mean. 34 Cs = summed acyl chain and sphingoid base chain lengths of 34 carbons. See Supporting Figure S2 for a version of this figure with individual lipid identifiers associated with the heat map.

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    Figure 3

    Figure 3. Heat map showing clustering of the 25 lipid species with the most significant changes, selected by t-test, across 3D cultures of MCF10DCIS.com (precancer) and MCF10CA1a (invasive) cells as detected with LCMS. Each group consists of four biological replicates. So(d18:0) = sphinganine. Color bar indicates the scaled distance from the row mean of the normalized transformed data.

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    Figure 4

    Figure 4. Characterization of the lipid droplets formed in 3D multicellular spheroids of malignant cell lines. (a, b, e) Precancer spheroid cross sections. (c, d, g) Invasive spheroid cross sections. Asterisks show the necrotic core. (a, c) Oil-Red-O lipid staining showing lipid accumulation in the necrotic core area of the spheroids as well as lipid droplets in the invasive spheroid (arrows). (b, d) Cross-polarized light images of the spheroid cross sections showing birefringence (arrows in part d point at the same areas as in part c). (e, g) Overlaid spatial distribution maps of key basis spectra resultant from NMF multivariate analysis of Raman mapping. (f) Corresponding NMF basis spectra (precancer: black, invasive: gray). The precancer overlay map (e) shows an increase in lipid content toward the spheroid center, while the invasive overlay map confirms the birefringent  regions are lipid-rich droplets (cyan). Arrows indicate the same bodies as in parts c and d.

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    Figure 5

    Figure 5. Spatial characterization of DCIS (precancer) from human tissue. (a) H&E stained cryo-section showing the duct cross section containing cells (purple), necrosis (dark pink and purple), and surrounding stromal tissue (pink). (b) Confocal Raman mapping and component analysis of a serial section from the same duct in part a, showing the spatial distribution of the tissue components. Lipids, cyan; collagen, green; protein/cytochrome c, magenta; noncollagenous proteins, blue; cells, yellow. A distinct lipid signature consistent with neutral lipids, including cholesterol ester(s), is observed in the necrotic regions and occurs in spatially discrete domains (arrow). (c) The corresponding Raman component spectra for the Raman map in part b.

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    Figure 6

    Figure 6. A scheme describing the effects of dimensionality (top left) and the cell malignancy potential (bottom left) on lipid species amounts in the MCF10A breast cancer in vitro model. Lipid-rich areas (red) are observed in the necrotic core with decreasing amounts toward the spheroid periphery alongside large lipid droplets at the periphery. The observed increase in the ratio of neutral to membrane lipid species in 3D versus 2D may be related to large lipid droplet formation through TG synthesis and/or lipid droplet coalescence (top right). The observed increase in sphingolipid species in invasive versus precancer spheroids could be due to enhancement of the de novo sphingolipid synthesis pathway (bottom right, adapted from Ogretmen (46)). Species of lipids increased out of total lipids in 3D invasive spheroids are underlined. CoA = coenzyme A, SPT = serine palmitoyltransferase, KDSR = 3-ketosphinganine reductase, CERS = (dihydro)ceramide synthases, DES = dihydroceramide desaturase, SMS = sphingomyelin synthase, CDase = ceramidases.

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      The role of lipid droplets and adipocytes in cancer. Raman imaging of cell cultures: MCF10A, MCF7, and MDA-MB-231 compared to adipocytes in cancerous human breast tissue
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      16
      Lipidomic analysis of phospholipids from human mammary epithelial and breast cancer cell lines
      Doria, M. Luisa; Cotrim, Candida Z.; Simoes, Claudia; Macedo, Barbara; Domingues, Pedro; Domingues, M. Rosario; Helguero, Luisa A.
      Journal of Cellular Physiology (2013), 228 (2), 457-468CODEN: JCLLAX; ISSN:0021-9541. (Wiley-Blackwell)
      Alterations of phospholipid (PL) profiles have been assocd. to disease and specific lipids may be involved in the onset and evolution of cancer; yet, anal. of PL profiles using mass spectrometry (MS) in breast cancer cells is a novel approach. Previously, we reported a lipidomic anal. of PLs from mouse mammary epithelial and breast cancer cells using off-line thin layer chromatog. (TLC)-MS, where several changes in PL profile were found to be assocd. with the degree of malignancy of cells. In the present study, lipidomic anal. has been extended to human mammary epithelial cells and breast cancer cell lines (MCF10A, T47-D, and MDA-MB-231), using TLC-MS, validated by hydrophilic interaction liq. chromatog.-MS. Differences in phosphatidylethanolamine (PE) content relative to total amt. of PLs was highest in non-malignant cells while phosphatidic acid was present with highest relative abundance in metastatic cells. In addn., the following differences in PL mol. species assocd. to cancer phenotype, metastatic potential, and cell morphol. were found: higher levels of alkylacyl PCs and phosphatidylinositol (PI; 22:5/18:0) were detected in migratory cells, epithelial cells had less unsatd. fatty acyl chains and shorter aliph. tails in PE and sphingomyelin classes, while PI (18:0/18:1) was lowest in non-malignant cells compared to cancer cells. To date, information about PL changes in cancer progression is scarce, therefore results presented in this work will be useful as a starting point to define possible PLs with prospective as biomarkers and disclose metabolic pathways with potential for cancer therapy.
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    17. 17
      Baumann, J.; Sevinsky, C.; Conklin, D. S. Lipid Biology of Breast Cancer. Biochim. Biophys. Acta, Mol. Cell Biol. Lipids 2013, 1831 (10), 1509– 1517,  DOI: 10.1016/j.bbalip.2013.03.011
      17
      Lipid biology of breast cancer
      Baumann, Jan; Sevinsky, Christopher; Conklin, Douglas S.
      Biochimica et Biophysica Acta, Molecular and Cell Biology of Lipids (2013), 1831 (10), 1509-1517CODEN: BBMLFG; ISSN:1388-1981. (Elsevier B. V.)
      A review. Alterations in lipid metab. have been reported in many types of cancer. Lipids have been implicated in the regulation of proliferation, differentiation, apoptosis, inflammation, autophagy, motility and membrane homeostasis. It is required that their biosynthesis is tightly regulated to ensure homeostasis and to prevent unnecessary energy expenditure. This review focuses on the emerging understanding of the role of lipids and lipogenic pathway regulation in breast cancer, including parallels drawn from the study of metabolic disease models, and suggestions on how these findings can potentially be exploited to promote gains in HER2/neu-pos. breast cancer research. This article is part of a Special Issue entitled Lipid Metab. in Cancer.
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    18. 18
      Liu, Q.; Luo, Q.; Halim, A.; Song, G. Targeting Lipid Metabolism of Cancer Cells: A Promising Therapeutic Strategy for Cancer. Cancer Lett. 2017, 401, 39– 45,  DOI: 10.1016/j.canlet.2017.05.002
      18
      Targeting lipid metabolism of cancer cells: A promising therapeutic strategy for cancer
      Liu, Qiuping; Luo, Qing; Halim, Alexander; Song, Guanbin
      Cancer Letters (New York, NY, United States) (2017), 401 (), 39-45CODEN: CALEDQ; ISSN:0304-3835. (Elsevier)
      One of the most important metabolic hallmarks of cancer cells is deregulation of lipid metab. In addn., enhancing de novo fatty acid (FA) synthesis, increasing lipid uptake and lipolysis have also been considered as means of FA acquisition in cancer cells. FAs are involved in various aspects of tumorigenesis and tumor progression. Therefore, targeting lipid metab. is a promising therapeutic strategy for human cancer. Recent studies have shown that reprogramming lipid metab. plays important roles in providing energy, macromols. for membrane synthesis, and lipid signals during cancer progression. Moreover, accumulation of lipid droplets in cancer cells acts as a pivotal adaptive response to harmful conditions. Here, we provide a brief review of the crucial roles of FA metab. in cancer development, and place emphasis on FA origin, utilization and storage in cancer cells. Understanding the regulation of lipid metab. in cancer cells has important implications for exploring a new therapeutic strategy for management and treatment of cancer.
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXotFynsr8%253D&md5=6e71f7f51e06bf38e99411ec9cf887a6
    19. 19
      Infanger, D. W.; Lynch, M. E.; Fischbach, C. Engineered Culture Models for Studies of Tumor-Microenvironment Interactions. Annu. Rev. Biomed. Eng. 2013, 15 (1), 29– 53,  DOI: 10.1146/annurev-bioeng-071811-150028
      19
      Engineered culture models for studies of tumor-microenvironment interactions
      Infanger, David W.; Lynch, Maureen E.; Fischbach, Claudia
      Annual Review of Biomedical Engineering (2013), 15 (), 29-53CODEN: ARBEF7; ISSN:1523-9829. (Annual Reviews)
      A review. Heterogeneous microenvironmental conditions play crit. roles in cancer pathogenesis and therapy resistance and arise from changes in tissue dimensionality, cell-extracellular matrix (ECM) interactions, sol. factor signaling, oxygen as well as metabolic gradients, and exogenous biomech. cues. Traditional cell culture approaches are restricted in their ability to mimic this complexity with physiol. relevance, offering only partial explanation as to why novel therapeutic compds. are frequently efficacious in vitro but disappoint in preclin. and clin. studies. In an effort to overcome these limitations, phys. sciences-based strategies were employed to model specific aspects of the cancer microenvironment. Although these strategies offer promise to reveal the contributions of microenvironmental parameters on tumor initiation, progression, and therapy resistance, they, too, frequently suffer from limitations. This review highlights physicochem. and biol. key features of the tumor microenvironment, critically discusses advantages and limitations of current engineering strategies, and provides a perspective on future opportunities for engineered tumor models.
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    20. 20
      Fischbach, C.; Chen, R.; Matsumoto, T.; Schmelzle, T.; Brugge, J. S.; Polverini, P. J.; Mooney, D. J. Engineering Tumors with 3D Scaffolds. Nat. Methods 2007, 4 (10), 855– 860,  DOI: 10.1038/nmeth1085
      20
      Engineering tumors with 3D scaffolds
      Fischbach, Claudia; Chen, Ruth; Matsumoto, Takuya; Schmelzle, Tobias; Brugge, Joan S.; Polverini, Peter J.; Mooney, David J.
      Nature Methods (2007), 4 (10), 855-860CODEN: NMAEA3; ISSN:1548-7091. (Nature Publishing Group)
      Microenvironmental conditions control tumorigenesis and biomimetic culture systems that allow for in vitro and in vivo tumor modeling may greatly aid studies of cancer cells' dependency on these conditions. The authors engineered 3-dimensional (3D) human tumor models using carcinoma cells in polymeric scaffolds that recreated microenvironmental characteristics representative of tumors in vivo. Strikingly, the angiogenic characteristics of tumor cells were dramatically altered upon 3D culture within this system, and corresponded much more closely to tumors formed in vivo. Cells in this model were also less sensitive to chemotherapy and yielded tumors with enhanced malignant potential. The authors assessed the broad relevance of these findings with 3D culture of other tumor cell lines in this same model, comparison with std. 3D Matrigel culture and in vivo expts. This new biomimetic model may provide a broadly applicable 3D culture system to study the effect of microenvironmental conditions on tumor malignancy in vitro and in vivo.
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    21. 21
      Shekhar, M. P. V.V.; Tait, L.; Pauley, R. J.; Wu, G. S.; Santner, S. J.; Nangia-Makker, P.; Shekhar, V.; Nassar, H.; Visscher, D. W.; Heppner, G. H. Comedo-Ductal Carcinoma in Situ: A Paradoxical Role for Programmed Cell Death. Cancer Biol. Ther. 2008, 7 (11), 1774– 1782,  DOI: 10.4161/cbt.7.11.6781
      21
      Comedo-ductal carcinoma in situ: a paradoxical role for programmed cell death
      Shekhar, Malathy P. V.; Tait, Larry; Pauley, Robert J.; Wu, Gen Sheng; Santner, Steven J.; Nangia-Makker, Pratima; Shekhar, Varun; Nassar, Hind; Visscher, Daniel W.; Heppner, Gloria H.; Miller, Fred R.
