Hypoxia, lipids, and cancer: surviving the harsh tumor microenvironment.

Solid tumors typically develop hostile microenvironments characterized by irregular vascularization and poor oxygen (O2) and nutrient supply. Whereas normal cells modulate anabolic and catabolic pathways in response to changes in nutrient availability, cancer cells exhibit unregulated growth even under nutrient scarcity. Recent studies have demonstrated that constitutive activation of growth-promoting pathways results in dependence on unsaturated fatty acids for survival under O2 deprivation. In cancer cells, this dependence represents a critical metabolic vulnerability that could be exploited therapeutically. Here we review how this dependence on unsaturated lipids is affected by the microenvironmental conditions faced by cancer cells.

[1]  M. Sahin,et al.  Loss of the tuberous sclerosis complex tumor suppressors triggers the unfolded protein response to regulate insulin signaling and apoptosis. , 2008, Molecular cell.

[2]  P Vaupel,et al.  Metabolic microenvironment of tumor cells: a key factor in malignant progression. , 2010, Experimental oncology.

[3]  G. Lewis,et al.  Lipid-induced pancreatic β-cell dysfunction: focus on in vivo studies. , 2011, American journal of physiology. Endocrinology and metabolism.

[4]  Pingsheng Liu,et al.  Oleate blocks palmitate-induced abnormal lipid distribution, endoplasmic reticulum expansion and stress, and insulin resistance in skeletal muscle. , 2011, Endocrinology.

[5]  Lee H. Dicker,et al.  Aberrant lipid metabolism disrupts calcium homeostasis causing liver endoplasmic reticulum stress in obesity , 2011, Nature.

[6]  A. Giaccia,et al.  The unique physiology of solid tumors: opportunities (and problems) for cancer therapy. , 1998, Cancer research.

[7]  A. Harris,et al.  Sterol regulatory element binding protein-dependent regulation of lipid synthesis supports cell survival and tumor growth , 2013, Cancer & Metabolism.

[8]  S. Matsuda,et al.  Decrease in Membrane Phospholipid Unsaturation Induces Unfolded Protein Response* , 2010, The Journal of Biological Chemistry.

[9]  A. Mancuso,et al.  Dysregulated mTORC1 renders cells critically dependent on desaturated lipids for survival under tumor-like stress. , 2013, Genes & development.

[10]  M. Pagliassotti,et al.  Saturated fatty acids promote endoplasmic reticulum stress and liver injury in rats with hepatic steatosis. , 2006, Endocrinology.

[11]  E. White,et al.  Hypoxic and Ras-transformed cells support growth by scavenging unsaturated fatty acids from lysophospholipids , 2013, Proceedings of the National Academy of Sciences.

[12]  P. Edwards,et al.  LXRs regulate ER stress and inflammation through dynamic modulation of membrane phospholipid composition. , 2013, Cell metabolism.

[13]  P. Arner.  Lipases in Cachexia , 2011, Science.

[14]  S. Cohen,et al.  ER stress potentiates insulin resistance through PERK-mediated FOXO phosphorylation. , 2013, Genes & development.

[15]  Xianlin Han,et al.  Disruption of endoplasmic reticulum structure and integrity in lipotoxic cell death Published, JLR Papers in Press, September 7, 2006. , 2006, Journal of Lipid Research.

[16]  J. Swinnen,et al.  Lipogenesis and lipolysis: the pathways exploited by the cancer cells to acquire fatty acids. , 2013, Progress in lipid research.

[17]  M. Zwahlen,et al.  Body-mass index and incidence of cancer: a systematic review and meta-analysis of prospective observational studies , 2008, The Lancet.

[18]  D. Ron,et al.  Membrane lipid saturation activates endoplasmic reticulum unfolded protein response transducers through their transmembrane domains , 2013, Proceedings of the National Academy of Sciences.

[19]  Natalia Sovolyova,et al.  Stressed to death - mechanisms of ER stress-induced cell death. , 2014, Biological chemistry.

[20]  D. Sabatini,et al.  Regulation of mTORC1 and its impact on gene expression at a glance , 2013, Journal of Cell Science.

[21]  T. Graeber,et al.  An essential requirement for the SCAP/SREBP signaling axis to protect cancer cells from lipotoxicity. , 2013, Cancer research.

[22]  Qicheng Ma,et al.  Activation of a metabolic gene regulatory network downstream of mTOR complex 1. , 2010, Molecular cell.

