Inhibin function in tumor angiogenesis

卵巢癌是最具破坏性的妇科癌症之一，主要影响绝经后妇女。 女人。诱导血管生成，即血管的生成和重塑的过程，是一个关键的 包括卵巢在内的多种癌症对肿瘤生长和转移的要求，导致使用抗肿瘤药物 临床上使用的血管生成剂。然而，副作用和毒性会限制它们的使用。因此，仍有一种 需要确定癌症特异性的、安全的方法来控制卵巢癌的血管生成。抑制素是一种独特的转化生长因子-β 在正常绝经后妇女中水平极低的家庭成员。然而，抑制素是一种 已建立的卵巢癌生物标记物功能未知。我们的初步研究表明，抑制素 表达受低氧调节，低氧是肿瘤血管生成的重要调节因子。我们发现抑制素 在体外和体内通过促进血管生成而显示出对内皮的旁分泌作用。从机械上讲， 抑制素需要内皮特异性受体endoglin和Alk1来诱导血管生成。因为抑制素是 在卵巢癌中表达，但在正常绝经后妇女中存在于低水平的全身 探讨抑制素作为一种潜在的肿瘤血管生成新靶点的作用机制。假设是为了 被测试的是阻断肿瘤抑制素，一种新的内皮特异性转化生长因子-β受体的配体，以及一种产品 促进血管生成的缺氧适应性反应将导致肿瘤血管生成的抑制。 具体目的是：1)检测阻断抑制素是否具有治疗卵巢癌血管生成的作用 单独或与目前的抗血管生成疗法联合使用。2)阐明抑制素的作用机制 结合细胞信号、生化和血管生成诱导内皮细胞重塑和血管生成 生物物理方法测试抑制素作为内皮受体endoglin和Alk1的直接新配体和 利用转录组学鉴定抑制素新的信号靶点。3)明确低氧调控机制 抑制素的表达。我相信，这些关于抑制素介导的血管生成的研究将提供第一个 对抑制素以前未知功能的洞察，抑制素在癌症中广泛表达并提供新的 安全治疗癌症血管生成的靶点。

Ovarian cancer is among the most devastating of gynecological cancers primarily impacting postmenopausal women. Induction of angiogenesis, the process of generating and remodeling blood vessels, is a critical requirement for tumor growth and metastasis in multiple cancers including ovarian, leading to the use anti- angiogenic agents in the clinic. However side effects and toxicities can limit their use. Thus there remains a need to identify cancer specific, safe ways to control angiogenesis in ovarian cancer. Inhibin is a unique TGF-β family member whose levels are extremely low in normal post-menopausal women. However Inhibin is an established biomarker for ovarian cancers with unknown functions. Our preliminary studies show that Inhibin expression is regulated by hypoxia, a well-appreciated regulator of tumor angiogenesis. We find that Inhibin exhibits paracrine effects on the endothelium by increasing angiogenesis in vitro and in vivo. Mechanistically, Inhibin requires the endothelial specific receptors Endoglin and Alk1 to induce angiogenesis. Since Inhibin is expressed in ovarian cancers, but present at low systemic levels in normal post-menopausal women we will examine Inhibin as a potential novel angiogenic target for cancer the mechanism of action. The hypothesis to be tested is that blocking tumoral Inhibin, a novel ligand for endothelial specific TGF-β receptors, and a product of the hypoxia adaptive response that promotes angiogenesis will result in suppression of tumor angiogenesis. The specific aims are: 1) To test if blocking Inhibin has therapeutic anti-angiogenic effects in ovarian cancer alone or in combination with current anti-angiogenic therapies. 2) To delineate the mechanism of Inhibin induced endothelial cell remodeling and angiogenesis using a combination of cell signaling, biochemical and biophysical approaches to test Inhibin as a direct novel ligand for endothelial receptors endoglin and Alk1 and identify novel signaling targets of Inhibin using transcriptomics. 3) To define hypoxia mechanisms regulating Inhibin expression. I believe that these investigations into Inhibin-mediated angiogenesis will provide the first insights into previously unknown functions for Inhibin that is broadly expressed in cancer and provide new targets to safely treat angiogenesis in cancer.