      Cancer Biology & Therapy (2008), 7 (11), 1774-1782CODEN: CBTAAO; ISSN:1538-4047. (Landes Bioscience)
      Comedo-DCIS is a histol. subtype of preinvasive breast neoplasia that is characterized by prominent apoptotic cell death and has greater malignant potential than other DCIS subtypes. We investigated the mechanisms of apoptosis in comedo-DCIS and its role in conversion of comedo-DCIS to invasive cancer. Clin. comedo-DCIS excisions and the MCF10DCIS.com human breast cancer model which produces lesions resembling comedo-DCIS were analyzed. Apoptotic luminal and myoepithelial cells were identified by TUNEL and reactivity to cleaved PARP antibody and cell death assessed by Western blotting, Mitocapture and immunohistochem. assays. MCF10DCIS.com cells undergo spontaneous apoptosis in vitro, both in monolayers and multicellular spheroids; it is assocd. with increased mitochondrial membrane permeability, increase in Bax/Bcl-2 ratio and occurs via caspase-9-dependent p53-independent pathway. This suggests that apoptosis is stromal-independent and that the cells are programmed to undergo apoptosis. Immunostaining with cleaved PARP antibody showed that myoepithelial apoptosis occurs before lesions progress to comedo-DCIS in both clin. comedo-DCIS and in vivo MCF10DCIS.com lesions. Intense staining for MMP-2, MMP-3, MMP-9 and MMP-11 was obsd. in the stroma and epithelia of solid DCIS lesions prior to conversion to comedo-DCIS in clin. and MCF10DCIS.com lesions. Gelatin zymog. showed higher MMP-2 levels in lysates and conditioned media of MCF10DCIS.com cells undergoing apoptosis. These data suggest that signals arising from the outside (microenvironmental) and inside (internal genetic alterations) of the duct act in concert to trigger apoptosis of myoepithelial and luminal epithelial cells. Our findings implicate spontaneous apoptosis in both the etiol. and progression of comedo-DCIS. It is possible that spontaneous apoptosis facilitates elimination of cells thus permitting expansion and malignant transformation of cancer cells that are resistant to spontaneous apoptosis.
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    22. 22
      McElwee, J. L.; Mohanan, S.; Griffith, O. L.; Breuer, H. C.; Anguish, L. J.; Cherrington, B. D.; Palmer, A. M.; Howe, L. R.; Subramanian, V.; Causey, C. P.; Identification of PADI2 as a Potential Breast Cancer Biomarker and Therapeutic Target. BMC Cancer 2012.  DOI: 10.1186/1471-2407-12-500 .
      There is no corresponding record for this reference.
    23. 23
      Vidavsky, N.; Kunitake, J. A.; Chiou, A. E.; Northrup, P. A.; Porri, T. J.; Ling, L.; Fischbach, C.; Estroff, L. A. Studying Biomineralization Pathways in a 3D Culture Model of Breast Cancer Microcalcifications. Biomaterials 2018, 179, 71– 82,  DOI: 10.1016/j.biomaterials.2018.06.030
      There is no corresponding record for this reference.
    24. 24
      DelNero, P.; Lane, M.; Verbridge, S. S.; Kwee, B.; Kermani, P.; Hempstead, B.; Stroock, A.; Fischbach, C. 3D Culture Broadly Regulates Tumor Cell Hypoxia Response and Angiogenesis via Pro-Inflammatory Pathways. Biomaterials 2015, 55, 110– 118,  DOI: 10.1016/j.biomaterials.2015.03.035
      24
      3D culture broadly regulates tumor cell hypoxia response and angiogenesis via pro-inflammatory pathways
      DelNero, Peter; Lane, Maureen; Verbridge, Scott S.; Kwee, Brian; Kermani, Pouneh; Hempstead, Barbara; Stroock, Abraham; Fischbach, Claudia
      Biomaterials (2015), 55 (), 110-118CODEN: BIMADU; ISSN:0142-9612. (Elsevier Ltd.)
      Oxygen status and tissue dimensionality are crit. determinants of tumor angiogenesis, a hallmark of cancer and an enduring target for therapeutic intervention. However, it is unclear how these microenvironmental conditions interact to promote neovascularization, due in part to a lack of comprehensive, unbiased data sets describing tumor cell gene expression as a function of oxygen levels within three-dimensional (3D) culture. Here, we utilized alginate-based, oxygen-controlled 3D tumor models to study the interdependence of culture context and the hypoxia response. Microarray gene expression anal. of tumor cells cultured in 2D vs. 3D under ambient or hypoxic conditions revealed striking interdependence between culture dimensionality and hypoxia response, which was mediated in part by pro-inflammatory signaling pathways. In particular, interleukin-8 (IL-8) emerged as a major player in the microenvironmental regulation of the hypoxia program. Notably, this interaction between dimensionality and oxygen status via IL-8 increased angiogenic sprouting in a 3D endothelial invasion assay. Taken together, our data suggest that pro-inflammatory pathways are crit. regulators of tumor hypoxia response within 3D environments that ultimately impact tumor angiogenesis, potentially providing important therapeutic targets. Furthermore, these results highlight the importance of pathol. relevant tissue culture models to study the complex phys. and chem. processes by which the cancer microenvironment mediates new vessel formation.
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    25. 25
      Kang, H. S.; Lee, S. C.; Park, Y. S.; Jeon, Y. E.; Lee, J. H.; Jung, S. Y.; Park, I. H.; Jang, S. H.; Park, H. M.; Yoo, C. W. Protein and Lipid MALDI Profiles Classify Breast Cancers According to the Intrinsic Subtype. BMC Cancer 2011, 11 (1), 465,  DOI: 10.1186/1471-2407-11-465
      There is no corresponding record for this reference.
    26. 26
      Kawashima, M.; Iwamoto, N.; Kawaguchi-Sakita, N.; Sugimoto, M.; Ueno, T.; Mikami, Y.; Terasawa, K.; Sato, T. A.; Tanaka, K.; Shimizu, K. High-Resolution Imaging Mass Spectrometry Reveals Detailed Spatial Distribution of Phosphatidylinositols in Human Breast Cancer. Cancer Sci. 2013, 104 (10), 1372– 1379,  DOI: 10.1111/cas.12229
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      High-resolution imaging mass spectrometry reveals detailed spatial distribution of phosphatidylinositols in human breast cancer
      Kawashima, Masahiro; Iwamoto, Noriko; Kawaguchi-Sakita, Nobuko; Sugimoto, Masahiro; Ueno, Takayuki; Mikami, Yoshiki; Terasawa, Kazuya; Sato, Taka-Aki; Tanaka, Koichi; Shimizu, Kazuharu; Toi, Masakazu
      Cancer Science (2013), 104 (10), 1372-1379CODEN: CSACCM; ISSN:1349-7006. (Wiley-Blackwell)
      High-resoln. matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI IMS) is an emerging application for lipid research that provides a comprehensive and detailed spatial distribution of ionized mols. Recent lipidomic approach has identified several phospholipids and phosphatidylinositols (PIs) are accumulated in breast cancer tissues and are therefore novel biomarker candidates. Because their distribution and significance remain unclear, we investigated the precise spatial distribution of PIs in human breast cancer tissues using high-resoln. MALDI IMS. We evaluated tissues from nine human breast cancers and one normal mammary gland by neg. ion MALDI IMS at a resoln. of 10 μm. We detected 10 PIs with different fatty acid compns., and their proportions were remarkably variable in the malignant epithelial regions. High-resoln. imaging enabled us to discriminate cancer cell clusters from the adjacent stromal tissue within epithelial regions; moreover, this technique revealed that several PIs were specifically localized to cancer cell clusters. These PIs were heterogeneously distributed within cancer cell clusters, allowing us to identify two different populations of cancer cells that predominantly expressed either PI(18:0/18:1) or PI(18:0/20:3). Tracing the expression level of PIs during cancer cell progression suggested that the latter population is assocd. with the invasion. Our study documents a novel model for phospholipid anal. of breast cancer tissues by using high-resoln. MALDI IMS and identifies candidate PIs that can describe a specific phenotype of cancer cells.
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    27. 27
      Angerer, T. B.; Magnusson, Y.; Landberg, G.; Fletcher, J. S. Lipid Heterogeneity Resulting from Fatty Acid Processing in the Human Breast Cancer Microenvironment Identified by GCIB-ToF-SIMS Imaging. Anal. Chem. 2016, 88 (23), 11946– 11954,  DOI: 10.1021/acs.analchem.6b03884
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      Lipid Heterogeneity Resulting from Fatty Acid Processing in the Human Breast Cancer Microenvironment Identified by GCIB-ToF-SIMS Imaging
      Angerer, Tina B.; Magnusson, Ylva; Landberg, Goeran; Fletcher, John S.
      Analytical Chemistry (Washington, DC, United States) (2016), 88 (23), 11946-11954CODEN: ANCHAM; ISSN:0003-2700. (American Chemical Society)
      Breast cancer is an umbrella term used to describe a collection of different diseases with broad inter- and intra-tumor heterogeneity. Understanding this variation is crit. in order to develop, and precisely prescribe, new treatments. Changes in the lipid metab. of cancerous cells can provide important indications as to the metabolic state of the cells but are difficult to investigate with conventional histol. methods. Due to the introduction of new higher energy (40 kV) gas cluster ion beams (GCIBs) time-of-flight secondary ion mass spectrometry (ToF-SIMS) imaging is now capable of providing information on the distribution of hundreds of mol. species simultaneously on a cellular to sub-cellular scale. GCIB-ToF-SIMS was used to elucidate changes in lipid compn. in 9 breast cancer biopsy samples. Improved mol. signal generation by the GCIB produced location specific information that revealed elevated levels of essential lipids to be related to inflammatory cells in the stroma while cancerous areas are dominated by non-essential fatty acids and a variety of phosphatidylinositol species with further in-tumor variety arising from decreased desaturase activity. These changes in lipid compn. due to different enzyme activity are seemingly independent of oxygen availability and can be linked to favorable cell membrane properties for either proliferation/invasion or drug resistance/survival.
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    28. 28
      Cífková, E.; Holčapek, M.; Lísa, M.; Vrána, D.; Melichar, B.; Študent, V. Lipidomic Differentiation between Human Kidney Tumors and Surrounding Normal Tissues Using HILIC-HPLC/ESI-MS and Multivariate Data Analysis. J. Chromatogr. B: Anal. Technol. Biomed. Life Sci. 2015, 1000, 14– 21,  DOI: 10.1016/j.jchromb.2015.07.011
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      Lipidomic differentiation between human kidney tumors and surrounding normal tissues using HILIC-HPLC/ESI-MS and multivariate data analysis
      Cifkova, Eva; Holcapek, Michal; Lisa, Miroslav; Vrana, David; Melichar, Bohuslav; Student, Vladimir
      Journal of Chromatography B: Analytical Technologies in the Biomedical and Life Sciences (2015), 1000 (), 14-21CODEN: JCBAAI; ISSN:1570-0232. (Elsevier B.V.)
      The characterization of differences among polar lipid classes in tumors and surrounding normal tissues of 20 kidney cancer patients is performed by hydrophilic interaction liq. chromatog. (HILIC) coupled to electrospray ionization mass spectrometry (ESI-MS). The detailed anal. of identified lipid classes using relative abundances of characteristic ions in neg.- and pos.-ion modes is used for the detn. of more than 120 individual lipid species contg. attached fatty acyls of different chain length and double bond no. Lipid species are described using relative abundances, providing a better visualization of lipidomic differences between tumor and normal tissues. The multivariate data anal. methods using unsupervised principal component anal. (PCA) and supervised orthogonal partial least square (OPLS) are used for the characterization of statistically significant differences in identified lipid species. Ten most significant up- and down-regulated lipids in OPLS score plots are also displayed by box plots. A notable increase of relative abundances of lipids contg. four and more double bonds is detected in tumor compared to normal tissues.
