Inhibin function in tumor angiogenesis

抑制素在肿瘤血管生成中的作用

• 批准号: 10140041
• 负责人: Mythreye Karthikeyan
• 金额: $ 31.69万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10140041
• 关键词: Inhibin; function; tumor; angiogenesis

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.

卵巢癌是妇科癌的最毁灭性癌症之一，主要影响绝经后 女性。诱导血管生成是产生和重塑血管的过程，是一个关键 在包括卵巢在内的多种癌症中肿瘤生长和转移的需求，导致使用抗 诊所中的血管生成剂。但是，副作用和毒性可能会限制其使用。还有一个 需要鉴定癌症特定的安全方法来控制卵巢癌的血管生成。抑制素是独特的TGF-β 正常的绝经后妇女的水平极低的家庭成员。但是抑制素是 建立了具有未知功能的卵巢癌的生物标志物。我们的初步研究表明抑制素 表达受到肿瘤血管生成的良好调节剂缺氧的调节。我们发现抑制素 通过增加体外和体内血管生成来表现出对内皮的旁分泌作用。机械上， 抑制素需要内皮细胞内皮特异性受体和ALK1诱导血管生成。因为抑制剂是 在卵巢癌中表达，但在正常的绝经后妇女的全身水平低，我们将 将抑制素视为癌症的潜在新型血管生成靶标的作用机理。假设 可以测试的是阻断肿瘤抑制素，一种新型的内皮特异性TGF-β受体的配体，产物 促进血管生成的缺氧自适应反应将导致肿瘤血管生成。 具体目的是：1）测试阻断抑制剂是否在卵巢癌中具有治疗性抗血管生成作用 单独或与当前的抗血管生成疗法结合使用。 2）描述抑制素的机制 使用细胞信号传导，生化和 生物物理方法测试抑制素作为内皮细胞受体内o和alk1和ALK1和ALK1和 使用转录组学识别抑制素的新信号传导靶标。 3）定义调节的缺氧机制 抑制素表达。我认为，这些对抑制蛋白介导的血管生成的投资将提供第一个 对以前未知功能的抑制素功能的见解，该功能在癌症中广泛表达并提供了新的 安全治疗癌症血管生成的靶标。