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Adipocytes promote ovarian cancer metastasis and provide energy for rapid tumor growth

Abstract

Intra-abdominal tumors, such as ovarian cancer1,2, 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-oxidation 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 metabolism and transport as new targets for the treatment of cancers where adipocytes are a major component of the microenvironment.

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Figure 1: Adipocytes promote homing of ovarian cancer cells to the omentum.
Figure 2: Ovarian cancer cells use adipocyte-derived lipids for tumor growth.
Figure 3: Cocultivation of ovarian cancer cells with adipocytes activates lipolysis in adipocytes and β-oxidation in cancer cells.
Figure 4: FABP4 has a key role in the interaction of cancer cells with adipocytes.

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References

  1. Landen, C.N., Birrer, M.J. & Sood, A.K. Early events in the pathogenesis of epithelial ovarian cancer. J. Clin. Oncol. 26, 995–1005 (2008).

    Article  PubMed  Google Scholar 

  2. Cho, K.R. & Shih, I.-M. Ovarian cancer. Annu. Rev. Pathol. 4, 287–313 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Folkins, A.K., Jarboe, E.A., Roh, M.H. & Crum, C.P. Precursor to pelvic serous carcinoma and their clinical implications. Gynecol. Oncol. 113, 391–396 (2009).

    Article  PubMed  Google Scholar 

  4. Lengyel, E. Ovarian cancer development and metastasis. Am. J. Pathol. 177, 1053–1064 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  5. Rodbell, M. Metabolism of isolated fat cells. J. Biol. Chem. 239, 375–380 (1964).

    CAS  PubMed  Google Scholar 

  6. Merritt, W.M. et al. Effect of interleukin-8 gene silencing with liposome-encapsulated small interfering RNA on ovarian cancer cell growth. J. Natl. Cancer Inst. 100, 359–372 (2008).

    Article  CAS  PubMed  Google Scholar 

  7. Nilsson, M.B., Langley, R.R. & Fidler, I.J. Interleukin-6 secreted by human ovarian carcinoma cells is a potent proangiogenic cytokine. Cancer Res. 65, 10794–10800 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Manabe, Y., Toda, S., Miyazaki, K. & Sugihara, H. Mature adipocytes, but not preadipocytes, promote the growth of breast carcinoma cells in collagen gel matrix culture through cancer-stromal cell interactions. J. Pathol. 201, 221–228 (2003).

    Article  PubMed  Google Scholar 

  9. Tokuda, Y. et al. Prostate cancer cell growth is modulated by adipocyte–cancer cell interaction. BJU Int. 91, 716–720 (2003).

    Article  CAS  PubMed  Google Scholar 

  10. Dirat, B. et al. Cancer-associated adipocytes exhibit an activated phenotype and contribute to breast cancer invasion. Cancer Res. 71, 2455–2465 (2011).

    Article  CAS  PubMed  Google Scholar 

  11. Kaur, S. et al. β3-integrin expression on tumor cells inhibits tumor progression, reduces metastasis, and is associated with a favorable prognosis in patients with ovarian cancer. Am. J. Pathol. 175, 2184–2196 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Elliott, B.E., Tam, S.P., Dexter, D. & Chen, Z.Q. Capacity of adipose tissue to promote growth and metastasis of a murine mammary carcinoma: Effect of estrogen and progesterone. Int. J. Cancer 51, 416–424 (1992).

    Article  CAS  PubMed  Google Scholar 

  13. Wakil, S.J. & Abu-Elheiga, L.A. Fatty acid metabolism: target for metabolic syndrome. J. Lipid Res. 50, S138–S143 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  14. Gonzalez-Yanes, C. & Sanchez-Margalet, V. Signalling mechanisms regulating lipolysis. Cell. Signal. 18, 401–408 (2006).