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    29. 29
      Hilvo, M.; Denkert, C.; Lehtinen, L.; Muller, B.; Brockmoller, S.; Seppanen-Laakso, T.; Budczies, J.; Bucher, E.; Yetukuri, L.; Castillo, S. Novel Theranostic Opportunities Offered by Characterization of Altered Membrane Lipid Metabolism in Breast Cancer Progression. Cancer Res. 2011, 71 (9), 3236– 3245,  DOI: 10.1158/0008-5472.CAN-10-3894
      There is no corresponding record for this reference.
    30. 30
      Perrotti, F.; Rosa, C.; Cicalini, I.; Sacchetta, P.; Del Boccio, P.; Genovesi, D.; Pieragostino, D. Advances in Lipidomics for Cancer Biomarkers Discovery. Int. J. Mol. Sci. 2016, 17 (12), 1992,  DOI: 10.3390/ijms17121992
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      Advances in lipidomics for cancer biomarkers discovery
      Perrotti, Francesca; Rosa, Consuelo; Cicalini, Ilaria; Sacchetta, Paolo; Del Boccio, Piero; Genovesi, Domenico; Pieragostino, Damiana
      International Journal of Molecular Sciences (2016), 17 (12), 1992/1-1992/26CODEN: IJMCFK; ISSN:1422-0067. (MDPI AG)
      Lipids play crit. functions in cellular survival, proliferation, interaction and death, since they are involved in chem.-energy storage, cellular signaling, cell membranes, and cell-cell interactions. These cellular processes are strongly related to carcinogenesis pathways, particularly to transformation, progression, and metastasis, suggesting the bioactive lipids are mediators of a no. of oncogenic processes. The current review gives a synopsis of a lipidomic approach in tumor characterization; we provide an overview on potential lipid biomarkers in the oncol. field and on the principal lipidomic methodologies applied. The novel lipidomic biomarkers are reviewed in an effort to underline their role in diagnosis, in prognostic characterization and in prediction of therapeutic outcomes. A lipidomic investigation through mass spectrometry highlights new insights on mol. mechanisms underlying cancer disease. This new understanding will promote clin. applications in drug discovery and personalized therapy.
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    31. 31
      Chughtai, K.; Jiang, L.; Greenwood, T. R.; Glunde, K.; Heeren, R. M. A. Mass Spectrometry Images Acylcarnitines, Phosphatidylcholines, and Sphingomyelin in MDA-MB-231 Breast Tumor Models. J. Lipid Res. 2013, 54 (2), 333– 344,  DOI: 10.1194/jlr.M027961
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      Mass spectrometry images acylcarnitines, phosphatidylcholines, and sphingomyelin in MDA-MB-231 breast tumor models
      Chughtai, Kamila; Lu, Jiang; Greenwood, Tiffany R.; Glunde, Kristine; Heeren, Ron M. A.
      Journal of Lipid Research (2013), 54 (2), 333-344CODEN: JLPRAW; ISSN:0022-2275. (American Society for Biochemistry and Molecular Biology, Inc.)
      The lipid compns. of different breast tumor microenvironments are largely unknown due to limitations in lipid imaging techniques. Imaging lipid distributions would enhance our understanding of processes occurring inside growing tumors, such as cancer cell proliferation, invasion, and metastasis. Recent developments in MALDI mass spectrometry imaging (MSI) enable rapid and specific detection of lipids directly from thin tissue sections. In this study, we performed multimodal imaging of acylcarnitines, phosphatidylcholines (PC), a lysophosphatidylcholine (LPC), and a sphingomyelin (SM) from different microenvironments of breast tumor xenograft models, which carried tdTomato red fluorescent protein as a hypoxia-response element-driven reporter gene. The MSI mol. lipid images revealed spatially heterogeneous lipid distributions within tumor tissue. Four of the most-abundant lipid species, namely PC(16:0/16:0), PC(16:0/18:1), PC(18:1/18:1), and PC(18:0/18:1), were localized in viable tumor regions, whereas LPC(16:0/0:0) was detected in necrotic tumor regions. We identified a heterogeneous distribution of palmitoylcarnitine, stearoylcarnitine, PC(16:0/22:1), and SM(d18:1/16:0) sodium adduct, which colocalized primarily with hypoxic tumor regions. For the first time, we have applied a multimodal imaging approach that has combined optical imaging and MALDI-MSI with ion mobility sepn. to spatially localize and structurally identify acylcarnitines and a variety of lipid species present in breast tumor xenograft models.
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    32. 32
      Confocal Raman Microscopy; Dieing, T., Hollricher, O., Toporski, J., Eds.; Springer Berlin Heidelberg: Berlin, Heidelberg, 2011.
      There is no corresponding record for this reference.
    33. 33
      Butler, H. J.; Ashton, L.; Bird, B.; Cinque, G.; Curtis, K.; Dorney, J.; Esmonde-White, K.; Fullwood, N. J.; Gardner, B.; Martin-Hirsch, P. L. Using Raman Spectroscopy to Characterize Biological Materials. Nat. Protoc. 2016, 11 (4), 664– 687,  DOI: 10.1038/nprot.2016.036
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      Using Raman spectroscopy to characterize biological materials
      Butler, Holly J.; Ashton, Lorna; Bird, Benjamin; Cinque, Gianfelice; Curtis, Kelly; Dorney, Jennifer; Esmonde-White, Karen; Fullwood, Nigel J.; Gardner, Benjamin; Martin-Hirsch, Pierre L.; Walsh, Michael J.; McAinsh, Martin R.; Stone, Nicholas; Martin, Francis L.
      Nature Protocols (2016), 11 (4), 664-687CODEN: NPARDW; ISSN:1750-2799. (Nature Publishing Group)
      Raman spectroscopy can be used to measure the chem. compn. of a sample, which can in turn be used to ext. biol. information. Many materials have characteristic Raman spectra, which means that Raman spectroscopy has proven to be an effective anal. approach in geol., semiconductor, materials and polymer science fields. The application of Raman spectroscopy and microscopy within biol. is rapidly increasing because it can provide chem. and compositional information, but it does not typically suffer from interference from water mols. Anal. does not conventionally require extensive sample prepn.; biochem. and structural information can usually be obtained without labeling. In this protocol, we aim to standardize and bring together multiple exptl. approaches from key leaders in the field for obtaining Raman spectra using a microspectrometer. As examples of the range of biol. samples that can be analyzed, we provide instructions for acquiring Raman spectra, maps and images for fresh plant tissue, formalin-fixed and fresh frozen mammalian tissue, fixed cells and biofluids. We explore a robust approach for sample prepn., instrumentation, acquisition parameters and data processing. By using this approach, we expect that a typical Raman expt. can be performed by a nonspecialist user to generate high-quality data for biol. materials anal.
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    34. 34
      Talari, A. C. S.; Movasaghi, Z.; Rehman, S.; Rehman, I. U. Raman Spectroscopy of Biological Tissues. Appl. Spectrosc. Rev. 2015, 50 (1), 46– 111,  DOI: 10.1080/05704928.2014.923902
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      Raman Spectroscopy of Biological Tissues
      Talari, Abdullah Chandra Sekhar; Movasaghi, Zanyar; Rehman, Shazza; Rehman, Ihtesham ur
      Applied Spectroscopy Reviews (2015), 50 (1), 46-111CODEN: APSRBB; ISSN:0570-4928. (Taylor & Francis, Inc.)
      A review. We previously published a comprehensive review paper reviewing the Raman spectroscopy of biol. mols. This research area has expanded rapidly, which warranted an update to the existing review paper by adding the recently reported studies in literature. This article reviews some of the recent advances of Raman spectroscopy in relation to biomedical applications starting from natural tissues to cancer biol. Raman spectroscopy, an optical mol. detective, is a vibrational spectroscopic technique that has potential not only in cancer diagnosis but also in understanding progression of the disease. This article summarizes some of the most widely obsd. peak frequencies and their assignments. The aim of this review is to develop a database of mol. fingerprints, which will facilitate researchers in identifying the chem. structure of the biol. tissues including most of the significant peaks reported both in the normal and cancerous tissues. It has covered a variety of Raman approaches and its quant. and qual. biochem. information. In addn., it covers the use of Raman spectroscopy to analyze a variety of different malignancies including breast, brain, cervical, gastrointestinal, lung, oral, and skin cancer. Multivariate anal. approaches used in these studies have also been covered.
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    35. 35
      Soule, H. D.; Maloney, T. M.; Wolman, S. R.; Peterson, W. D.; Brenz, R.; McGrath, C. M.; Russo, J.; Pauley, R. J.; Jones, R. F.; Brooks, S. C. Isolation and Characterization of a Spontaneously Immortalized Human Breast Epithelial Cell Line, MCF-10. Cancer Res. 1990, 50 (18), 6075– 6086
      35
      Isolation and characterization of a spontaneously immortalized human breast epithelial cell line, MCF-10
      Soule, Herbert D.; Maloney, Terry M.; Wolman, Sandra R.; Peterson, Ward D., Jr.; Brenz, Richard, Jr.; McGrath, Charles M.; Russo, Jose; Pauley, Robert J.; Jones, Richard F.; Brooks, S. C.
      Cancer Research (1990), 50 (18), 6075-86CODEN: CNREA8; ISSN:0008-5472.
      Two sublines of a breast epithelial cell culture, MCF-10, derived from human fibrocystic mammary tissue exhibit immortality after extended cultivation in low calcium concns. (0.03-0.06 mM) and floating transfers in low calcium (MCF-10F), or by trypsin-Versene passages in the customary (normal) calcium levels, 1.05 mM (MCF-10A). Both sublines have been maintained as sep. entities after 2.3 yr (849 days) in vitro and at present have been in culture for longer than 4 yr. MCF-10 has the characteristics of normal breast epithelium by the following criteria: (a) lack of tumorigenicity in nude mice; (b) three-dimensional growth in collagen; (c) growth in culture that is controlled by hormones and growth factors; (d) lack of anchorage-independent growth; and (e) dome formation in confluent cultures. Cytogenetic anal. prior to immortalization showed normal diploid cells; although later passages showed minimal rearrangement and near-diploidy, the immortal cells were not karyotypically normal. The emergence of an immortal culture in normal calcium media was not an inherent characteristic of the original tissue from which MCF-10 was derived since reactivated cryo-preserved cells from cultures grown for 0.3 to 1.2 yr in low calcium were incapable of sustained growth in normal calcium.
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    36. 36
      Miller, F. R.; Santner, S. J.; Tait, L.; Dawson, P. J. MCF10DCIS.Com Xenograft Model of Human Comedo Ductal Carcinoma in Situ. J. Natl. Cancer Inst. 2000, 92 (14), 1185– 1186,  DOI: 10.1093/jnci/92.14.1185a
      36
      MCF10DCIS.com xenograft model of human comedo ductal carcinoma in situ
      Miller F R; Santner S J; Tait L; Dawson P J
      Journal of the National Cancer Institute (2000), 92 (14), 1185-6 ISSN:0027-8874.
      There is no expanded citation for this reference.
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    37. 37
      Barnabas, N.; Cohen, D. Phenotypic and Molecular Characterization of MCF10DCIS and SUM Breast Cancer Cell Lines. Int. J. Breast Cancer 2013, 2013, 872743,  DOI: 10.1155/2013/872743
      37
      Phenotypic and Molecular Characterization of MCF10DCIS and SUM Breast Cancer Cell Lines
      Barnabas Nandita; Cohen Dalia
      International journal of breast cancer (2013), 2013 (), 872743 ISSN:2090-3170.
