Genetic Regulation of Angiogenesis in Colonic Polyps

结肠息肉血管生成的遗传调控

• 批准号: 6724897
• 负责人: DANIEL C CHUNG
• 金额: $ 24.65万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-01 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6724897
• 关键词: HeLa cells; RNase protection assay; adenocarcinoma; adenoma; angiogenesis; biological signal transduction; colon polyp; colorectal neoplasms; gel mobility shift assay; gene expression; genetic regulation; genetic regulatory element; human tissue; hypoxia; immunoprecipitation; molecular oncology; molecular pathology; neoplasm /cancer genetics; neoplastic growth; neoplastic transformation; phosphorylation; polymerase chain reaction; protein binding; site directed mutagenesis; vascular endothelial growth factors; western blottings

DESCRIPTION (provided by applicant): The controlled induction of angiogenesis plays a critical role in a variety of both physiological and pathological states. In particular the formation of new blood vessels in response to the hypoxic environment that develops within a tumor mass is crucial for the survival of advanced malignancies. However, the role of angiogenesis in the pathogenesis of benign precursor lesions is unknown. In the well-described progression of colon cancer, angiogenesis begins early at the stage of the premalignant adenomatous polyp. In colonic epithelial cells, this is associated with upregulation of the key pro-angiogenic factor VEGF. The genetic mechanisms underlying this upregulation of VEGF in benign colonic polyps are poorly described. Activation of the Wnt (APC beta-catenin) and K-ras signaling pathways is characteristically observed in these colon polyps. Preliminary studies demonstrate the novel upregulation of VEGF by Wnt signaling. In addition, K-ras regulates VEGF expression in a phosphatidyl inositol 3-kinase dependent manner. Furthermore, K-ras functions synergistically with the Wnt pathway to upregulate VEGF. To address the hypothesis that these signaling pathways that are frequently altered in early colonic neoplasia may also play an important role in angiogenesis through the regulation of VEGF, the following specific aims are proposed: (1) to define the critical cis-regulatory elements in the VEGF promoter that mediate Wnt signaling. (2) to define the K-ras effector pathways that regulate VEGF expression, and (3) to define the interaction of hypoxia with Wnt signaling in the upregulation of VEGF. Collectively, these studies will highlight the important role of angiogenesis in premalignant colonic polyps and provide the foundation for novel strategies that specifically target angiogenesis in the prevention of these colon cancer precursors.

描述(申请人提供)：血管生成的受控诱导 在各种生理和病理过程中都起着关键作用 各州。尤其是新血管的形成 在肿瘤内形成的低氧环境对肿瘤的生长至关重要 晚期恶性肿瘤的存活率。然而，血管生成在血管生成中的作用 良性前驱病变的发病机制尚不清楚。在描述得很好的 结肠癌的进展，血管生成在结肠癌早期就开始了 癌前腺瘤性息肉。在结肠上皮细胞中，这与 随着关键促血管生成因子血管内皮生长因子的上调。遗传机制 良性结肠息肉中血管内皮生长因子上调的潜在原因是 描述。Wnt(APCβ-catenin)和K-ras信号的激活 在这些结肠息肉中可见典型的小路。初步 研究表明Wnt信号可上调血管内皮细胞生长因子的表达。在……里面 此外，K-ras调节磷脂酰肌醇3-激酶中血管内皮生长因子的表达 依赖的态度。此外，K-ras与WNT具有协同作用 上调血管内皮生长因子的途径。来解决这样一个假设，即这些信号 在早期结肠肿瘤中经常改变的通路也可能起作用 通过调节血管内皮生长因子在血管生成中的重要作用，如下 提出了具体的目标：(1)确定关键的顺式监管要素 在介导Wnt信号的血管内皮生长因子启动子中。(2)定义K-RAS 调节血管内皮生长因子表达的效应通路，以及(3)定义 低氧与Wnt信号在上调血管内皮生长因子中的相互作用。 总的来说，这些研究将突出血管生成的重要作用 并为新的治疗策略提供了基础 专门针对血管生成来预防这些结肠癌 先驱物。