Peritoneal Modulators of Endometriosis-Associated Ovarian Cancer

Abstract

Ovarian cancer is the 4th largest cause of cancer death in women. Approximately 10-15% of women of childbearing age suffer from endometriosis. Endometriosis is defined by the growth and presence of endometrial tissue (lesions) outside of the uterus. The women with endometriosis also have an increased presence of peritoneal fluid (PF) that comprises of inflammatory cells, growth factors, cytokines/chemokines, etc. Epidemiological studies have shown that >3% of women with endometriosis develop ovarian cancer (low-grade serous or endometrioid types). Our hypothesis is that the PF from women with endometriosis induces transformative changes in the ovarian cells, leading to ovarian cancer development. PF from women with and without endometriosis was collected after IRB approval and patient consent. IOSE (human normal ovarian epithelial cells) and TOV-21G cells (human ovarian clear cell carcinoma cell line) were treated with various volumes of PF (no endometriosis or endometriosis) for 48 or 96 h and proliferation measured. Expression levels of epigenetic regulators and FoxP3, an inflammatory tumor suppressor, were determined. A Human Cancer Inflammation and Immunity Crosstalk RT² Profiler PCR array was used to measure changes in cancer related genes in treated cells. Results showed increased growth of TOV-21G cells treated with PF from women with endometriosis versus without endometriosis and compared to IOSE cells. Endo PF treatment induced EZH2, H3K27me3, and FoxP3. The RT² PCR array of TOV-21G cells treated with endo PF showed upregulation of various inflammatory genes (TLRs, Myd88, etc.). These studies indicate that PF from women with endometriosis can both proliferate and transform ovarian cells and hence this microenvironment plays a major mechanistic role in the progression of endometriosis to ovarian cancer.

Keywords: EZH2; FoxP3; endometriosis; ovarian cancer; peritoneal fluid.

Figure 1

Peritoneal fluid increases proliferation of TOV-21G cells as determined by increase in Cell Index. **p < 005.

Figure 2

Peritoneal fluid modulates the expression of EZH2/H3k27me3 in IOSE and TOV-21G cells. *p < 0.05.

Figure 3

Peritoneal fluid induces FoxP3 and TLR pathway genes in TOV-21G cells. *p < 05; **p < 0.005.

Figure 4

Schematic representation of the plausible mechanisms involved in the role of endometriotic PF in EAOC.