      We reviewed the phenotypic and molecular characteristics of MCF10DCIS.com and the SUM cell lines based on numerous studies performed over the years. The major signaling pathways that give rise to the phenotype of these cells may serve as a good resource of information when researchers in drug discovery and development use these cells to identify novel targets and biomarkers. Major signaling pathways and mutations affecting the coding sequence are also described providing important information when using these cells as a model in a variety of studies.
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    38. 38
      Santner, S. J.; Dawson, P. J.; Tait, L.; Soule, H. D.; Eliason, J.; Mohamed, A. N.; Wolman, S. R.; Heppner, G. H.; Miller, F. R. Malignant MCF10CA1 Cell Lines Derived from Premalignant Human Breast Epithelial MCF10AT Cells. Breast Cancer Res. Treat. 2001, 65 (2), 101– 110,  DOI: 10.1023/A:1006461422273
      38
      Malignant MCF10CA1 cell lines derived from premalignant human breast epithelial MCF10AT cells
      Santner S J; Dawson P J; Tait L; Soule H D; Eliason J; Mohamed A N; Wolman S R; Heppner G H; Miller F R
      Breast cancer research and treatment (2001), 65 (2), 101-10 ISSN:0167-6806.
      The MCF10 series of cell lines was derived from benign breast tissue from a woman with fibrocystic disease. The MCF10 human breast epithelial model system consists of mortal MCF10M and MCF10MS (mortal cells grown in serum-free and serum-containing media, respectively), immortalized but otherwise normal MCF10F and MCF10A lines (free-floating versus growth as attached cells), transformed MCF10AneoT cells transfected with T24 Ha-ras, and premalignant MCF10AT cells with potential for neoplastic progression. The MCF10AT, derived from xenograft-passaged MCF10-AneoT cells, generates carcinomas in approximately 25% of xenografts. We now report the derivation of fully malignant MCF10CA1 lines that complete the spectrum of progression from relatively normal breast epithelial cells to breast cancer cells capable of metastasis. MCF10CA1 lines display histologic variations ranging from undifferentiated carcinomas, sometimes with focal squamous differentiation, to well-differentiated adenocarcinomas. At least two metastasize to the lung following injection of cells into the tail vein; one line grows very rapidly in the lung, with animals moribund within 4 weeks, whereas the other requires 15 weeks to reach the same endpoint. In addition to variations in efficiency of tumor production, the MCF10CA1 lines show differences in morphology in culture, anchorage-independent growth, karyotype, and immunocytochemistry profiles. The MCF10 model provides a unique tool for the investigation of molecular changes during progression of human breast neoplasia and the generation of tumor heterogeneity on a common genetic background.
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    39. 39
      Alo, P. L.; Visca, P.; Marci, A.; Mangoni, A.; Botti, C.; Di Tondo, U. Expression of Fatty Acid Synthase (FAS) as a Predictor of Recurrence in Stage I Breast Carcinoma Patients. Cancer 1996, 77 (3), 474– 482,  DOI: 10.1002/(SICI)1097-0142(19960201)77:3<474::AID-CNCR8>3.0.CO;2-K
      39
      Expression of fatty acid synthase (FAS) as a predictor of recurrence in stage I breast carcinoma patients
      Alo, Piero L.; Visca, Paolo; Marci, Adele; Mangoni, Antonella; Botti, Claudio; Di Tondo, Ugo
      Cancer (New York) (1996), 77 (3), 474-82CODEN: CANCAR; ISSN:0008-543X. (Wiley-Liss)
      Fatty acid synthase (FAS) is a mol. found in tumor cells from breast carcinomas of patients whose prognosis is very poor. Recently, this mol. has been identified as the key enzyme in fatty acid biosynthesis. This study was done to test the strength of FAS as a prognostic indicator for disease free survival (DFS) and overall survival (OS). Clin. records, histol. features, immunohistochem. expression of cathepsin D and c-erbB-2, and estrogen and progesterone receptor status of 110 Stage I breast carcinoma patients were all assocd. with FAS by a chi-square test. The patterns of DFS and OS were estd. over a ten-year follow-up period using the Kaplan-Meier method. Univariate and multivariate anal. were evaluated using a log logistic regression model. Multivariate regression anal. was based on the Cox proportional hazard model. To detect FAS, cathepsin D and c-erbB-2 expression as well as estrogen and progesterone receptor status, the authors used the unlabeled immunoperoxidase technique on formalin fixed, paraffin embedded tissue. FAS was significantly assocd. with a higher risk of recurrence because it predicted both DFS and OS when evaluated as a continuous variable and DFS when evaluated with other prognostic markers. Peritumoral lymphatic vessel invasion was the other most significant independent predictor for DFS and OS. FAS is a reliable prognostic marker to predict DFS and OS in patients with early breast cancer.
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    40. 40
      Milgraum, L. Z.; Witters, L. A.; Pasternack, G. R.; Kuhajda, F. P. Enzymes of the Fatty Acid Synthesis Pathway Are Highly Expressed in in Situ Breast Carcinoma. Clin. Cancer Res. 1997, 3 (11), 2115– 2120
      40
      Enzymes of the fatty acid synthesis pathway are highly expressed in in situ breast carcinoma
      Milgraum, Lea Z.; Witters, Lee A.; Pasternack, Gary R.; Kuhajda, Francis P.
      Clinical Cancer Research (1997), 3 (11), 2115-2120CODEN: CCREF4; ISSN:1078-0432. (American Association for Cancer Research)
      Expression of high levels of fatty acid synthase (FAS), an important enzyme in fatty acid synthesis, has been identified in a wide variety of human carcinomas. In breast and prostate carcinoma, FAS expression appears to be assocd. with aggressive disease. Recent biochem. studies have demonstrated that FAS expression in cancer cells connotes activation of the entire fatty acid synthesis pathway leading to the prodn. of palmitic acid. Here, we explore the immunohistochem. expression of FAS and human acetyl-CoA carboxylase (HACC), the rate-limiting enzyme in fatty acid synthesis, in breast cancer progression from histol. normal breast through the development of in situ duct and lobular carcinoma to infiltrating carcinoma. Both FAS and the Mr 275,000 isoform of HACC are expressed in a small subset of cells in normal breast lobules and terminal ducts. Upon development of either in situ duct or lobular carcinoma, FAS and both isoforms of HACC are expressed at higher levels and in a majority of the cells. These findings suggest that expression of the enzymes of fatty acid synthesis are frequently altered early in the progression of human breast carcinoma.
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    41. 41
      Menendez, J. A.; Lupu, R. Fatty Acid Synthase and the Lipogenic Phenotype in Cancer Pathogenesis. Nat. Rev. Cancer 2007, 7 (10), 763– 777,  DOI: 10.1038/nrc2222
      41
      Fatty acid synthase and the lipogenic phenotype in cancer pathogenesis
      Menendez, Javier A.; Lupu, Ruth
      Nature Reviews Cancer (2007), 7 (10), 763-777CODEN: NRCAC4; ISSN:1474-175X. (Nature Publishing Group)
      A review. Fatty acid synthase (FASN) catalyzes the synthesis of fatty acids, and this synthetic pathway is upregulated in many tumors. How might FASN and increased lipogenesis be involved in cancer, and is FASN a valid therapeutic target. There is a renewed interest in the ultimate role of fatty acid synthase (FASN) - a key lipogenic enzyme catalyzing the terminal steps in the de novo biogenesis of fatty acids - in cancer pathogenesis. Tumor-assocd. FASN, by conferring growth and survival advantages rather than functioning as an anabolic energy-storage pathway, appears to necessarily accompany the natural history of most human cancers. A recent identification of cross-talk between FASN and well-established cancer-controlling networks begins to delineate the oncogenic nature of FASN-driven lipogenesis. FASN, a nearly-universal druggable target in many human carcinomas and their precursor lesions, offers new therapeutic opportunities for metabolically treating and preventing cancer.
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    42. 42
      Ghosh, C.; Nandi, S.; Bhattacharyya, K. Probing Micro-Environment of Lipid Droplets in a Live Breast Cell: MCF7 and MCF10A. Chem. Phys. Lett. 2017, 670, 27– 31,  DOI: 10.1016/j.cplett.2016.12.068
      42
      Probing micro-environment of lipid droplets in a live breast cell: MCF7 and MCF10A
      Ghosh, Catherine; Nandi, Somen; Bhattacharyya, Kankan
      Chemical Physics Letters (2017), 670 (), 27-31CODEN: CHPLBC; ISSN:0009-2614. (Elsevier B.V.)
      Local environment of the lipid droplets inside the breast cancer cells, MCF7 and in non-malignant breast cells, MCF10A is monitored using time-resolved confocal microscopy. For this study, a coumarin-based dye C153 has been used. The local polarity and the solvation dynamics indicate that a cytoplasmic lipid droplet is less polar and displays slower solvation dynamics compared to the cytosol. Significant differences in terms of no. of lipid droplets, polarity and solvation dynamics are obsd. between the cancer cell (MCF7) and its non-malignant cell (MCF10A).
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    43. 43
      Wilmanski, T.; Buhman, K.; Donkin, S. S.; Burgess, J. R.; Teegarden, D. 1α,25-Dihydroxyvitamin D Inhibits de Novo Fatty Acid Synthesis and Lipid Accumulation in Metastatic Breast Cancer Cells through down-Regulation of Pyruvate Carboxylase. J. Nutr. Biochem. 2017, 40, 194– 200,  DOI: 10.1016/j.jnutbio.2016.11.006
      43
      1α,25-dihydroxyvitamin D inhibits de novo fatty acid synthesis and lipid accumulation in metastatic breast cancer cells through down-regulation of pyruvate carboxylase
      Wilmanski, Tomasz; Buhman, Kimberly; Donkin, Shawn S.; Burgess, John R.; Teegarden, Dorothy
      Journal of Nutritional Biochemistry (2017), 40 (), 194-200CODEN: JNBIEL; ISSN:0955-2863. (Elsevier)
      Both increased de novo fatty acid synthesis and higher neutral lipid accumulation are a common phenotype obsd. in aggressive breast cancer cells, making lipid metab. a promising target for breast cancer prevention. In the present studies, we demonstrate a novel effect of the active metabolite of vitamin D, 1α,25-dihydroxyvitamin D (1,25(OH)2D) on lipid metab. in malignant breast epithelial cells. Treatment of MCF10CA1a breast epithelial cells with 1,25(OH)2D (10 nM) for 5 and 7 days decreased the level of triacylglycerol, the most abundant form of neutral lipids, by 20%(±3.9) and 50%(±5.9), resp. In addn., 1,25(OH)2D treatment for 5 days decreased palmitate synthesis from glucose, the major fatty acid synthesized de novo (48% ± 5.5 relative to vehicle). We have further identified the anaplerotic enzyme pyruvate carboxylase (PC) as a target of 1,25(OH)2D-mediated regulation and hypothesized that 1,25(OH)2D regulates breast cancer cell lipid metab. through inhibition of PC. PC mRNA expression was down-regulated with 1,25(OH)2D treatment at 2 (73% ± 6 relative to vehicle) and 5 (56% ± 8 relative to vehicle) days. Decrease in mRNA abundance corresponded with a decrease in PC protein expression at 5 days of treatment (54% ± 12 relative to vehicle). Constitutive overexpression of PC in MCF10CA1a cells using a pCMV6-PC plasmid inhibited the effect of 1,25(OH)2D on both TAG accumulation and de novo palmitate synthesis from glucose. Together, these studies demonstrate a novel mechanism through which 1,25(OH)2D regulates lipid metab. in malignant breast epithelial cells.
