Inhibin function in tumor angiogenesis

抑制素在肿瘤血管生成中的作用

• 批准号: 10318556
• 负责人: Mythreye Karthikeyan
• 金额: $ 33.55万
• 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/10318556
• 关键词: Angiogenesis Inhibitors; Antibodies; Ascites; Binding; Biochemical; Biological Assay; Biological Markers; Blood Vessels; Bypass; Cancer Model; Cancer cell line; Clinic; Clinical; Complex; Data; ENG gene; Endocrine; Endoglin; Endothelial Cells; Endothelium; Exhibits; Family; Family member; Gene Expression Profiling; Genes; Goals; Growth Factor; HIF1A gene; Hormones; Human; Hypoxia; In Vitro; Inhibin A; Investigation; Knowledge; Ligands; Malignant Female Reproductive System Neoplasm; Malignant Neoplasms; Malignant neoplasm of ovary; Mediating; Mediator of activation protein; Menopause; Molecular; Neoplasm Metastasis; Ovarian; Pathway interactions; Patients; Pharmaceutical Preparations; Postmenopause; Process; Prognostic Marker; Receptor Cell; Resistance; Role; Signal Transduction; Testing; Therapeutic; Toxic effect; Transcriptional Regulation; Transforming Growth Factor beta; Transforming Growth Factor beta Receptors; Tumor Angiogenesis; Tumor Suppression; Vascular Endothelial Growth Factors; Woman; Xenograft procedure; angiogenesis; autocrine; base; bevacizumab; biophysical techniques; cancer cell; diagnostic biomarker; improved; in vitro Assay; in vivo; inhibin; insight; loss of function; neoplastic cell; neutralizing antibody; novel; novel therapeutics; ovarian neoplasm; overexpression; paracrine; promoter; receptor; response; side effect; small hairpin RNA; targeted treatment; therapeutic target; transcription factor; transcriptomics; tumor; tumor growth; tumor progression

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.

卵巢癌是最具破坏性的妇科癌症之一，主要影响绝经后妇女。 妇女诱导血管生成，即生成和重塑血管的过程，是一个关键的过程。 在包括卵巢癌在内的多种癌症中肿瘤生长和转移的需要，导致使用抗- 血管生成剂在临床上。然而，副作用和毒性会限制其使用。因此，仍然存在一个 需要确定癌症特异性，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TGF-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 功能未知的卵巢癌的生物标志物。我们的初步研究表明抑制素 表达受缺氧调节，缺氧是肿瘤血管生成的公认调节剂。我们发现抑制素 在体外和体内通过增加血管生成对内皮表现出旁分泌作用。机械地说， 抑制素需要内皮特异性受体Endoglin和Alk 1来诱导血管生成。由于抑制素是 在卵巢癌中表达，但在正常绝经后妇女中以低全身水平存在，我们将 研究抑制素作为一种潜在的新型肿瘤血管生成靶点的作用机制。假设， 阻断肿瘤抑制素是一种内皮特异性TGF-β受体的新型配体， 促进血管生成的低氧适应性反应的降低将导致肿瘤血管生成的抑制。 具体的目的是：1）检测阻断抑制素是否对卵巢癌具有治疗性抗血管生成作用 单独或与目前的抗血管生成疗法联合。2)阐明抑制素的作用机制 诱导内皮细胞重塑和血管生成，使用细胞信号传导，生物化学和 测试抑制素作为内皮受体内皮糖蛋白和Alk 1的直接新型配体的生物物理方法， 使用转录组学鉴定抑制素的新信号传导靶点。3)定义调节缺氧的机制 抑制素表达。我相信，这些研究抑制素介导的血管生成将提供第一个 深入了解抑制素以前未知的功能，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。