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.
Highlights
Epithelial ovarian cancer (EOC), which is the leading cause of death in women with gynecological malignancies, is very difficult to diagnose and treat due to its asymptomatic presentation and insufficient knowledge on factors that initiate tumorigenesis [1,2,3]
Endometriosis and EOC may have some relation since they both pertain to pelvic tissues that grow uncontrollably. We propose that this connection between endometriosis and its malignant progression to EOC may be the result of these peritoneal fluid (PF) microenvironmental changes which induce cancer-related genetic alterations
We showed that when PF from women with endometriosis was added to endometrial cells, there was an increase in the PRC2 complex, EZH2, and its target H3K27me3
Summary
Epithelial ovarian cancer (EOC), which is the leading cause of death in women with gynecological malignancies, is very difficult to diagnose and treat due to its asymptomatic presentation and insufficient knowledge on factors that initiate tumorigenesis [1,2,3]. It comprises over 95% of existing ovarian cancers [4] and women have a one in 78 chance of developing EOC [5]. The endometrioid or clear cell carcinoma represents the main types of endometriosis-associated ovarian cancer (EAOC) that may develop from precursor endometriotic lesions in the ovary. The reason for this increased risk of developing ovarian cancer from the progression of endometriosis currently remains unclear
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