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    44. 44
      Liu, X.; Kim, C. N.; Yang, J.; Jemmerson, R.; Wang, X. Induction of Apoptotic Program in Cell-Free Extracts: Requirement for DATP and Cytochrome C. Cell 1996, 86 (1), 147– 157,  DOI: 10.1016/S0092-8674(00)80085-9
      44
      Induction of apoptotic program in cell-free extracts: requirement for dATP and cytochrome c
      Liu, Xuesong; Kim, Caryn Naekyung; Yang, Jie; Jemmerson, Ronald; Wang, Xiaodong
      Cell (Cambridge, Massachusetts) (1996), 86 (1), 147-157CODEN: CELLB5; ISSN:0092-8674. (Cell Press)
      A cell-free system based on cytosols of normally growing cells was established that reproduces aspects of the apoptotic program in vitro. The apoptotic program was initiated by the addn. of dATP. Fractionation of cytosol yielded a 15-kDa protein that was required for in vitro apoptosis. The absorption spectrum and protein sequence revealed that this protein is cytochrome c. Elimination of cytochrome c from cytosol by immunodepletion, or inclusion of sucrose to stabilize mitochondria during cytosol prepn., diminished the apoptotic activity. Adding cytochrome c back to the cytochrome c-depleted exts. restored their apoptotic activity. Cells undergoing apoptosis in vivo showed increased release of cytochrome c to their cytosol, suggesting that mitochondria may function in apoptosis by releasing cytochrome c.
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    45. 45
      Rygula, A.; Majzner, K.; Marzec, K. M.; Kaczor, A.; Pilarczyk, M.; Baranska, M. Raman Spectroscopy of Proteins: A Review. J. Raman Spectrosc. 2013, 44 (8), 1061– 1076,  DOI: 10.1002/jrs.4335
      45
      Raman spectroscopy of proteins: a review
      Rygula, A.; Majzner, K.; Marzec, K. M.; Kaczor, A.; Pilarczyk, M.; Baranska, M.
      Journal of Raman Spectroscopy (2013), 44 (8), 1061-1076CODEN: JRSPAF; ISSN:0377-0486. (John Wiley & Sons Ltd.)
      A review. In this work, 26 proteins of different structure, function and properties are investigated by Raman spectroscopy with 488, 532 and 1064 nm laser lines. The excitation lines were chosen in NIR and Vis range as the most common and to show the difference due to normal and resonance effect, sometimes accompanied by the fluorescence. The selected proteins were divided, according to the Structural Classification of Proteins, into four classes according to their secondary structure, i.e. α-helical (α), β-sheet (β), mixed structures (α/β, α + β, s) and others. For all compds., FT-Raman and two Vis spectra are presented along with the detailed band assignment. To the best of our knowledge, this is the first review showing the potential of Raman spectroscopy for the measurement and anal. of such a large collection of individual proteins. This work can serve as a comprehensive vibrational spectra library, based on our and previous Raman measurements. Copyright © 2013 John Wiley & Sons, Ltd.
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    46. 46
      Ogretmen, B. Sphingolipid Metabolism in Cancer Signalling and Therapy. Nat. Rev. Cancer 2017, 18 (1), 33– 50,  DOI: 10.1038/nrc.2017.96
      There is no corresponding record for this reference.
    47. 47
      Kenny, P. A.; Lee, G. Y.; Myers, C. A.; Neve, R. M.; Semeiks, J. R.; Spellman, P. T.; Lorenz, K.; Lee, E. H.; Barcellos-Hoff, M. H.; Petersen, O. W. The Morphologies of Breast Cancer Cell Lines in Three-Dimensional Assays Correlate with Their Profiles of Gene Expression. Mol. Oncol. 2007, 1 (1), 84– 96,  DOI: 10.1016/j.molonc.2007.02.004
      47
      The morphologies of breast cancer cell lines in three-dimensional assays correlate with their profiles of gene expression
      Kenny, Paraic A.; Lee, Genee Y.; Myers, Connie A.; Neve, Richard M.; Semeiks, Jeremy R.; Spellman, Paul T.; Lorenz, Katrin; Lee, Eva H.; Barcellos-Hoff, Mary Helen; Petersen, Ole W.; Gray, Joe W.; Bissell, Mina J.
      Molecular Oncology (2007), 1 (1), 84-96CODEN: MOONC3; ISSN:1574-7891. (Elsevier B.V.)
      3D cell cultures are rapidly becoming the method of choice for the physiol. relevant modeling of many aspects of non-malignant and malignant cell behavior ex vivo. Nevertheless, only a limited no. of distinct cell types have been evaluated in this assay to date. Here we report the first large scale comparison of the transcriptional profiles and 3D cell culture phenotypes of a substantial panel of human breast cancer cell lines. Each cell line adopts a colony morphol. of one of four main classes in 3D culture. These morphologies reflect, at least in part, the underlying gene expression profile and protein expression patterns of the cell lines, and distinct morphologies were also assocd. with tumor cell invasiveness and with cell lines originating from metastases. We further demonstrate that consistent differences in genes encoding signal transduction proteins emerge when even tumor cells are cultured in 3D microenvironments.
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    48. 48
      Nath, S.; Devi, G. R. Three-Dimensional Culture Systems in Cancer Research: Focus on Tumor Spheroid Model. Pharmacol. Ther. 2016, 163, 94– 108,  DOI: 10.1016/j.pharmthera.2016.03.013
      48
      Three-dimensional culture systems in cancer research: Focus on tumor spheroid model
      Nath, Sritama; Devi, Gayathri R.
      Pharmacology & Therapeutics (2016), 163 (), 94-108CODEN: PHTHDT; ISSN:0163-7258. (Elsevier)
      Cancer cells propagated in three-dimensional (3D) culture systems exhibit physiol. relevant cell-cell and cell-matrix interactions, gene expression and signaling pathway profiles, heterogeneity and structural complexity that reflect in vivo tumors. In recent years, development of various 3D models has improved the study of host-tumor interaction and use of high-throughput screening platforms for anti-cancer drug discovery and development. This review attempts to summarize the various 3D culture systems, with an emphasis on the most well characterized and widely applied model - multicellular tumor spheroids. This review also highlights the various techniques to generate tumor spheroids, methods to characterize them, and its applicability in cancer research.
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    49. 49
      Edmondson, R.; Broglie, J. J.; Adcock, A. F.; Yang, L. Three-Dimensional Cell Culture Systems and Their Applications in Drug Discovery and Cell-Based Biosensors. Assay Drug Dev. Technol. 2014, 12 (4), 207– 218,  DOI: 10.1089/adt.2014.573
      49
      Three-Dimensional Cell Culture Systems and Their Applications in Drug Discovery and Cell-Based Biosensors
      Edmondson, Rasheena; Broglie, Jessica Jenkins; Adcock, Audrey F.; Yang, Liju
      Assay and Drug Development Technologies (2014), 12 (4), 207-218CODEN: ADDTAR; ISSN:1540-658X. (Mary Ann Liebert, Inc.)
      A review. Three-dimensional (3D) cell culture systems have gained increasing interest in drug discovery and tissue engineering due to their evident advantages in providing more physiol. relevant information and more predictive data for in vivo tests. In this review, we discuss the characteristics of 3D cell culture systems in comparison to the two-dimensional (2D) monolayer culture, focusing on cell growth conditions, cell proliferation, population, and gene and protein expression profiles. The innovations and development in 3D culture systems for drug discovery over the past 5 years are also reviewed in the article, emphasizing the cellular response to different classes of anticancer drugs, focusing particularly on similarities and differences between 3D and 2D models across the field. The progression and advancement in the application of 3D cell cultures in cell-based biosensors is another focal point of this review.
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    50. 50
      Tauchi-Sato, K.; Ozeki, S.; Houjou, T.; Taguchi, R.; Fujimoto, T. The Surface of Lipid Droplets Is a Phospholipid Monolayer with a Unique Fatty Acid Composition. J. Biol. Chem. 2002, 277 (46), 44507– 44512,  DOI: 10.1074/jbc.M207712200
      50
      The Surface of Lipid Droplets Is a Phospholipid Monolayer with a Unique Fatty Acid Composition
      Tauchi-Sato, Kumi; Ozeki, Shintaro; Houjou, Toshiaki; Taguchi, Ryo; Fujimoto, Toyoshi
      Journal of Biological Chemistry (2002), 277 (46), 44507-44512CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)
      We found that caveolin-2 is targeted to the surface of lipid droplets (Fujimoto, T., Kogo, H., Ishiguro, K., Tauchi, K., and Nomura, R. (2001) J. Cell Biol. 152, 1079-1085) and hypothesized that the lipid droplet surface is a kind of membrane. To elucidate the characteristics of the lipid droplet surface, we isolated lipid droplets from HepG2 cells and analyzed them by cryoelectron microscopy and by mass spectrometry. By use of cryoelectron microscopy at the stage temp. of 4.2 K, the lipid droplet surface was obsd. as a single line without any fixation or staining, indicating the presence of a single layer of phospholipids. This result appeared consistent with the hypothesis that the lipid droplet surface is derived from the cytoplasmic leaflet of the endoplasmic reticulum membrane and may be continuous to it. However, mass spectrometry revealed that the fatty acid compn. of phosphatidylcholine and lysophosphatidylcholine in lipid droplets is different from that of the rough endoplasmic reticulum. The ample presence of free cholesterol in lipid droplets also suggests that their surface is differentiated from the bulk endoplasmic reticulum membrane. On the other hand, although caveolin-2β and adipose differentiation-related protein, both localizing in lipid droplets, were enriched in the low d. floating fraction, the fatty acid compn. of the fraction was distinct from lipid droplets. Collectively, the result indicates that the lipid droplet surface is a hemi-membrane or a phospholipid monolayer contg. cholesterol but is compositionally different from the endoplasmic reticulum membrane or the sphingolipid/cholesterol-rich microdomain.
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    51. 51
      Penno, A.; Hackenbroich, G.; Thiele, C. Phospholipids and Lipid Droplets. Biochim. Biophys. Acta, Mol. Cell Biol. Lipids 2013, 1831 (3), 589– 594,  DOI: 10.1016/j.bbalip.2012.12.001
      51
      Phospholipids and lipid droplets
      Penno, Anke; Hackenbroich, Gregor; Thiele, Christoph
      Biochimica et Biophysica Acta, Molecular and Cell Biology of Lipids (2013), 1831 (3), 589-594CODEN: BBMLFG; ISSN:1388-1981. (Elsevier B. V.)
      A review. Lipid droplets are ubiquitous cellular organelles that allow cells to store large amts. of neutral lipids for membrane synthesis and energy supply in times of starvation. Compared to other cellular organelles, lipid droplets are structurally unique as they are made of a hydrophobic core of neutral lipids and are sepd. to the cytosol only by a surrounding phospholipid monolayer. This phospholipid monolayer consists of over a hundred different phospholipid mol. species of which phosphatidylcholine is the most abundant lipid class. However, lipid droplets lack some indispensable activities of the phosphatidylcholine biogenic pathways suggesting that they partially depend on other organelles for phosphatidylcholine synthesis. Here, the authors discuss very recent data on the compn., origin, transport and function of the phospholipid monolayer with a particular emphasis on the phosphatidylcholine metab. on and for lipid droplets. In addn., we highlight two very important quant. aspects: (i) The amt. of phospholipid required for lipid droplet monolayer expansion is remarkably small and (ii) to maintain the invariably round shape of lipid droplets, a cell must have a highly sensitive but so far unknown mechanism that regulates the ratio of phospholipid to neutral lipid in lipid droplets. This article is part of a Special Issue entitled Phospholipids and Phospholipid Metab.
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    52. 52
      Wilfling, F.; Wang, H.; Haas, J. T.; Krahmer, N.; Gould, T. J.; Uchida, A.; Cheng, J.-X.; Graham, M.; Christiano, R.; Fröhlich, F. Triacylglycerol Synthesis Enzymes Mediate Lipid Droplet Growth by Relocalizing from the ER to Lipid Droplets. Dev. Cell 2013, 24 (4), 384– 399,  DOI: 10.1016/j.devcel.2013.01.013
      52
      Triacylglycerol Synthesis Enzymes Mediate Lipid Droplet Growth by Relocalizing from the ER to Lipid Droplets
      Wilfling, Florian; Wang, Huajin; Haas, Joel T.; Krahmer, Natalie; Gould, Travis J.; Uchida, Aki; Cheng, Ji-Xin; Graham, Morven; Christiano, Romain; Frohlich, Florian; Liu, Xinran; Buhman, Kimberly K.; Coleman, Rosalind A.; Bewersdorf, Joerg; Farese, Robert V.; Walther, Tobias C.