    Article  Google Scholar 

  15. Sengenès, C. et al. Involvement of a cGMP pathway in the natriuretic peptide–mediated hormone sensitive lipase phosphorylation in human adipocytes. J. Biol. Chem. 278, 48617–48626 (2003).

    Article  PubMed  Google Scholar 

  16. Brasaemle, D.L., Subramanian, V., Garcia, A., Marcinkiewicz, A. & Rothenberg, A. Perilipin A and the control of triacylglycerol metabolism. Mol. Cell. Biochem. 326, 15–21 (2009).

    Article  CAS  PubMed  Google Scholar 

  17. Gagnon, A. et al. Thyroid-stimulating hormose stimulates lipolysis in adipocytes in culture and raises serum free fatty acid levels in vivo. Metabolism 59, 547–553 (2010).

    Article  CAS  PubMed  Google Scholar 

  18. Wang, W. & Guan, K.-L. AMP-activated protein kinase and cancer. Acta Physiol. (Oxf.) 196, 55–63 (2009).

    Article  CAS  Google Scholar 

  19. Munday, M.R., Campbell, D.G., Carling, D. & Hardie, D.G. Identification by amino acid sequencing of three major regulatory phosphorylation sites on rat acetyl-CoA carboxylase. Eur. J. Biochem. 175, 331–338 (1988).

    Article  CAS  PubMed  Google Scholar 

  20. Carey, M.S. et al. Functional proteomic analysis of advanced serous ovarian cancer using reverse phase protein array: TGF-β pathway signaling indicates response to primary chemotherapy. Clin. Cancer Res. 16, 2852–2860 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Hotamisligil, G.S. et al. Uncoupling of obesity from insulin resistance through a targeted mutation in aP2, the adipocyte fatty acid binding protein. Science 274, 1377–1379 (1996).

    Article  CAS  PubMed  Google Scholar 

  22. Furuhashi, M. & Hotamisligil, G.S. Fatty acid binding proteins: Role in metabolic diseases and potential as drug targets. Nat. Rev. Drug Discov. 7, 489–503 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Scheja, L. et al. Altered insulin secretion associated with reduced lipolytic efficiency in aP2−/− mice. Diabetes 48, 1987–1994 (1999).

    Article  CAS  PubMed  Google Scholar 

  24. Furuhashi, M. et al. Treatment of diabetes and atherosclerosis by inhibiting fatty-acid-binding protein aP2. Nature 447, 959–965 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Hertzel, A.V. et al. Identification and characterization of a small molecule inhibitor of fatty acid binding proteins. J. Med. Chem. 52, 6024–6031 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Uysal, K.T., Scheja, L., Wiesbrock, S.M., Bonner-Wier, S. & Hotamisligil, G.S. Improved glucose and lipid metabolism in genetically obese mice lacking aP2. Endocrinology 141, 3388–3396 (2000).

    Article  CAS  PubMed  Google Scholar 

  27. Martinez-Outschoorn, U.E. et al. The autophagic tumor stroma model of cancer or “battery-operated tumor growth” a simple solution to the autophagy paradox. Cell Cycle 9, 4297–4306 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Pavlides, S. et al. The reverse Warburg effect: aerobic glycolysis in cancer associated fibroblasts and the tumor stroma. Cell Cycle 8, 3984–4001 (2009).

    Article  CAS  PubMed  Google Scholar 

  29. Levine, A.J. & Puzio-Kuter, A.M. The control of the metabolic switch in cancers by oncogenes and tumor suppressor genes. Science 330, 1340–1344 (2010).

    Article  CAS  PubMed  Google Scholar 

  30. DeBerardinis, R.J., Lum, J.J., Hatzivassiliou, G. & Thompson, C.B. The biology of cancer: Metabolic programming fuels cell growth and proliferation. Cell Metab. 7, 11–20 (2008).

    Article  CAS  PubMed  Google Scholar 

  31. Liu, Y. Fatty acid oxidation is a dominant bioenergetic pathway in prostate cancer. Prostate Cancer Prostatic Dis. 9, 230–234 (2006).

