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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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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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Authors

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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