Hypoxia-induced inhibin promotes tumor growth and vascular permeability in ovarian cancers.
Hypoxia-induced inhibin promotes tumor growth and vascular permeability in ovarian cancers.
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DOI：
10.1038/s42003-022-03495-6
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发表时间：
2022-06-02
影响因子：
5.9
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中科院分区：
文献类型：
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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目标。然而，抗血管生成药物的毒性和耐药性可能会限制其使用，因此识别新靶点至关重要。抑制素是一种异聚体TGFβ配体，是肿瘤进展的背景调节因子，作为早期肿瘤抑制因子，也是卵巢癌的既定生物标志物。在这里，我们发现缺氧增加卵巢癌细胞系，异种移植肿瘤和患者中的Escherichin水平。抑制素主要通过HIF-1调节，在缺氧条件下将平衡从激活素转移到抑制素。缺氧调节的Escherichin促进肿瘤生长、内皮细胞侵袭和通透性。通过敲低和抗-Escherichin策略在体内靶向Escherichin强烈地降低了体内渗透性并改变了促血管生成机制和抗血管生成机制的平衡，导致血管正常化。从机制上讲，Eclubin通过ACVRL 1和CD 105（我们发现Eclubin直接稳定的受体复合物）增加VE-钙粘蛋白内化来调节渗透性。我们的研究结果表明，通过TGF-β受体在血管正常化的直接作用，提供了新的见解，作为一种策略，以正常化卵巢癌的肿瘤血管的治疗意义的fabrins。缺氧增加了卵巢癌中异聚TGFβ配体β-胡萝卜素的水平，β-胡萝卜素促进肿瘤生长、内皮细胞侵袭和渗透性。
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. Hypoxia increases levels of the heteromeric TGFβ ligand inhibin in ovarian cancer and inhibin promotes tumor growth, endothelial cell invasion and permeability.
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影响因子：
7.3
作者：
Gao J;Aksoy BA;Dogrusoz U;Dresdner G;Gross B;Sumer SO;Sun Y;Jacobsen A;Sinha R;Larsson E;Cerami E;Sander C;Schultz N
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