      Developmental Cell (2013), 24 (4), 384-399CODEN: DCEEBE; ISSN:1534-5807. (Cell Press)
      Lipid droplets (LDs) store metabolic energy and membrane lipid precursors. With excess metabolic energy, cells synthesize triacylglycerol (TG) and form LDs that grow dramatically. It is unclear how TG synthesis relates to LD formation and growth. Here, we identify two LD subpopulations: smaller LDs of relatively const. size, and LDs that grow larger. The latter population contains isoenzymes for each step of TG synthesis. Glycerol-3-phosphate acyltransferase 4 (GPAT4), which catalyzes the first and rate-limiting step, relocalizes from the endoplasmic reticulum (ER) to a subset of forming LDs, where it becomes stably assocd. ER-to-LD targeting of GPAT4 and other LD-localized TG synthesis isoenzymes is required for LD growth. Key features of GPAT4 ER-to-LD targeting and function in LD growth are conserved between Drosophila and mammalian cells. Our results explain how TG synthesis is coupled with LD growth and identify two distinct LD subpopulations based on their capacity for localized TG synthesis.
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    53. 53
      Mouritsen, O. G.; Bagatolli, L. A. Life-as a Matter of Fat, 2nd ed.; Springer-Verlag: Heidelberg, 2005.
      There is no corresponding record for this reference.
    54. 54
      Walther, T. C.; Farese, R. V. The Life of Lipid Droplets. Biochim. Biophys. Acta, Mol. Cell Biol. Lipids 2009, 1791 (6), 459– 466,  DOI: 10.1016/j.bbalip.2008.10.009
      54
      The life of lipid droplets
      Walther, Tobias C.; Farese, Robert V.
      Biochimica et Biophysica Acta, Molecular and Cell Biology of Lipids (2009), 1791 (6), 459-466CODEN: BBMLFG; ISSN:1388-1981. (Elsevier B. V.)
      A review. Lipid droplets are the least characterized of cellular organelles. Long considered simple lipid storage depots, these dynamic and remarkable organelles have recently been implicated in many biol. processes, and investigators are only now beginning to gain insights into their fascinating lives in cells. Here, the authors examine what is known of the life of lipid droplets. The authors review emerging data concerning their cellular biol. and present their thoughts on some of the most salient questions for investigation.
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    55. 55
      Nieman, K. M.; Kenny, H. A.; Penicka, C. V.; Ladanyi, A.; Buell-Gutbrod, R.; Zillhardt, M. R.; Romero, I. L.; Carey, M. S.; Mills, G. B.; Hotamisligil, G. S. Adipocytes Promote Ovarian Cancer Metastasis and Provide Energy for Rapid Tumor Growth. Nat. Med. 2011, 17, 1498– 1503,  DOI: 10.1038/nm.2492
      55
      Adipocytes promote ovarian cancer metastasis and provide energy for rapid tumor growth
      Nieman, Kristin M.; Kenny, Hilary A.; Penicka, Carla V.; Ladanyi, Andras; Buell-Gutbrod, Rebecca; Zillhardt, Marion R.; Romero, Iris L.; Carey, Mark S.; Mills, Gordon B.; Hotamisligil, Goekhan S.; Yamada, S. Diane; Peter, Marcus E.; Gwin, Katja; Lengyel, Ernst
      Nature Medicine (New York, NY, United States) (2011), 17 (11), 1498-1503CODEN: NAMEFI; ISSN:1078-8956. (Nature Publishing Group)
      Intra-abdominal tumors, such as ovarian cancer, have a clear predilection for metastasis to the omentum, an organ primarily composed of adipocytes. Currently, it is unclear why tumor cells preferentially home to and proliferate in the omentum, yet omental metastases typically represent the largest tumor in the abdominal cavities of women with ovarian cancer. We show here that primary human omental adipocytes promote homing, migration and invasion of ovarian cancer cells, and that adipokines including interleukin-8 (IL-8) mediate these activities. Adipocyte-ovarian cancer cell coculture led to the direct transfer of lipids from adipocytes to ovarian cancer cells and promoted in vitro and in vivo tumor growth. Furthermore, coculture induced lipolysis in adipocytes and β-oxidn. in cancer cells, suggesting adipocytes act as an energy source for the cancer cells. A protein array identified upregulation of fatty acid-binding protein 4 (FABP4, also known as aP2) in omental metastases as compared to primary ovarian tumors, and FABP4 expression was detected in ovarian cancer cells at the adipocyte-tumor cell interface. FABP4 deficiency substantially impaired metastatic tumor growth in mice, indicating that FABP4 has a key role in ovarian cancer metastasis. These data indicate adipocytes provide fatty acids for rapid tumor growth, identifying lipid metab. and transport as new targets for the treatment of cancers where adipocytes are a major component of the microenvironment.
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    56. 56
      Nieman, K. M.; Romero, I. L.; Van Houten, B.; Lengyel, E. Adipose Tissue and Adipocytes Support Tumorigenesis and Metastasis. Biochim. Biophys. Acta, Mol. Cell Biol. Lipids 2013, 1831 (10), 1533– 1541,  DOI: 10.1016/j.bbalip.2013.02.010
      56
      Adipose tissue and adipocytes support tumorigenesis and metastasis
      Nieman, Kristin M.; Romero, Iris L.; Van Houten, Bennett; Lengyel, Ernst
      Biochimica et Biophysica Acta, Molecular and Cell Biology of Lipids (2013), 1831 (10), 1533-1541CODEN: BBMLFG; ISSN:1388-1981. (Elsevier B. V.)
      A review. Adipose tissue influences tumor development in two major ways. First, obese individuals have a higher risk of developing certain cancers (endometrial, esophageal, and renal cell cancer). However, the risk of developing other cancers (melanoma, rectal, and ovarian) is not altered by body mass. In obesity, hypertrophied adipose tissue depots are characterized by a state of low grade inflammation. In this activated state, adipocytes and inflammatory cells secrete adipokines and cytokines which are known to promote tumor development. In addn., the adipocyte mediated conversion of androgens to estrogen specifically contributes to the development of endometrial cancer, which shows the greatest relative risk (6.3-fold) increase between lean and obese individuals. Second, many tumor types (gastric, breast, colon, renal, and ovarian) grow in the anatomical vicinity of adipose tissue. During their interaction with cancer cells, adipocytes dedifferentiate into pre-adipocytes or are reprogrammed into cancer-assocd. adipocytes (CAA). CAA secrete adipokines which stimulate the adhesion, migration, and invasion of tumor cells. Cancer cells and CAA also engage in a dynamic exchange of metabolites. Specifically, CAA release fatty acids through lipolysis which are then transferred to cancer cells and used for energy prodn. through β-oxidn. The abundant availability of lipids from adipocytes in the tumor microenvironment, supports tumor progression and uncontrolled growth. Given that adipocytes are a major source of adipokines and energy for the cancer cell, understanding the mechanisms of metabolic symbiosis between cancer cells and adipocytes, should reveal new therapeutic possibilities. This article is part of a Special Issue entitled Lipid Metab. in Cancer.
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    57. 57
      Thiam, A. R.; Farese, R. V.; Walther, T. C. The Biophysics and Cell Biology of Lipid Droplets. Nat. Rev. Mol. Cell Biol. 2013, 14 (12), 775– 786,  DOI: 10.1038/nrm3699
      57
      The biophysics and cell biology of lipid droplets
      Thiam, Abdou Rachid; Farese, Robert V., Jr.; Walther, Tobias C.
      Nature Reviews Molecular Cell Biology (2013), 14 (12), 775-786CODEN: NRMCBP; ISSN:1471-0072. (Nature Publishing Group)
      A review. Lipid droplets are intracellular organelles that are found in most cells, where they have fundamental roles in metab. They function prominently in storing oil-based reserves of metabolic energy and components of membrane lipids. Lipid droplets are the dispersed phase of an oil-in-water emulsion in the aq. cytosol of cells, and the importance of basic biophys. principles of emulsions for lipid droplet biol. is now being appreciated. Because of their unique architecture, with an interface between the dispersed oil phase and the aq. cytosol, specific mechanisms underlie their formation, growth and shrinkage. Such mechanisms enable cells to use emulsified oil when the demands for metabolic energy or membrane synthesis change. The regulation of the compn. of the phospholipid surfactants at the surface of lipid droplets is crucial for lipid droplet homeostasis and protein targeting to their surfaces.
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    58. 58
      Pelletier, J.; Bellot, G.; Gounon, P.; Lacas-Gervais, S.; Pouysségur, J.; Mazure, N. M. Glycogen Synthesis Is Induced in Hypoxia by the Hypoxia-Inducible Factor and Promotes Cancer Cell Survival. Front. Oncol. 2012, 2, 18,  DOI: 10.3389/fonc.2012.00018
      58
      Glycogen Synthesis is Induced in Hypoxia by the Hypoxia-Inducible Factor and Promotes Cancer Cell Survival
      Pelletier Joffrey; Bellot Gregory; Gounon Pierre; Lacas-Gervais Sandra; Pouyssegur Jacques; Mazure Nathalie M
      Frontiers in oncology (2012), 2 (), 18 ISSN:.
      The hypoxia-inducible factor 1 (HIF-1), in addition to genetic and epigenetic changes, is largely responsible for alterations in cell metabolism in hypoxic tumor cells. This transcription factor not only favors cell proliferation through the metabolic shift from oxidative phosphorylation to glycolysis and lactic acid production but also stimulates nutrient supply by mediating adaptive survival mechanisms. In this study we showed that glycogen synthesis is enhanced in non-cancer and cancer cells when exposed to hypoxia, resulting in a large increase in glycogen stores. Furthermore, we demonstrated that the mRNA and protein levels of the first enzyme of glycogenesis, phosphoglucomutase1 (PGM1), were increased in hypoxia. We showed that induction of glycogen storage as well as PGM1 expression were dependent on HIF-1 and HIF-2. We established that hypoxia-induced glycogen stores are rapidly mobilized in cells that are starved of glucose. Glycogenolysis allows these "hypoxia-preconditioned" cells to confront and survive glucose deprivation. In contrast normoxic control cells exhibit a high rate of cell death following glucose removal. These findings point to the important role of hypoxia and HIF in inducing mechanisms of rapid adaptation and survival in response to a decrease in oxygen tension. We propose that a decrease in pO(2) acts as an "alarm" that prepares the cells to face subsequent nutrient depletion and to survive.
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    59. 59
      Pescador, N.; Villar, D.; Cifuentes, D.; Garcia-Rocha, M.; Ortiz-Barahona, A.; Vazquez, S.; Ordoñez, A.; Cuevas, Y.; Saez-Morales, D.; Garcia-Bermejo, M. L. Hypoxia Promotes Glycogen Accumulation through Hypoxia Inducible Factor (HIF)-Mediated Induction of Glycogen Synthase 1. PLoS One 2010, 5 (3), e9644  DOI: 10.1371/journal.pone.0009644
      There is no corresponding record for this reference.
    60. 60
      Favaro, E.; Bensaad, K.; Chong, M. G.; Tennant, D. A.; Ferguson, D. J. P.; Snell, C.; Steers, G.; Turley, H.; Li, J.-L.; Günther, U. L. Glucose Utilization via Glycogen Phosphorylase Sustains Proliferation and Prevents Premature Senescence in Cancer Cells. Cell Metab. 2012, 16 (6), 751– 764,  DOI: 10.1016/j.cmet.2012.10.017
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      Glucose Utilization via Glycogen Phosphorylase Sustains Proliferation and Prevents Premature Senescence in Cancer Cells
      Favaro, Elena; Bensaad, Karim; Chong, Mei G.; Tennant, Daniel A.; Ferguson, David J. P.; Snell, Cameron; Steers, Graham; Turley, Helen; Li, Ji-Liang; Guenther, Ulrich L.; Buffa, Francesca M.; McIntyre, Alan; Harris, Adrian L.
