Hypoxia Regulated Inhibin Promotes Tumor Growth and Vascular Permeability By ACVRL1 and CD105 Dependent VE-Cadherin Internalization

Abstract

Hypoxia, a driver of tumor growth and metastasis, regulates angiogenic pathways that are targets for vessel normalization and ovarian cancer management. However, toxicities and resistance to anti-angiogenics limits their use making identification of new targets vital. Inhibin, a heteromeric TGFb ligand, is a contextual regulator of tumor progression acting as an early tumor suppressor, yet also an established biomarker for ovarian cancers. Here, we demonstrate a previously unknown role for inhibins and find that hypoxia increases inhibin levels in ovarian cancer cell lines, xenograft tumors, and patients. Inhibin is regulated specifically through HIF-1, shifting the balance from activins to inhibins. Hypoxia regulated inhibin promotes tumor growth, endothelial cell invasion and permeability. Targeting inhibin in vivo through knockdown and anti-inhibin strategies robustly reduces permeability in vivo and alters the balance of pro and anti-angiogenic mechanisms resulting in vascular normalization. Mechanistically, inhibin regulates permeability by increasing VE-cadherin internalization via ACVRL1 and CD105, a receptor complex that we find stabilized directly by inhibin. Our findings are the first to demonstrate direct roles for inhibins in vascular normalization via TGF-b receptors providing new insights into the therapeutic significance of inhibins as a strategy to normalize the tumor vasculature in ovarian cancer.