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Adipocyte-induced CD36 expression drives ovarian cancer progression and metastasis

Abstract

Ovarian cancer (OvCa) is characterized by widespread and rapid metastasis in the peritoneal cavity. Visceral adipocytes promote this process by providing fatty acids (FAs) for tumour growth. However, the exact mechanism of FA transfer from adipocytes to cancer cells remains unknown. This study shows that OvCa cells co-cultured with primary human omental adipocytes express high levels of the FA receptor, CD36, in the plasma membrane, thereby facilitating exogenous FA uptake. Depriving OvCa cells of adipocyte-derived FAs using CD36 inhibitors and short hairpin RNA knockdown prevented development of the adipocyte-induced malignant phenotype. Specifically, inhibition of CD36 attenuated adipocyte-induced cholesterol and lipid droplet accumulation and reduced intracellular reactive oxygen species (ROS) content. Metabolic analysis suggested that CD36 plays an essential role in the bioenergetic adaptation of OvCa cells in the adipocyte-rich microenvironment and governs their metabolic plasticity. Furthermore, the absence of CD36 affected cellular processes that play a causal role in peritoneal dissemination, including adhesion, invasion, migration and anchorage independent growth. Intraperitoneal injection of CD36-deficient cells or treatment with an anti-CD36 monoclonal antibody reduced tumour burden in mouse xenografts. Moreover, a matched cohort of primary and metastatic human ovarian tumours showed upregulation of CD36 in the metastatic tissues, a finding confirmed in three public gene expression data sets. These results suggest that omental adipocytes reprogram tumour metabolism through the upregulation of CD36 in OvCa cells. Targeting the stromal-tumour metabolic interface via CD36 inhibition may prove to be an effective treatment strategy against OvCa metastasis.

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References

  1. Lengyel E. Ovarian cancer development and metastasis. Am J Pathol. 2010;177:1053–64.

    Article  Google Scholar 

  2. Mwaikambo BR, Yang C, Chemtob S, Hardy P. Hypoxia up-regulates CD36 expression and function via hypoxia-inducible factor-1- and phosphatidylinositol 3-kinase-dependent mechanisms. J Biol Chem. 2009;284:26695–707.

    Article  CAS  Google Scholar 

  3. Tan D, Agarwal R, Kaye SB. Mechanisms of transcoelomic metastasis in ovarian cancer. Lancet. 2006;7:925–34.

    Article  Google Scholar 

  4. Miller KD, Siegel RL, Lin CC, Mariotto AB, Kramer JL, Rowland JH, et al. Cancer treatment and survivorship statistics, 2016. CA Cancer J Clin. 2016;66:271–89.

    Article  Google Scholar 

  5. Sehouli J, Senyuva F, Fotopoulou C, Neumann U, Denkert C, Lichtenegger W, et al. Intra-abdominal tumor dissemination pattern and surgical outcome in 214 patients with primary ovarian cancer. J Surg Oncol. 2009;99:424–7.

    Article  Google Scholar 

  6. Bowtell DD, Bohm S, Ahmed AA, Aspuria PJ, Bast RC, Jr., Beral V, et al. Rethinking ovarian cancer II: reducing mortality from high-grade serous ovarian cancer. Nat Rev Cancer. 2015;15:668–79.

    Article  CAS  Google Scholar 

  7. Eckert MA, Pan S, Hernandez KM, Loth RM, Andrade J, Volchenboum SL, et al. Genomics of ovarian cancer progression reveals diverse metastatic trajectories including intraepithelial metastasis to the fallopian tube. Cancer Discov. 2016;6:1342–51.

    Article  CAS  Google Scholar 

  8. Nieman KM, Kenny HA, Penicka CV, Ladanyi A, Buell-Gutbrod R, Zillhardt M, et al. Adipocytes promote ovarian cancer metastasis and provide energy for rapid tumor growth. Nat Med. 2011;17:1498–503.

    Article  CAS  Google Scholar 

  9. Nieman KM, Romero IL, Van Houten B, Lengyel E. Adipocyte tissue and adipocytes support tumorigenesis and metastasis. Biochim Biophys Acta. 2013;1831:1533–41.

    Article  CAS  Google Scholar 

  10. Romero IL, Mukherjee A, Kenny HA, Litchfield L, Lengyel E. Molecular pathways: trafficking of metabolic resources in the tumor microenvironment. Clin Cancer Res. 2015;21:680–6.

    Article  CAS  Google Scholar 

  11. Abumrad NA, Sfeir Z, Connelly MA, Coburn C. Lipid transporters: membrane transport systems for cholesterol and fatty acids. Curr Opin Clin Nutr Metab Care. 2000;3:255–62.

