OBJECTIVES: Epithelial ovarian cancers frequently metastasize and grow to a considerable size in the omentum, a peritoneal fold largely comprised of adipocytes. We have previously shown ovarian cancer cells induce lipolysis in adipocytes and utilize adipocyte-derived fatty acids as an energy source. However, the mechanism of adipocyte-induced fatty acid uptake in ovarian cancer has not yet been established.

The goal of this study was to determine whether adipocytes alter the expression of fatty acid transport receptors in ovarian cancer cells and whether inhibition of these receptors impedes tumor progression.

METHODS: Immunofluorescence microscopy and western blot analysis were used to study the expression profile of fatty acid transport receptors in a panel of ovarian cancer cell lines cultured in the presence and absence of omental adipocytes. To determine the impact of the identified fatty acid receptor on tumor progression, its expression was silenced in SKOV3ip1 cells using a short hairpin RNA (shRNA) lentiviral vector. Stably-transfected SKOV3ip1-shRNA cells (1x10ˆ6) were injected intraperitoneally into nude mice. Fatty acid transporter mRNA levels of laser-microdissected human high-grade serous ovarian cancer cells and their corresponding omental metastases were measured using real-time quantitative PCR analysis.

RESULTS: Among the fatty acid transport receptors evaluated, CD36 was found to be selectively upregulated in ovarian cancer cells in the presence of omental adipocytes. CD36 knockdown in SKOV3ip1 cells reduced lipid accumulation and fatty acid uptake (81% and 35%, respectively, p<0.01) and prevented adhesion to extracellular matrix proteins (collagen I and laminin). CD36-shRNA cells exhibited reduced clone formation (5-fold, p<0.01) in a soft agar clonogenicity assay, compared to scrambled shRNA controls. Metastatic tumor burden was significantly reduced in CD36-shRNA injected mice compared to scrambled shRNA controls, as assessed by tumor weight and number of metastatic foci (1.19g vs. 0.20g, p<0.01 and 188 vs. 18, p<0.01, respectively). In human omental metastases samples (n=10), CD36 mRNA levels were elevated 6-fold as compared to their primary tumor counterparts.

CONCLUSIONS: In the presence of omental adipocytes, CD36 is an important regulator of fatty acid uptake in ovarian cancer cells. Disruption of fatty acid trafficking may offer a novel treatment approach in reducing tumor dissemination within the abdominal cavity.

Citation Format: Andras Ladanyi, Kristin Nieman, Carla Penicka, Anirban Mitra, Hilary Kenny, Katja Gwin, Rebecca Wolsky, S Diane Yamada, Ernst Lengyel. Omental adipocytes promote overexpression of CD36 in ovarian cancer cells and enhance tumorigenicity. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1870. doi:10.1158/1538-7445.AM2013-1870