[23]  Jonathan S Weissman,et al.  Decay of Endoplasmic Reticulum-Localized mRNAs During the Unfolded Protein Response , 2006, Science.

[24]  Robert V Farese,et al.  Cellular fatty acid metabolism and cancer. , 2013, Cell metabolism.

[25]  Jamey D. Young,et al.  Molecular mechanisms and the role of saturated fatty acids in the progression of non-alcoholic fatty liver disease. , 2013, Progress in lipid research.

[26]  Christian M. Metallo,et al.  Macropinocytosis of protein is an amino acid supply route in Ras-transformed cells , 2013, Nature.

[27]  Christopher B. Newgard,et al.  Molecular and metabolic mechanisms of insulin resistance and β-cell failure in type 2 diabetes , 2008, Nature Reviews Molecular Cell Biology.

[28]  J. Menéndez,et al.  Fatty acid synthase and the lipogenic phenotype in cancer pathogenesis , 2007, Nature Reviews Cancer.

[29]  N. Habib,et al.  Partial characterization of a cDNA for human stearoyl‐CoA desaturase and changes in its mRNA expression in some normal and malignant tissues , 1994, International journal of cancer.

[30]  C. Friedenreich,et al.  Case–Control Study of the Metabolic Syndrome and Metabolic Risk Factors for Endometrial Cancer , 2011, Cancer Epidemiology, Biomarkers & Prevention.

[31]  C. Hetz.  The unfolded protein response: controlling cell fate decisions under ER stress and beyond , 2012, Nature Reviews Molecular Cell Biology.

[32]  B. M. Rasmussen,et al.  Substituting dietary saturated for monounsaturated fat impairs insulin sensitivity in healthy men and women: The KANWU study , 2001, Diabetologia.

[33]  B. Manning,et al.  Common corruption of the mTOR signaling network in human tumors , 2008, Oncogene.

[34]  Claudio R. Santos,et al.  SREBP Activity Is Regulated by mTORC1 and Contributes to Akt-Dependent Cell Growth , 2008, Cell metabolism.

[35]  Michael T. McManus,et al.  IRE1α Cleaves Select microRNAs During ER Stress to Derepress Translation of Proapoptotic Caspase-2 , 2012, Science.

[36]  L. Serra-Majem,et al.  Scientific evidence of interventions using the Mediterranean diet: a systematic review. , 2006, Nutrition reviews.

[37]  K. Mori,et al.  XBP1 mRNA Is Induced by ATF6 and Spliced by IRE1 in Response to ER Stress to Produce a Highly Active Transcription Factor , 2001, Cell.

[38]  E. Lengyel,et al.  Adipose tissue and adipocytes support tumorigenesis and metastasis. , 2013, Biochimica et biophysica acta.

[39]  J. Copland,et al.  Stearoyl-CoA Desaturase 1 Is a Novel Molecular Therapeutic Target for Clear Cell Renal Cell Carcinoma , 2013, Clinical Cancer Research.

[40]  S. Horvath,et al.  EGFR Signaling Through an Akt-SREBP-1–Dependent, Rapamycin-Resistant Pathway Sensitizes Glioblastomas to Antilipogenic Therapy , 2009, Science Signaling.

[41]  Shuichi Kaneko,et al.  Palmitate Induces Insulin Resistance in H4IIEC3 Hepatocytes through Reactive Oxygen Species Produced by Mitochondria , 2009, Journal of Biological Chemistry.

[42]  P. Greengard,et al.  IRE1α induces thioredoxin-interacting protein to activate the NLRP3 inflammasome and promote programmed cell death under irremediable ER stress. , 2012, Cell metabolism.

[43]  Lei Xu,et al.  Normalization of the vasculature for treatment of cancer and other diseases. , 2011, Physiological reviews.

[44]  V. Beral,et al.  Cancer incidence and mortality in relation to body mass index in the Million Women Study: cohort study , 2007, BMJ : British Medical Journal.

[45]  William Y. Kim,et al.  Stearoyl Co-A Desaturase 1 as a ccRCC Therapeutic Target: Death by Stress , 2013, Clinical Cancer Research.

[46]  Clemens Diwoky,et al.  Adipose Triglyceride Lipase Contributes to Cancer-Associated Cachexia , 2011, Science.