    Article  CAS  Google Scholar 

  12. Pepino MY, Kuda O, Samovski D, Abumrad NA. Structure-function of CD36 and importance of fatty acid signal transduction in fat metabolism. Annu Rev Nutr. 2014;34:281–303.

    Article  CAS  Google Scholar 

  13. Silverstein RL, Febbraio M. CD36, a scavenger receptor involved in immunity, metabolism, angiogenesis, and behavior. Sci Signal. 2009;2:1–9.

    Article  Google Scholar 

  14. Su X, Abumrad NA. Cellular fatty acid uptake: a pathway under construction. Trends Endocrinol Metab. 2009;20:72–77.

    Article  CAS  Google Scholar 

  15. Coscia F, Watters KM, Curtis M, Eckert MA, Chiang CY, Tyanova S, et al. Integrative proteomic profiling of ovarian cancer cell lines reveals precursor cell associated proteins and functional status. Nat Commun. 2016;7:12645

    Article  CAS  Google Scholar 

  16. Ehehalt R, Füllekrun J, Pohl J, Ring A, Herrmann T, Stremmel W. Translocation of long chain fatty acids across the plasma membrane-lipid rafts and fatty acid transport proteins. Mol Cell Biochem. 2006;284:135–40.

    Article  CAS  Google Scholar 

  17. Thompson BR, Loho S, Bernlohr DA. Fatty acid flux in adipocytes: the in’s and out’s of fat cell lipid trafficking. Mol Cell Endocrinol. 2010;318:24–33.

    Article  CAS  Google Scholar 

  18. Parrales A, Iwakuma T. p53 as a regulator of lipid metabolism in cancer. Int J Mol Sci. 2016;17:2074–84.

    Article  Google Scholar 

  19. Harmon CM, Abumrad NA. Binding of sulfosuccinimidyl fatty acids to adipocyte membrane proteins: isolation and amino-terminal sequence of an 88-kD protein implicated in transport of long-chain fatty acids. J Membr Biol. 1993;133:43–49.

    Article  CAS  Google Scholar 

  20. Santos CR, Schulze A. Lipid metabolism in cancer. FEBS J. 2012;279:2610–23.

    Article  CAS  Google Scholar 

  21. Morgan MJ, Liu ZG. Crosstalk of reactive oxygen species and NF-kappaB signaling. Cell Res. 2011;21:103–15.

    Article  CAS  Google Scholar 

  22. Agrawal S, Febbraio M, Podrez E, Cathcart MK, Stark GR, Chisolm GM. Signal transducer and activator of transcription 1 is required for optimal foam cell formation and atherosclerotic lesion development. Circulation. 2007;115:2939–47.

    Article  CAS  Google Scholar 

  23. Bastie CC, Nahle Z, McLoughlin T, Esser K, Zhang W, Unterman T, et al. FoxO1 stimulates fatty acid uptake and oxidation in muscle cells through CD36-dependent and -independent mechanisms. J Biol Chem. 2005;280:14222–9.

    Article  CAS  Google Scholar 

  24. Baranova IN, Bocharov AV, Vishnyakova TG, Kurlander R, Chen Z, Fu D, et al. CD36 is a novel serum amyloid A (SAA) receptor mediating SAA binding and SAA-induced signaling in human and rodent cells. J Biol Chem. 2010;285:8492–506.

    Article  CAS  Google Scholar 

  25. Janabi M, Yamashita S, Hirano K, Sakai N, Hiraoka H, Matsumoto K, et al. Oxidized LDL-induced NF-kappa B activation and subsequent expression of proinflammatory genes are defective in monocyte-derived macrophages from CD36-deficient patients. Arterioscler Thromb Vasc Biol. 2000;20:1953–60.

    Article  CAS  Google Scholar 

  26. Li W, Febbraio M, Reddy SP, Yu DY, Yamamoto M, Silverstein RL. CD36 participates in a signaling pathway that regulates ROS formation in murine VSMCs. J Clin Invest. 2010;120:3996–4006.

    Article  CAS  Google Scholar 

  27. Samovski D, Sun J, Pietka T, Gross RW, Eckel RH, Su X, et al. Regulation of AMPK activation by CD36 links fatty acid uptake to beta-oxidation. Diabetes. 2015;64:353–9.

    Article  CAS  Google Scholar 

  28. Cho S, Park EM, Febbraio M, Anrather J, Park L, Racchumi G, et al. The class B scavenger receptor CD36 mediates free radical production and tissue injury in cerebral ischemia. J Neurosci. 2005;25:2504–12.

