|Hypoxia-induced inhibin promotes tumor growth and vascular permeability in ovarian cancers.
|Year of Publication
|Horst B, Pradhan S, Chaudhary R, Listik E, Quintero-Macias L, Choi ASeok, Southard M, Liu Y, Whitaker R, Hempel N, Berchuck A, Nixon AB, Lee NY, Henis YI, Mythreye K
|2022 Jun 02
|Activin Receptors, Type II, Activins, Capillary Permeability, Female, Humans, Hypoxia, Inhibins, Ovarian Neoplasms
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.
|PubMed Central ID
|R01 CA219495 / CA / NCI NIH HHS / United States
Hypoxia-induced inhibin promotes tumor growth and vascular permeability in ovarian cancers.
Faculty Member Reference:
Nam Lee, Ph.D.