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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Objective To test if estrogen promotes carcinogenesis in vitro and in a genetic mouse model of ovarian cancer and whether its effects can be inhibited by a novel selective estrogen receptor modulator (SERM), bazedoxifene. Methods Bazedoxifene was synthesized and it was confirmed that the drug abrogated the uterine stimulatory effect of 17β-estradiol in mice. To determine if hormones alter tumorigenesis in vivo LSL-K-rasG12D/+PtenloxP/loxP mice were treated with vehicle control, 17β-estradiol or bazedoxifene. Hormone receptor status of a cell line established from LSL-K-rasG12D/+PtenloxP/loxP mouse ovarian tumors was characterized using western blotting and immunohistochemistry. The cell line was treated with hormones and invasion assays were performed using Boyden chambers and proliferation was assessed using MTT assays. Results In vitro 17β-estradiol increased both the invasion and proliferation of ovarian cancer cells and bazedoxifene reversed these effects. However, in the genetic mouse model neither treatment with 17β-estradiol nor bazedoxifene changed mean tumor burden when compared to treatment with placebo. The mice in all treatment groups had similar tumor incidence, metastatic nodules and ascites. Conclusion While 17β-estradiol increases the invasion and proliferation of ovarian cancer cells, these effects do not translate into increased tumor burden in a genetic mouse model of endometrioid ovarian cancer. Likewise, while the SERM reversed the detrimental effects of estrogen in vitro, there was no change in tumor burden in mice treated with bazedoxifene. These findings demonstrate the complex interplay between hormones and ovarian carcinogenesis.

Ovarian cancer (OvCa) is the 5th leading cause of cancer‐related deaths in women. The primary site of OvCa metastasis is the adipocyte (ADI)‐dominated omentum. A growing body of evidence supports metabolic dysregulation as a cancer hallmark. This research was aimed at investigating metabolic changes in interacting OvCa cells and ADIs. Human omental ADIs were plated on OvCa cells for coculture experiments and protein detection. Fatty acid (FA) oxidation was assessed by radioisotopic assay. FA binding protein 4 knockout (FABP4−/−) and wild‐type (WT) mice were inoculated with OvCa cells and sacrificed 10 weeks later. Human OvCa and omental metastatic tissues were utilized for IHC. Lipid accumulation and transfer, from ADIs into OvCa cells, were evident following coculture. FA oxidation was elevated in cocultured OvCa cells in a time‐dependent manner. Increased activated hormone‐sensitive lipase abundance in cocultured ADIs indicates upregulated lipolysis. FABP4 deficiency reduced tumor growth in FABP4−/− mice compared to WT mice. FABP4 was evident in OvCa cells at the ADI interface of omental metastasis but absent in the primary tumor. These results suggest ADIs promote OvCa metastasis and alter metabolic activity. FABP4 may mediate trafficking of FAs, providing energy for OvCa survival and metastasis. These findings may identify novel therapeutic targets for OvCa treatment. Support: NIH‐NCI T32 CA 9594‐21.

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