    Article  CAS  Google Scholar 

  29. Coraci IS, Husemann J, Berman JW, Hulette C, Dufour JH, Campanella GK, et al. CD36, a class B scavenger receptor, is expressed on microglia in Alzheimer’s disease brains and can mediate production of reactive oxygen species in response to beta-amyloid fibrils. Am J Pathol. 2002;160:101–12.

    Article  CAS  Google Scholar 

  30. Anderson EJ, Lustig ME, Boyle KE, Woodlief TL, Kane DA, Lin CT,et al. Mitochondrial H2O2 emission and cellular redox state link excess fat intake to insulin resistance in both rodents and humans. J Clin Invest. 2009;119:573–81.

    Article  CAS  Google Scholar 

  31. Asch AS, Barnwell J, Silverstein RL, Nachman RL. Isolation of the thrombospondin membrane receptor. J Clin Invest. 1987;79:1054–61.

    Article  CAS  Google Scholar 

  32. Janabi M, Yamashita S, Hirano K, Matsumoto K, Sakai N, Hiraoka H, et al. Reduced adhesion of monocyte-derived macrophages from CD36-deficient patients to type I collagen. Biochem Biophys Res Commun. 2001;283:26–30.

    Article  CAS  Google Scholar 

  33. Witz CA, Montoya-Rodriguez IA, Cho S, Centonze VE, Bonewald L, Schenken RS. Composition of the extracellular matrix of the peritoneum. J Soc Gynecol Investig. 2001;8:299–304.

    Article  CAS  Google Scholar 

  34. Pascual G, Avgustinova A, Mejetta S, Martin M, Castellanos A, Attolini CS, et al. Targeting metastasis-initiating cells through the fatty acid receptor CD36. Nature. 2017;541:41–5.

    Article  Google Scholar 

  35. Cheng JJ, Li JR, Huang MH, Ma LL, Wu ZY, Jiang CC, et al. CD36 is a co-receptor for hepatitis C virus E1 protein attachment. Sci Rep. 2016;6:21808

    Article  CAS  Google Scholar 

  36. Naville D, Duchampt A, Vigier M, Oursel D, Lessire R, Poirier H, et al. Link between intestinal CD36 ligand binding and satiety induced by a high protein diet in mice. PLoS ONE. 2012;7:e30686

    Article  CAS  Google Scholar 

  37. Adib TR, Henderson S, Perrett C, Hewitt D, Bourmpoulia D, Ledermann J, et al. Predicting biomarkers for ovarian cancer using gene-expression microarrays. Brit J Cancer. 2004;90:686–92.

    Article  CAS  Google Scholar 

  38. Rhodes D, Yu J, Shanker K, Deshpande N, Varambally R, Ghosh D, et al. Oncomine: A cancer microarray database and integrated data-mining platform. Neoplasia. 2004;6:1–6.

    Article  CAS  Google Scholar 

  39. Tothill RW, Tinker AV, George J, Brown R, Fox SB, Lade S, et al. Novel molecular subtypes of serous and endometrioid ovarian cancer linked to clinical outcome. Clin Cancer Res. 2008;14:5198–208.

    Article  CAS  Google Scholar 

  40. Pavlova NN, Thompson CB, The emerging hallmarks of cancer metabolism. Cell Metab. 2016;23:27–47.

    Article  CAS  Google Scholar 

  41. Kamphorst JJ, Cross JR, Fan J, de Stanchina E, Mathew R, White EP, et al. Hypoxic and Ras-transformed cells support growth by scavenging unsaturated fatty acids from lysophospholipids. Proc Natl Acad Sci USA. 2013;110:8882–7.

    Article  CAS  Google Scholar 

  42. Liu Y, Metzinger MN, Lewellen KA, Cripps SN, Carey KD, Harper EI, et al. Obesity contributes to ovarian cancer metastatic success through increased lipogenesis, enhanced vascularity, and decreased infiltration of M1 macrophages. Cancer Res. 2015;75:5046–57.

    Article  CAS  Google Scholar 

  43. Coburn CT, Knapp FF Jr, Febbraio M, Beets AL, Silverstein RL, Abumrad NA. Defective uptake and utilization of long chain fatty acids in muscle and adipose tissues of CD36 knockout mice. J Biol Chem. 2000;275:32523–9.

    Article  CAS  Google Scholar 

  44. Kazantzis M, Stahl A. Fatty acid transport proteins, implications in physiology and disease. Biochim Biophys Acta. 2012;1821:852–7.

    Article  CAS  Google Scholar 

  45. Randle PJ, Garland PB, Hales CN, Newsholme EA. The glucose fatty-acid cycle. Its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus. Lancet. 1963;1:785–9.

