Ascites tumor microenvironment and chemoresistance in ovarian cancer

Abstract

Ovarian cancer is inherently silent; most patients are diagnosed in late stage of the disease progression. The progression and resistance to chemotherapy in ovarian cancer patients is closely associated with aberrant accumulation of fluid in the peritoneal cavity, called ascites formation. Malignant ascites constitutes a unique tumor microenvironment providing a physical structure for the accumulation of both pro‐tumorigenic and anti‐tumorigenic factors, each of which cumulatively favor cancer cell proliferation, metastasis and chemoresistance. Almost all patients with recurrent ovarian cancer are presented with ascites and have acquired resistance to chemotherapy. However, underlying mechanism of ascites induced acquired resistance to chemotherapy have not been fully understood yet. We used patient derived ascites to delineate the role of ascites in acquired chemoresistance in ovarian cancer. Of those many soluble factors, we focused on the levels of cholesterol in malignant ascites. We found that cholesterol levels are highly elevated in malignant ascites to that of benign peritoneal fluid from ovarian cyst patients. Treatment of cholesterol significantly induced resistance to cisplatin and paclitaxel via increased expression of drug resistance proteins, ABCG2 and MDR1, together with upregulation of LXRα/β. Moreover, LXRα/β expression was positively correlated with MDR1 but not with ABCG2 expression in ovarian cancer patient‐derived ascites cells. The importance of cholesterol induced LXRα/β in acquired resistance were further confirmed by silencing LXRα/β. In addition, elevated cholesterol in malignant ascites was associated with shorter recurrence free survival in ovarian cancer patients. Collectively, these results suggest that cholesterol in ovarian cancer patient derived ascites causes resistance to cisplatin through upregulation of MDR1 via activation of LXRα/β in ovarian cancer. Targeting the pathological interaction between cancer cell and ascites tumor microenvironment may be an efficient strategy to overcome acquired resistance in ovarian cancer patients.Support or Funding InformationThis research was supported by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (HA17C0037, HI16C2037) and grants from Seoul National University College of Medicine (800‐20150304) and the National R&D Program for Cancer Control, Ministry of Health & Welfare, Republic of Korea (1720110).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.