Follicle stimulating hormone is an autocrine regulator of the ovarian cancer metastatic niche through Notch signaling

The association between the upregulated Notch and FSH signaling and ovarian cancer is well documented. However, their signaling has been investigated independently and only in the primary tumor tissues. The aim of this study was to investigate the interactive effects of FSH and Notch signaling on the ovarian cancer proliferation, formation and maintenance of the disseminated ovarian cancer cells. Roles of Notch and FSH in the ovarian cancer pathogenesis was investigated using ovarian cancer cell lines and specific antibodies against Notch and FSH receptor (FSHR). FSH upregulated Notch signaling and proliferation in the ovarian cancer cells. High levels of FSH were detected in the ascites of patients with serous ovarian adenocarcinoma. The spheroids from the ascites of the patients, as well as, the spheroids from the ovarian cancer cell lines under low attachment culture conditions, expressed FSH{beta} subunit mRNAs and secreted the hormone into the medium. In contrast, the primary ovarian tumor tissues and cell line monolayers expressed very low levels of FSH{beta}. The ovarian cancer cell spheroids also exhibited higher expression of the FSH receptor and Notch downstream genes than their monolayer counterparts. A combination of FSHR and Notch antagonistic antibodies significantly inhibited spheroid formation and cell proliferation in vitro. This study demonstrates that spheroids in ascites express and secrete FSH, which regulates cancer cell proliferation and spheroidogenesis through Notch signaling, suggesting that FSH is an autocrine regulator of cancer metastasis. Further, Notch and FSHR are potential immunotherapeutic targets for ovarian cancer treatment.