      Cell Metabolism (2012), 16 (6), 751-764CODEN: CMEEB5; ISSN:1550-4131. (Elsevier Inc.)
      Metabolic reprogramming of cancer cells provides energy and multiple intermediates crit. for cell growth. Hypoxia in tumors represents a hostile environment that can encourage these transformations. We report that glycogen metab. is upregulated in tumors in vivo and in cancer cells in vitro in response to hypoxia. In vitro, hypoxia induced an early accumulation of glycogen, followed by a gradual decline. Concordantly, glycogen synthase (GYS1) showed a rapid induction, followed by a later increase of glycogen phosphorylase (PYGL). PYGL depletion and the consequent glycogen accumulation led to increased reactive oxygen species (ROS) levels that contributed to a p53-dependent induction of senescence and markedly impaired tumorigenesis in vivo. Metabolic analyses indicated that glycogen degrdn. by PYGL is important for the optimal function of the pentose phosphate pathway. Thus, glycogen metab. is a key pathway induced by hypoxia, necessary for optimal glucose utilization, which represents a targetable mechanism of metabolic adaptation.
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    61. 61
      Okada, M.; Smith, N. I.; Palonpon, A. F.; Endo, H.; Kawata, S.; Sodeoka, M.; Fujita, K. Label-Free Raman Observation of Cytochrome c Dynamics during Apoptosis. Proc. Natl. Acad. Sci. U. S. A. 2012, 109 (1), 28– 32,  DOI: 10.1073/pnas.1107524108
      61
      Label-free Raman observation of cytochrome c dynamics during apoptosis
      Okada, Masaya; Smith, Nicholas Isaac; Palonpon, Almar Flotildes; Endo, Hiromi; Kawata, Satoshi; Sodeoka, Mikiko; Fujita, Katsumasa
      Proceedings of the National Academy of Sciences of the United States of America (2012), 109 (1), 28-32, S28/1-S28/2CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
      We performed label-free observation of mol. dynamics in apoptotic cells by Raman microscopy. Dynamic changes in cytochrome c distribution at the Raman band of 750 cm-1 were obsd. after adding an apoptosis inducer to the cells. The comparison of mitochondria fluorescence images and Raman images of cytochrome c confirmed that changes in cytochrome c distribution can be distinguished as release of cytochrome c from mitochondria. Our observation also revealed that the redox state of cytochrome c was maintained during the release from the mitochondria. Monitoring mitochondrial membrane potential with JC-1 dye confirmed that the obsd. cytochrome c release was assocd. with apoptosis.
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    62. 62
      Vazquez, A.; Kamphorst, J. J.; Markert, E. K.; Schug, Z. T.; Tardito, S.; Gottlieb, E. Cancer Metabolism at a Glance. J. Cell Sci. 2016, 129 (18), 3367– 3373,  DOI: 10.1242/jcs.181016
      62
      Cancer metabolism at a glance
      Vazquez, Alexei; Kamphorst, Jurre J.; Markert, Elke K.; Schug, Zachary T.; Tardito, Saverio; Gottlieb, Eyal
      Journal of Cell Science (2016), 129 (18), 3367-3373CODEN: JNCSAI; ISSN:0021-9533. (Company of Biologists Ltd.)
      A defining hallmark of cancer is uncontrolled cell proliferation. This is initiated once cells have accumulated alterations in signaling pathways that control metab. and proliferation, wherein the metabolic alterations provide the energetic and anabolic demands of enhanced cell proliferation. How these metabolic requirements are satisfied depends, in part, on the tumor microenvironment, which dets. the availability of nutrients and oxygen. In this Cell Science at a Glance paper and the accompanying poster, we summarize our current understanding of cancer metab., emphasizing pathways of nutrient utilization and metab. that either appear or have been proven essential for cancer cells. We also review how this knowledge has contributed to the development of anticancer therapies that target cancer metab.
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    63. 63
      Worgall, T. S. Sphingolipids: Major Regulators of Lipid Metabolism. Curr. Opin. Clin. Nutr. Metab. Care 2007, 10 (2), 149– 155,  DOI: 10.1097/MCO.0b013e328028fda3
      63
      Sphingolipids: major regulators of lipid metabolism
      Worgall, Tilla S.
      Current Opinion in Clinical Nutrition and Metabolic Care (2007), 10 (2), 149-155CODEN: COCMF3; ISSN:1363-1950. (Lippincott Williams & Wilkins)
      A review. Emerging data strongly suggest a role of sphingolipid synthesis in the regulation of transcription factors and regulatory proteins that control cellular lipid homeostasis.
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    64. 64
      Eichmann, T. O.; Lass, A. DAG Tales: The Multiple Faces of Diacylglycerol—stereochemistry, Metabolism, and Signaling. Cell. Mol. Life Sci. 2015, 72 (20), 3931– 3952,  DOI: 10.1007/s00018-015-1982-3
      64
      DAG tales: the multiple faces of diacylglycerol-stereochemistry, metabolism, and signaling
      Eichmann, Thomas Oliver; Lass, Achim
      Cellular and Molecular Life Sciences (2015), 72 (20), 3931-3952CODEN: CMLSFI; ISSN:1420-682X. (Birkhaeuser Basel)
      The neutral lipids diacylglycerols (DAGs) are involved in a plethora of metabolic pathways. They function as components of cellular membranes, as building blocks for glycero(phospho)lipids, and as lipid second messengers. Considering their central role in multiple metabolic processes and signaling pathways, cellular DAG levels require a tight regulation to ensure a const. and controlled availability. Interestingly, DAG species are versatile in their chem. structure. Besides the different fatty acid species esterified to the glycerol backbone, DAGs can occur in three different stereo/regioisoforms, each with unique biol. properties. Recent scientific advances have revealed that DAG metabolizing enzymes generate and distinguish different DAG isoforms, and that only one DAG isoform holds signaling properties. Herein, we review the current knowledge of DAG stereochem. and their impact on cellular metab. and signaling. Further, we describe intracellular DAG turnover and its stereochem. in a 3-pool model to illustrate the spatial and stereochem. sepn. and hereby the diversity of cellular DAG metab.
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    65. 65
      Kadota, M.; Yang, H. H.; Gomez, B.; Sato, M.; Clifford, R. J.; Meerzaman, D.; Dunn, B. K.; Wakefield, L. M.; Lee, M. P. Delineating Genetic Alterations for Tumor Progression in the MCF10A Series of Breast Cancer Cell Lines. PLoS One 2010, 5 (2), e9201  DOI: 10.1371/journal.pone.0009201
      There is no corresponding record for this reference.
    66. 66
      Han, G.; Gupta, S. D.; Gable, K.; Niranjanakumari, S.; Moitra, P.; Eichler, F.; Brown, R. H.; Harmon, J. M.; Dunn, T. M. Identification of Small Subunits of Mammalian Serine Palmitoyltransferase That Confer Distinct Acyl-CoA Substrate Specificities. Proc. Natl. Acad. Sci. U. S. A. 2009, 106 (20), 8186– 8191,  DOI: 10.1073/pnas.0811269106
      There is no corresponding record for this reference.
    67. 67
      Knapp, P.; Baranowski, M.; Knapp, M.; Zabielski, P.; Błachnio-Zabielska, A. U.; Górski, J. Altered Sphingolipid Metabolism in Human Endometrial Cancer. Prostaglandins Other Lipid Mediators 2010, 92 (1–4), 62– 66,  DOI: 10.1016/j.prostaglandins.2010.03.002
      67
      Altered sphingolipid metabolism in human endometrial cancer
      Knapp, Pawel; Baranowski, Marcin; Knapp, Malgorzata; Zabielski, Piotr; Blachnio-Zabielska, Agnieszka U.; Gorski, Jan
      Prostaglandins & Other Lipid Mediators (2010), 92 (1-4), 62-66CODEN: POLMFL; ISSN:1098-8823. (Elsevier)
      There is a growing body of evidence indicating that bioactive sphingolipids play a key role in cancer development, progression and metastasis. However, sphingolipid metab. in malignant tumors is poorly investigated. Therefore, the aim of the present study was to examine the content of selected intermediates of ceramide metab. and the activity of key enzymes of ceramide de novo synthesis and sphingosine-1-phosphate (S1P) prodn. in the endometrial cancer. The specimens of cancer tissue and healthy endometrium were obtained from women undergoing surgery because of the cancer (n = 23) and because of myomas (n = 18), resp. The content of sphinganine, dihydroceramide, ceramide, sphingosine and S1P was measured using high pressure liq. chromatog. The activity of the enzymes was detd. using radioactive substrates. It has been found that the content of each examd. sphingolipid was markedly elevated in the cancer tissue compared with the healthy endometrium. Namely, sphinganine, sphingosine and dihydroceramide by 3-4.6-fold, ceramide and S1P by 1.9- and 1.6-fold, resp. Interestingly, the ratio of S1P to ceramide remained stable. The activity of serine palmitoyltransferase and sphingosine kinase 1 was increased by 2.3- and 2.6-fold, resp. We conclude that endometrial carcinoma is characterized by profound changes in sphingolipid metab. that likely contribute to its progression and chemoresistance.
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    68. 68
      Patra, S. K. Dissecting Lipid Raft Facilitated Cell Signaling Pathways in Cancer. Biochim. Biophys. Acta, Rev. Cancer 2008, 1785 (2), 182– 206,  DOI: 10.1016/j.bbcan.2007.11.002
      68
      Dissecting lipid raft facilitated cell signaling pathways in cancer
      Patra, Samir Kumar
      Biochimica et Biophysica Acta, Reviews on Cancer (2008), 1785 (2), 182-206CODEN: BBACEU; ISSN:0304-419X. (Elsevier Ltd.)
      A review. Cancer is one of the most devastating disorders in our lives. Higher rate of proliferation than death of cells is one of the essential factors for development of cancer. The dynamicity of cell membrane plays some vital roles in cell survival and cell death, including protection, endocytosis, signaling, and increases in mech. stability during cell division, as well as decrease of shear forces during sepn. of two cells after division, and cell sepn. from tissues for cancer metastasis. Within the membrane, there are specialized domains, known as lipid rafts. A raft can coordinate various signaling pathways. Recent data on the proteomics of lipid rafts/caveolae have highlighted the enigmatic role of various signaling proteins in cancer development. Anal. of these data of raft proteome from various tumors, cancer tissues, and cell lines cultured without and with therapeutic agents, as well as from model rafts revealed that there may be two subsets of raft assemblage in cell membrane. One subset of raft is enriched with cholesterol-sphingomyelins-ganglioside-cav-1/Src/EGFR (hereafter, "chol-raft") that is involved in normal cell signaling, and when dysregulated promotes cell transformation and tumor progression; another subset of raft is enriched with ceramide-sphingomyeline-ganglioside-FAS/Ezrin (hereafter, "cer-raft") that generally promotes apoptosis. In view of this, and to focus insight into the cancer cell physiol. caused by the lipid rafts mediated signals and their receptors, and the downstream transmitters, either proliferative (for example, EGF and EGFR) or death-inducing (for example, FASL and FAS), and the precise roles of some therapeutic drugs and endogenous acid sphingomylenase in this scenario in in situ transformation of "chol-raft" into "cer-raft" are summarized and discussed in this contribution.
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    69. 69
      Hannun, Y. A.; Obeid, L. M. Principles of Bioactive Lipid Signalling: Lessons from Sphingolipids. Nat. Rev. Mol. Cell Biol. 2008, 9 (2), 139– 150,  DOI: 10.1038/nrm2329
      69
      Principles of bioactive lipid signalling: lessons from sphingolipids
      Hannun, Yusuf A.; Obeid, Lina M.
