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 can limit their use making identification of new targets vital.
Inhibin, a heteromeric TGFβ
ligand, is a contextual regulator of
tumor progression acting as an early
tumor suppressor, yet also an established
biomarker for
ovarian cancers. Here, we find that
hypoxia increases
inhibin levels in
ovarian cancer cell lines, xenograft
tumors, and patients.
Inhibin is regulated primarily through HIF-1, shifting the balance under
hypoxia 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 to be stabilized directly by
inhibin. Our findings demonstrate direct roles for
inhibins in vascular normalization via TGF-β receptors providing new insights into the therapeutic significance of
inhibins as a strategy to normalize the
tumor vasculature in
ovarian cancer.