The role of ascites tumor-microenvironment in ovarian cancer invasion and chemoresistance

Abstract

Ovarian cancer is the most lethal gynecologic malignancy, because of asymptomatic nature of this disease, most patients are diagnosed in late stage with peritoneal dissemination and distant metastasis. The importance of tumor microenvironment and cancer progression are increasingly recognized and the abnormal accumulation of fluid in the peritoneal cavity, called ascites is found in almost all recurrent ovarian cancer patients. Indeed, the presence of ascites correlates with peritoneal tumor spread and decreased 5-year survival in ovarian cancer. In current studies, we provide the malignant role of ascites in ovarian cancer progression. The cytokine profiles of ovarian cancer patient derived ascites demonstrated the presence of pro-inflammatory cytokines. Of those, a significantly elevated levels of interleukin 6 (IL-6), increased invasion of ovarian cancer cells. Neutralization of IL-6 in ascites reduced the stimulatory effects of ascites on ovarian cancer cell invasion. Ascites increased invasion through JAK2 and STAT3 signaling pathway, confirmed by use of selective inhibitors. Moreover, the expression of IL-6 receptor (IL-6R) on cell membrane of ovarian cancer cells correlated with ascites-induced invasion. Cholesterol is elevated in ascites and treatment of cholesterol reduced response to cisplatin and increased membrane expression of ATP-binding cassette transporters (ABC transporters), via liver x receptor / (LXR/ in ovarian cancer cells. Similarly, ascites treatment reduced response to cisplatin and increased membrane expression of ABC transporters, with increased LXR/ expression. Excess cellular cholesterol is toxic, a feed-forward regulatory system such as the liver x receptor (LXR) family are activated in response to free cholesterol accumulation. Depletion of free cholesterol reduced ascites mediated increased ABC transporter expression and increased response to cisplatin. Our findings highlight the important role of ascites tumor microenvironment in ovarian cancer invasion and chemoresistance. Hence, better understanding of individual components of ascites in ovarian cancer progression will provide novel therapeutic targets as well as prognostic markers.