    Article  CAS  PubMed  Google Scholar 

  32. Zaugg, K. et al. Carnitine palmitoyltransferase 1C promotes cell survival and tumor growth under conditions of metabolic stress. Genes Dev. 25, 1041–1051 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Pike, L.S., Smift, A.L., Croteau, N.J., Ferrick, D.A. & Wu, M. Inhibition of fatty acid oxidation by etomoxir impairs NADPH production and increases reactive oxygen species resulting in ATP depletion and cell death in human glioblastoma cells. Biochim. Biophys. Acta 1807, 726–734 (2011).

    Article  CAS  PubMed  Google Scholar 

  34. Hernlund, E. et al. Potentiation of chemotherapeutic drugs by energy metabolism inhibitors 2-deoxyglucose and etomoxir. Int. J. Cancer 123, 476–483 (2008).

    Article  CAS  PubMed  Google Scholar 

  35. Moon, A. & Rhead, W.J. Complementation analysis of fatty acid oxidation disorders. J. Clin. Invest. 79, 59–64 (1987).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Hennessy, B.T. et al. A technical assessment of the utility of reverse phase protein arrays for the study of the functional proteome in non-microdissected human breast cancers. Clin. Proteomics 6, 129–151 (2010).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank A.F. Haney (University of Chicago) for collecting omental biopsies and D. Bernlohr (University of Minnesota) for helpful discussions and kindly providing the FABP4 inhibitor. We thank S. Dogan for her contribution to the initiation of this project, G. Isenberg (University of Chicago) for editing the manuscript and A. Mitra (University of Chicago) for helpful discussions regarding the in vitro homing assay. We also thank K. Roby (University of Kansas Medical Center), N. Auersperg (University of British Columbia) and C. Clevenger (Northwestern University) for providing the ID8, IOSE and T47D cell lines, respectively. Finally, we thank all the patients, resident physicians and attending physicians in the Department of Obstetrics and Gynecology at the University of Chicago; without their commitment to tissue donation, this project would not have been possible. E.L. holds a Clinical Scientist Award in Translational Research from the Burroughs Wellcome Fund. He is also supported by grants from the Ovarian Cancer Research Fund (Liz Tilberis Scholars Program), the US National Cancer Institute (R01 CA111882) and Bears Care, the charitable beneficiary of the Chicago Bears Football Club. K.M.N. is funded by a Cancer Biology Training Grant from the Committee on Cancer Biology at the University of Chicago and the National Cancer Institute (T32 CA959421). H.A.K. is supported by an award from the National Cancer Institute K99 CA134750). G.S.H. is supported by a grant from the US National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK064360).

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Contributions

K.M.N. and H.A.K. performed most of the experiments. C.V.P. performed the western blots. M.R.Z., I.L.R. and C.V.P. assisted with some of the animal experiments. A.L., M.S.C. and G.B.M. performed and interpreted the protein array experiments. R.B.-G. and K.G. contributed to the immunohistochemistry for the human and mouse experiments. S.D.Y. and E.L. collected ovarian cancer tissues and clinicopathologic patient information. G.S.H. provided the Fabp4−/− mice and edited the manuscript. M.E.P. performed the bioinformatics analysis and edited the manuscript. K.M.N., H.A.K. and E.L. designed the experiments. K.M.N. and E.L. wrote the manuscript. E.L. directed the study.

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Correspondence to Ernst Lengyel.

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The University of Chicago has filed for a patent application directed at the subject matter of this manuscript. G.S.H. has intellectual property related to blocking aP2 (FABP4) function for the treatment of metabolic diseases.

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Nieman, K., Kenny, H., Penicka, C. et al. Adipocytes promote ovarian cancer metastasis and provide energy for rapid tumor growth. Nat Med 17, 1498–1503 (2011). https://doi.org/10.1038/nm.2492

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