Ovarian cancer is the most lethal of all gynecologic cancers. It is characterized by the presence of carcinomatosis at time of presentation and chemoresistant micrometastatic seedings at the time of recurrence. The omentum, an adipocyte-rich organ, is a frequent site of ovarian cancer metastasis in patients and the most common site of post-chemotherapy residual disease in animal models. Whereas previous studies have shown how the adipocyte microenvironment can induce metabolic re-programming in cancer cells, it is not clear if it can regulate pathways that affect chemoresponse. The objective of this study is to determine the effect of the adipocyte microenvironment on pathways that control cell cycle and apoptosis.
In vitro: Patient-derived epithelial ovarian cancer cell lines were cultured in the presence of absence of omentum conditioned-media. Cell growth was determined by measuring culture confluence using IncucyteTM. Protein expression was determined by western blot analysis, and flow cytometry. In vivo: Human ovarian cancer xenografts were established intra-peritoneally in nude mice. Tumor implants from adipocyte-rich organs such as the omentum, pelvic fat, and mesentery and tumor implants from non-adipocyte-rich organs such as liver, ovaries, and GI tract were collected and analyzed independently.
Compared to cells cultured in growth media, epithelial ovarian cancer cells cultured in omentum CM demonstrated a more fibroblastic morphology characterized by elongated shape and bipolarity, significantly slower growth kinetics (p < 0.0001) accompanied by upregulation of the cell cycle inhibitor, p27, and enhanced secretion of the pro-angiogenic factor, VEGF. More importantly, these cells express higher levels of the anti-apoptotic proteins Bclxl and Mcl-1. Consequently, ovarian cancer cells in growth media treated with Carboplatin had a IC50 of 14.5 μg/ml. In contrast, cells cultured in omentum CM demonstrated enhanced resistance to carboplatin with IC50 of > 50 μg/ml.
Analysis of tumor implants in vivo showed similar results as observed in vitro. Thus, tumor implants isolated from adipocyte-rich organs express higher levels of p27, Bclxl, and Mcl-1.
We demonstrate in this study that the adipocyte microenvironment induces major changes in the phenotype of ovarian cancer cells characterized by morphological changes chemoresistance and growth rate. These findings highlight the importance of the adipocyte microenvironment in the progression of ovarian cancer. Further studies that can identify specific therapeutic targets in the adipocyte-educated chemoresistant ovarian cancer cells may aid in the development of novel therapies and improve patient survival.
Citation Format: Carlos Cardenas, Ayesha B. Alvero, Mary Pitruzzello, Roslyn Tedja, Gil G. Mor. The omentum promotes ovarian cancer cell survival by increasing cell cycle duration and chemoresistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1995. doi:10.1158/1538-7445.AM2017-1995