      Nature Reviews Molecular Cell Biology (2008), 9 (2), 139-150CODEN: NRMCBP; ISSN:1471-0072. (Nature Publishing Group)
      A review. It has become increasingly difficult to find an area of cell biol. in which lipids do not have important, if not key, roles as signaling and regulatory mols. The rapidly expanding field of bioactive lipids is exemplified by many sphingolipids, such as ceramide, sphingosine, sphingosine-1-phosphate (S1P), ceramide-1-phosphate, and lyso-sphingomyelin, which have roles in the regulation of cell growth, death, senescence, adhesion, migration, inflammation, angiogenesis, and intracellular trafficking. Deciphering the mechanisms of these varied cell functions necessitates an understanding of the complex pathways of sphingolipid metab. and the mechanisms that regulate lipid generation and lipid action.
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXovFOntg%253D%253D&md5=0bee4e560d083ef4c43f7d0b591a0997
    70. 70
      Wallner, S.; Schmitz, G. Plasmalogens the Neglected Regulatory and Scavenging Lipid Species. Chem. Phys. Lipids 2011, 164 (6), 573– 589,  DOI: 10.1016/j.chemphyslip.2011.06.008
      70
      Plasmalogens the neglected regulatory and scavenging lipid species
      Wallner, Stefan; Schmitz, Gerd
      Chemistry and Physics of Lipids (2011), 164 (6), 573-589CODEN: CPLIA4; ISSN:0009-3084. (Elsevier Ltd.)
      A review. Plasmalogens are a class of phospholipids carrying a vinyl ether bond in sn-1 and an ester bond in sn-2 position of the glycerol backbone. Although they are widespread in all tissues and represent up to 18% of the total phospholipid mass in humans, their physiol. function is still poorly understood. The aim of this review is to give an overview over the current knowledge in plasmalogen biol. and pathol. with an emphasis on neglected aspects of their involvement in neurol. and metabolic diseases. Furthermore a better understanding of plasmalogen biol. in health and disease could also lead to the development of better diagnostic and prognostic biomarkers for vascular and metabolic diseases such as obesity and diabetes mellitus, inflammation, neuro-degeneration and cancer.
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    71. 71
      Benjamin, D. I.; Cozzo, A.; Ji, X.; Roberts, L. S.; Louie, S. M.; Mulvihill, M. M.; Luo, K.; Nomura, D. K. Ether Lipid Generating Enzyme AGPS Alters the Balance of Structural and Signaling Lipids to Fuel Cancer Pathogenicity. Proc. Natl. Acad. Sci. U. S. A. 2013, 110 (37), 14912– 14917,  DOI: 10.1073/pnas.1310894110
      71
      Ether lipid generating enzyme AGPS alters the balance of structural and signaling lipids to fuel cancer pathogenicity
      Benjamin, Daniel I.; Cozzo, Alyssa; Ji, Xiaodan; Roberts, Lindsay S.; Louie, Sharon M.; Mulvihill, Melinda M.; Luo, Kunxin; Nomura, Daniel K.
      Proceedings of the National Academy of Sciences of the United States of America (2013), 110 (37), 14912-14917,S14912/1-S14912/9CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
      Aberrant lipid metab. is an established hallmark of cancer cells. In particular, ether lipid levels have been shown to be elevated in tumors, but their specific function in cancer remains elusive. We show here that the metabolic enzyme alkylglyceronephosphate synthase (AGPS), a crit. step in the synthesis of ether lipids, is up-regulated across multiple types of aggressive human cancer cells and primary tumors. We demonstrate that ablation of AGPS in cancer cells results in reduced cell survival, cancer aggressiveness, and tumor growth through altering the balance of ether lipid, fatty acid, eicosanoid, and fatty acid-derived glycerophospholipid metab., resulting in an overall redn. in the levels of several oncogenic signaling lipids. Taken together, our results reveal that AGPS, in addn. to maintaining ether lipids, also controls cellular utilization of fatty acids, favoring the generation of signaling lipids necessary for promoting the aggressive features of cancer.
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    72. 72
      Piano, V.; Benjamin, D. I.; Valente, S.; Nenci, S.; Marrocco, B.; Mai, A.; Aliverti, A.; Nomura, D. K.; Mattevi, A. Discovery of Inhibitors for the Ether Lipid-Generating Enzyme AGPS as Anti-Cancer Agents. ACS Chem. Biol. 2015, 10 (11), 2589– 2597,  DOI: 10.1021/acschembio.5b00466
      There is no corresponding record for this reference.
    73. 73
      Dean, J. M.; Lodhi, I. J. Structural and Functional Roles of Ether Lipids. Protein Cell 2018, 9 (2), 196– 206,  DOI: 10.1007/s13238-017-0423-5
      73
      Structural and functional roles of ether lipids
      Dean, John M.; Lodhi, Irfan J.
      Protein & Cell (2018), 9 (2), 196-206CODEN: PCREFB; ISSN:1674-800X. (Higher Education Press)
      Ether lipids, such as plasmalogens, are peroxisome-derived glycerophospholipids in which the hydrocarbon chain at the sn-1 position of the glycerol backbone is attached by an ether bond, as opposed to an ester bond in the more common diacyl phospholipids. This seemingly simple biochem. change has profound structural and functional implications. Notably, the tendency of ether lipids to form non-lamellar inverted hexagonal structures in model membranes suggests that they have a role in facilitating membrane fusion processes. Ether lipids are also important for the organization and stability of lipid raft microdomains, cholesterol-rich membrane regions involved in cellular signaling. In addn. to their structural roles, a subset of ether lipids are thought to function as endogenous antioxidants, and emerging studies suggest that they are involved in cell differentiation and signaling pathways. Here, we review the biol. of ether lipids and their potential significance in human disorders, including neurol. diseases, cancer, and metabolic disorders.
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    74. 74
      Koivuniemi, A. The Biophysical Properties of Plasmalogens Originating from Their Unique Molecular Architecture. FEBS Lett. 2017, 591 (18), 2700– 2713,  DOI: 10.1002/1873-3468.12754
      74
      The biophysical properties of plasmalogens originating from their unique molecular architecture
      Koivuniemi, Artturi
      FEBS Letters (2017), 591 (18), 2700-2713CODEN: FEBLAL; ISSN:0014-5793. (Wiley-Blackwell)
      A review. Plasmalogens are a unique class of phospholipids that are present in many organisms. Their presence in cell membranes has intrigued researchers for decades due to their unique mol. structure, namely the vinyl-ether bond at the sn-1 position, and their assocn. with brain related disorders. Apparently, based on their amt. in the cell membranes, their function is to provide exclusive structural and dynamical properties to these complex mol. assemblies. Yet, many of their physiol. roles manifested through their biophys. properties have been challenging to identify. In this review, the biophys. properties of plasmalogens are discussed and compared to other lipid species. The role of plasmalogens is examd. in the context of cell membrane function, and some future directions are given.
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    75. 75
      Zeno, W. F.; Baul, U.; Snead, W. T.; DeGroot, A. C. M.; Wang, L.; Lafer, E. M.; Thirumalai, D.; Stachowiak, J. C. Synergy between Intrinsically Disordered Domains and Structured Proteins Amplifies Membrane Curvature Sensing. Nat. Commun. 2018, 9, 4152,  DOI: 10.1038/s41467-018-06532-3
      75
      Synergy between intrinsically disordered domains and structured proteins amplifies membrane curvature sensing
      Zeno Wade F; Snead Wilton T; DeGroot Andre C M; Stachowiak Jeanne C; Baul Upayan; Thirumalai D; Wang Liping; Lafer Eileen M; Stachowiak Jeanne C
      Nature communications (2018), 9 (1), 4152 ISSN:.
      The ability of proteins to sense membrane curvature is essential to cellular function. All known sensing mechanisms rely on protein domains with specific structural features such as wedge-like amphipathic helices and crescent-shaped BAR domains. Yet many proteins that contain these domains also contain large intrinsically disordered regions. Here we report that disordered domains are themselves potent sensors of membrane curvature. Comparison of Monte Carlo simulations with in vitro and live-cell measurements demonstrates that the polymer-like behavior of disordered domains found in endocytic proteins drives them to partition preferentially to convex membrane surfaces, which place fewer geometric constraints on their conformational entropy. Further, proteins containing both structured curvature sensors and disordered regions are more than twice as curvature sensitive as their respective structured domains alone. These findings demonstrate an entropic mechanism of curvature sensing that is independent of protein structure and illustrate how structured and disordered domains can synergistically enhance curvature sensitivity.
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    76. 76
      Huang, C.; Cao, Z.; Ma, J.; Shen, Y.; Bu, Y.; Khoshaba, R.; Shi, G.; Huang, D.; Liao, D.-F.; Ji, H. AKR1B10 Activates Diacylglycerol (DAG) Second Messenger in Breast Cancer Cells. Mol. Carcinog. 2018, 57 (10), 1300– 1310,  DOI: 10.1002/mc.22844
      76
      AKR1B10 activates diacylglycerol (DAG) second messenger in breast cancer cells
      Huang, Chenfei; Cao, Zhe; Ma, Jun; Shen, Yi; Bu, Yiwen; Khoshaba, Ramina; Shi, Guiyuan; Huang, Dan; Liao, Duan-Fang; Ji, Haitao; Jin, Junfei; Cao, Deliang
      Molecular Carcinogenesis (2018), 57 (10), 1300-1310CODEN: MOCAE8; ISSN:0899-1987. (Wiley-Blackwell)
      Aldo-keto reductase 1B10 (AKR1B10) is upregulated in breast cancer and promotes tumor growth and metastasis. However, little is known of the mol. mechanisms of action. Herein we report that AKR1B10 activates lipid second messengers to stimulate cell proliferation. Our data showed that ectopic expression of AKR1B10 in breast cancer cells MCF-7 promoted lipogenesis and enhanced levels of lipid second messengers, including phosphatidylinositol bisphosphate (PIP2), diacylglycerol (DAG), and inositol triphosphate (IP3). In contrast, silencing of AKR1B10 in breast cancer cells BT-20 and colon cancer cells HCT-8 led to decrease of these lipid messengers. Qual. analyses by liq. chromatog.-mass spectrum (LC-MS) revealed that AKR1B10 regulated the cellular levels of total DAG and majority of subspecies. This in turn modulated the phosphorylation of protein kinase C (PKC) isoforms PKCδ (Thr505), PKCμ (Ser744/748), and PKCα/βII (Thr638/641) and activity of the PKC-mediated c-Raf/MEK/ERK signaling cascade. A pan inhibitor of PKC (Go6983) blocked ERK1/2 activation by AKR1B10. In these cells, phospho-p90RSK, phospho-MSK, and Cyclin D1 expression was increased by AKR1B10, and pharmacol. inhibition of the ERK signaling cascade with MEK1/2 inhibitors U0126 and PD98059 eradicated induction of phospho-p90RSK, phospho-MSK, and Cyclin D1. In breast cancer cells, AKR1B10 promoted the clonogenic growth and proliferation of breast cancer cells in two-dimension (2D) and three-dimension (3D) cultures and tumor growth in immunodeficient female nude mice through activation of the PKC/ERK pathway. These data suggest that AKR1B10 stimulates breast cancer cell growth and proliferation through activation of DAG-mediated PKC/ERK signaling pathway.
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    77. 77
      Kunitake, J. A. M. R.; Choi, S.; Nguyen, K. X.; Lee, M. M.; He, F.; Sudilovsky, D.; Morris, P. G.; Jochelson, M. S.; Hudis, C. A.; Muller, D. A. Correlative Imaging Reveals Physiochemical Heterogeneity of Microcalcifications in Human Breast Carcinomas. J. Struct. Biol. 2018, 202 (1), 25– 34,  DOI: 10.1016/j.jsb.2017.12.002
      There is no corresponding record for this reference.

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