[47]  G. Mills,et al.  Adipocytes promote ovarian cancer metastasis and provide energy for rapid tumor growth , 2011, Nature Medicine.

[48]  Wendy A Wells,et al.  Lipoprotein Lipase Links Dietary Fat to Solid Tumor Cell Proliferation , 2011, Molecular Cancer Therapeutics.

[49]  Y. Kimata,et al.  Membrane aberrancy and unfolded proteins activate the endoplasmic reticulum stress sensor Ire1 in different ways , 2011, Molecular biology of the cell.

[50]  R. Coleman,et al.  Comparison of [18 F]fluorocholine and [18 F]fluorodeoxyglucose for positron emission tomography of androgen dependent and androgen independent prostate cancer. , 2002, The Journal of urology.

[51]  T. Iwawaki,et al.  Membrane lipid saturation activates IRE1α without inducing clustering , 2013, Genes to cells : devoted to molecular & cellular mechanisms.

[52]  Benjamin P Tu,et al.  The FAD- and O(2)-dependent reaction cycle of Ero1-mediated oxidative protein folding in the endoplasmic reticulum. , 2002, Molecular cell.

[53]  J. Reynolds,et al.  Cancer Cachexia: Mechanisms and Clinical Implications , 2011, Gastroenterology research and practice.

[54]  T. Hagemann,et al.  The tumor microenvironment at a glance , 2012, Journal of Cell Science.

[55]  G. Tomkin,et al.  Diabetes and the Mediterranean diet: a beneficial effect of oleic acid on insulin sensitivity, adipocyte glucose transport and endothelium-dependent vasoreactivity. , 2000, QJM : monthly journal of the Association of Physicians.

[56]  D. Hess,et al.  Inhibition of StearoylCoA Desaturase Activity Blocks Cell Cycle Progression and Induces Programmed Cell Death in Lung Cancer Cells , 2010, PloS one.

[57]  W. Isaacs,et al.  Peroxisomal branched chain fatty acid β‐oxidation pathway is upregulated in prostate cancer , 2005, The Prostate.

[58]  F. Church,et al.  Mature breast adipocytes promote breast cancer cell motility. , 2012, Experimental and molecular pathology.

[59]  X. Palomer,et al.  Oleate Reverses Palmitate-induced Insulin Resistance and Inflammation in Skeletal Muscle Cells* , 2008, Journal of Biological Chemistry.

[60]  M. Tisdale,et al.  Modulation of adipocyte G-protein expression in cancer cachexia by a lipid-mobilizing factor (LMF) , 2001, British Journal of Cancer.

[61]  George Kuriakose,et al.  The endoplasmic reticulum is the site of cholesterol-induced cytotoxicity in macrophages , 2003, Nature Cell Biology.

[62]  T. Mak,et al.  Regulation of cancer cell metabolism , 2011, Nature Reviews Cancer.

[63]  J. Fargnoli,et al.  Cancer Cell Dependence on Unsaturated Fatty Acids Implicates Stearoyl-CoA Desaturase as a Target for Cancer Therapy , 2011, Molecular Cancer Research.

[64]  D. Ron,et al.  Integrating the mechanisms of apoptosis induced by endoplasmic reticulum stress , 2011, Nature Cell Biology.

[65]  Yiyan Liu,et al.  Dominant uptake of fatty acid over glucose by prostate cells: a potential new diagnostic and therapeutic approach. , 2010, Anticancer research.

[66]  P. Arner,et al.  Mechanism of increased lipolysis in cancer cachexia. , 2007, Cancer research.

[67]  R. Russell,et al.  Increased apoptosis in high-fat diet-induced nonalcoholic steatohepatitis in rats is associated with c-Jun NH2-terminal kinase activation and elevated proapoptotic Bax. , 2008, The Journal of nutrition.

[68]  R. Kaufman,et al.  Endoplasmic reticulum stress and oxidative stress: a vicious cycle or a double-edged sword? , 2007, Antioxidants & redox signaling.

[69]  M. Makuuchi,et al.  Co-ordinate activation of lipogenic enzymes in hepatocellular carcinoma. , 2005, European journal of cancer.

[70]  Tsonwin Hai,et al.  Initiation and execution of lipotoxic ER stress in pancreatic β-cells , 2008, Journal of Cell Science.

[71]  B. Wang,et al.  SCD1 Inhibition Causes Cancer Cell Death by Depleting Mono-Unsaturated Fatty Acids , 2012, PloS one.