Abstract
BackgroundThe purpose of this study was to investigate the role of malignant ascites tumor microenvironment in ovarian cancer progression and chemoresistance.MethodsA total of 45 patients with ovarian cancer and three benign ascites were collected at the time of clinical intervention. Ascites cholesterol levels were quantitated using cholesterol quantitation kit and recurrence free survival (RFS) of ovarian cancer patients were collected. The sensitivity of ovarian cancer cells to cisplatin (CDDP) and paclitaxel (PAC) were assessed by viability assay, flow cytometry and protein expression. Receiver operating characteristics (ROC) curve and Youden index analysis were applied to calculate the optimal cut-off values for ascites cholesterol. Kaplan-Meier curve were applied to compare RFS between high and low ascites cholesterol levels in ovarian cancer patients.ResultsHere we show that cholesterol is elevated in malignant ascites and modulates the sensitivity of ovarian cancer cells to CDDP and PAC by upregulating the expression of drug efflux pump proteins, ABCG2 and MDR1, together with upregulation of LXRɑ/β, the cholesterol receptor. Transfection of LXRɑ/β siRNA inhibited cholesterol-induced chemoresistance and upregulation of MDR1. In addition, the cholesterol level in malignant ascites was negatively correlated with number of CDDP-induced apoptotic cell death, but not with that of PAC-induced apoptotic cell death. Cholesterol depletion by methyl beta cyclodextrin (MβCD) inhibited malignant ascites-induced chemoresistance to CDDP and upregulation of MDR1 and LXRɑ/β. For patients with ovarian cancer, high cholesterol level in malignant ascites correlated with short RFS.ConclusionsHigh cholesterol in malignant ascites contributes to poor prognosis in ovarian cancer patients, partly by contributing to multidrug resistance through upregulation of MDR1 via activation of LXRɑ/β.
Highlights
The purpose of this study was to investigate the role of malignant ascites tumor microenvironment in ovarian cancer progression and chemoresistance
ABCG2 and MDR1 protein expression were relatively high in SKOV-3 compared to PA-1 and OVCAR-3 (Fig. 1b) and IC50 to CDDP and PAC were directly correlated with ABCG2 and MDR1 protein expression (Fig. 1c and d)
We found that MDR1 but not ABCG2 protein expression was positively correlated with Liver x receptor α/β (LXRα/β) in primary cells isolated from ovarian cancer patient derived ascites at passage 0 (Additional file 1: Figure S3E)
Summary
The purpose of this study was to investigate the role of malignant ascites tumor microenvironment in ovarian cancer progression and chemoresistance. There is a growing evidence indicating the importance of tumor microenvironment in ovarian cancer progression, especially chemoresistance [3]. The aberrant accumulation of fluid in the peritoneal cavity called ascites formation occurs in more than one third of ovarian cancer patients and in almost all recurrent cases [2, 4]. Kim et al BMC Cancer (2018) 18:1232 shown that ascites serves as an important tumor microenvironment enriched in pro-tumorigenic signals that contribute to enhanced invasiveness and chemoresistance [5, 6]. It is critical to elucidate the mechanism of chemoresistance to improve the survival rate for ovarian cancer
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