Abstract MIP-063: DEFINING NOVEL PARACRINE FUNCTIONS FOR INHIBIN IN OVARIAN CANCER
Authors: Priyanka Singh, Laura Jenkins, Kathleen O'Connell, YingMiao Liu, Andy Nixon, Mythreye Karthikeyan
Journal: Clinical Cancer Research (2017)

Abstract BACKGROUND AND SIGNIFICANCE: Inhibins are members of the TGF-β superfamily loss of which in mice results in gonadal tumorigenesis. In humans, Inhibin is elevated in patients across several ovarian cancer subtypes including GCT's, mucinous, clear cell, to lesser extents in high grade serous and also in the stroma of Brenner tumors as reported by several others. Other cancers with elevated Inhibin include prostate and common cancers associated with ascites accumulation such as colon, gastric, and pancreatic. The Type III TGF-β receptor/ Betaglycan is the only high affinity receptor molecule that has been shown to directly bind Inhibin, that does not induce signaling, but is frequently lost in ovarian cancer as reported previously. The overall goal of our studies supported in part by the Rivkin Center for Ovarian Cancer were to 1) define the possible functional consequences of elevated Inhibin in cancers in the absence of Betaglycan, 2) determine whether elevated Inhibin may act as a tumor-promoter via a novel complement of receptors in the absence of Betaglycan and 3) to evaluate the impact of blocking inhibin using a neutralizing antibody on ovarian cancer growth and metastasis. RESULTS: We find that Inhibin (alpha subunit, INHA) is largely expressed by multiple ovarian cancer epithelial cells with Inhibin A significantly elevated in the ascites of ovarian cancer patients. Reducing autocrine production of Inhibin by silencing expression of the alpha subunit in epithelial cells has only modest effects on invitro cancer cell growth, migration and invasion either in the presence or absence of Betaglycan. However, most strikingly, we find that conditioned media from ovarian cancer cells with high Inhibin levels rapidly induce SMAD1/5 activation in a paracrine manner on endothelial cells. We find that both recombinant InhibinA and paracrine Inhibin are activators of endothelial cell signaling and angiogenesis both in -in vitro endothelial differentiation assays and in vivo in mice. Mechanistically, Inhibin utilizes an alternate endothelial receptor complement system, components of which are elevated in the ascites of ovarian cancer patients. Antibodies to both the receptors recognizing Inhibin and Inhibin itself suppress Inhibin induced endothelial cell differentiation and angiogenesis. Additionally, Inhibin is a more robust mediator of angiogenesis as compared to TGF-β or Activin and can synergize with VEGF to stimulate endothelial cell differentiation and angiogenesis. IMPLICATIONS: We have discovered a new mechanism and function for Inhibin that may be relevant for ovarian cancer subtypes and pathologies that present elevated Inhibin. While current anti-angiogenic therapies targeting VEGF show promise for the treatment of advanced ovarian cancers, significant side effects and toxicities exist. Our findings on the paracrine role of Inhibin that is normally at extremely low levels in postmenopausal women suggest that consideration of anti- Inhibin antibodies in conjunction with anti- VEGF therapies may hold promise in the future. These findings will be presented and discussed. Citation Format: Priyanka Singh, Laura Jenkins, Kathleen O'Connell, YingMiao Liu, Andy Nixon, and Mythreye Karthikeyan. DEFINING NOVEL PARACRINE FUNCTIONS FOR INHIBIN IN OVARIAN CANCER [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr MIP-063.