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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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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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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DOI: https://doi.org/10.1038/s41388-017-0093-z
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