Department of Pathology and O'Neal Comprehensive Cancer Center, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL, 35233, USA.
Department of Chemistry and Biochemistry, University of South Carolina, Columbia, SC, 29208, USA.
Commun Biol. 2022 Jun 2;5(1):536. doi: 10.1038/s42003-022-03495-6.
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.
缺氧是肿瘤生长和转移的驱动因素，调节血管生成途径，这些途径是血管正常化和卵巢癌管理的靶点。然而，抗血管生成药物的毒性和耐药性会限制其应用，因此确定新的靶点至关重要。抑制素是一种异源 TGFβ 配体，是肿瘤进展的上下文调节剂，作为早期肿瘤抑制因子，但也是卵巢癌的既定生物标志物。在这里，我们发现缺氧会增加卵巢癌细胞系、异种移植肿瘤和患者中的抑制素水平。抑制素主要通过 HIF-1 调节，在缺氧下将激活素与抑制素的平衡转移。缺氧调节的抑制素促进肿瘤生长、内皮细胞侵袭和通透性。通过体内敲低和抗抑制素策略靶向抑制素，可在体内显著降低通透性，并改变促血管生成和抗血管生成机制的平衡，从而导致血管正常化。从机制上讲，抑制素通过增加 ACVRL1 和 CD105 介导的 VE-钙粘蛋白内化来调节通透性，我们发现该受体复合物直接受抑制素稳定。我们的研究结果表明抑制素在通过 TGF-β 受体进行血管正常化中具有直接作用，为抑制素作为一种在卵巢癌中使肿瘤血管正常化的策略的治疗意义提供了新的见解。