    Article  CAS  Google Scholar 

  46. Rodrigue-Way A, Caron V, Bilodeau S, Keil S, Hassan M, Levy E, et al. Scavenger receptor CD36 mediates inhibition of cholesterol synthesis via activation of the PPARgamma/PGC-1alpha pathway and Insig1/2 expression in hepatocytes. FASEB J. 2014;28:1910–23.

    Article  CAS  Google Scholar 

  47. Dobrzyn P, Sampath H, Dobrzyn A, Miyazaki M, Ntambi JM. Loss of stearoyl-CoA desaturase 1 inhibits fatty acid oxidation and increases glucose utilization in the heart. Am J Physiol Endocrinol Metab. 2008;294:E357–364.

    Article  CAS  Google Scholar 

  48. Accioly MT, Pacheco P, Maya-Monteiro CM, Carrossini N, Robbs BK, Oliveira SS, et al. Lipid bodies are reservoirs of cyclooxygenase-2 and sites of prostaglandin-E2 synthesis in colon cancer cells. Cancer Res. 2008;68:1732–40.

    Article  CAS  Google Scholar 

  49. de Gonzalo-Calvo D, Lopez-Vilaro L, Nasarre L, Perez-Olabarria M, Vazquez T, Escuin D, et al. Intratumor cholesteryl ester accumulation is associated with human breast cancer proliferation and aggressive potential: a molecular and clinicopathological study. BMC Cancer. 2015;15:460

    Article  Google Scholar 

  50. Guillaumond F, Bidaut G, Ouaissi M, Servais S, Gouirand V, Olivares O, et al. Cholesterol uptake disruption, in association with chemotherapy, is a promising combined metabolic therapy for pancreatic adenocarcinoma. Proc Natl Acad Sci USA. 2015;112:2473–8.

    Article  CAS  Google Scholar 

  51. Wang S, Blois A, El Rayes T, Liu JF, Hirsch MS, Gravdal K, et al. Development of a prosaposin-derived therapeutic cyclic peptide that targets ovarian cancer via the tumor microenvironment. Sci Transl Med. 2016;8:329ra334

    Google Scholar 

  52. Nergiz-Unal R, Rademakers T, Cosemans JM, Heemskerk JW. CD36 as a multiple-ligand signaling receptor in atherothrombosis. Cardiovasc Hematol Agents Med Chem. 2011;9:42–55.

    Article  CAS  Google Scholar 

  53. Nath A, Li I, Roberts LR, Chan C. Elevated free fatty acid uptake via CD36 promotes epithelial-mesenchymal transition in hepatocellular carcinoma. Sci Rep. 2015;5:14752.

    Article  CAS  Google Scholar 

  54. Tandon NN, Lipsky RH, Burgess WH, Jamieson GA. Isolation and characterization of platelet glycoprotein IV (CD36). J Biol Chem. 1989;264:7570–5.

    CAS  PubMed  Google Scholar 

  55. Kenny HA, Krausz T, Yamada SD, Lengyel E. Use of a novel 3D culture model to elucidate the role of mesothelial cells, fibroblasts and extra-cellular matrices on adhesion and invasion of ovarian cancer cells. Int J Cancer. 2007;121:1463–72.

    Article  CAS  Google Scholar 

  56. Pfaffl M. A new mathematical model for relative quantification in real-time RT-PCR. Nucleic Acids Res. 2001;29:2002–7.

    Article  Google Scholar 

  57. Kenny HA, Chiang CY, White EA, Schryver EM, Habis M, Romero IL, et al. Mesothelial cells promote early ovarian cancer metastasis through fibronectin secretion. J Clin Invest. 2014;124:4614–28.

    Article  CAS  Google Scholar 

  58. Kenny HA, Leonhardt P, Ladanyi A, Yamada SD, Montag AG, Im HK, et al. Targeting the urokinase plasminogen activator receptor inhibits ovarian cancer metastasis. Clin Cancer Res. 2011;17:459–71.

    Article  CAS  Google Scholar 

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Acknowledgements

This work was supported by a grant from Bears Care, the charitable beneficiary of the Chicago Bears Football Club (SD Yamada and E Lengyel) by National Cancer Institute grant DK033301 (NA Abumrad) and by CA 169604 (E Lengyel) and the Foundation for Women’s Cancer, Amgen Ovarian Cancer Research Grant (A Ladanyi). We thank Chunling Zhang and the Center for Research Informatics at the University of Chicago for their bioinformatics support on the microarray data. We are grateful to Gail Isenberg for editing this manuscript.

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Correspondence to Ernst Lengyel.

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Ladanyi, A., Mukherjee, A., Kenny, H.A. et al. Adipocyte-induced CD36 expression drives ovarian cancer progression and metastasis. Oncogene 37, 2285–2301 (2018). https://doi.org/10.1038/s41388-017-0093-z

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