The significance of lipid metabolism in peritoneal metastases of ovarian cancer

Abstract

Metastatic progression is attributed to the high mortality rate of all human cancers including ovarian cancers and becomes a major obstacle in clinical management. Emerging clinical evidence has linked the dysregulated cell metabolism and cancer outcomes. The Warburg effect is a distinctive feature of many human cancers that allows cells exhibiting enhanced aerobic glycolysis in generating energy for their rapid cell proliferation. Hence, targeting this metabolic pathway could impair the tumor growth of various human cancers. However, different from other human cancers, advanced ovarian cancer is usually characterized by a late detection, peritoneal metastases, and the frequent acquisition of chemoresistance. The presence of ascites lead to a distinct tumor microenvironment significantly affecting ovarian cancer cells in different aspects of oncogenic capacities in peritoneal metastases and poor disease prognosis. Previous studies showed that malignant ascites acts as a reservoir of a complex mixture of bioactive lipids, pro-inflammatory factors and tumor-promoting microenvironment for metastatic progression of ovarian cancer cells. Of note, the high lipid content in ascetic fluid providing a huge energy source for ovarian cancer cells in peritoneal dissemination and intraperitoneal tumor colonization. In this study, we found that ovarian cancer cells co-cultured with an omental explant culture system (OCM) or ascetic fluid from ovarian cancer patients exhibited an increase in in vitro cell growth, cell migration/invasion through activation of TAK1/NF-B signaling cascade. Intriguingly, an increase of Acetyl-CoA Carboxylase activity (phospho-ACC), Fatty Acid Synthase (FASN) and hormone-sensitive lipase (HSL) was also observed, indicating the tumor cells synthesized ATP cellular energy by lipid metabolism. Indeed, ovarian cancer cells co-cultured of OCM showed increased lipid droplets accumulation in cytosol and enhanced intracellular ATP content. In contrast, the oncogenic capacities of ovarian cancer cells were impaired when cultured in OCM treated with Cleanascite Lipid Removal Reagent, suggesting that the bioactive lipids in OCM are required for enhanced oncogenic capacities. On the other hand, co-treatment of a GLUT-1 and glucose uptake inhibitor, STF 31, could not affect the cell growth when cultured in OCM, indicating there is a metabolic shift from aerobic glycolysis to fatty acid -oxidation in ovarian cancer cells. Taken together, these findings suggest that the metastatic ovarian cancer cells in OCM or ascetic fluid require lipid metabolism for peritoneal metastases.