Genetic Regulation of Angiogenesis in Colonic Polyps

结肠息肉血管生成的遗传调控

• 批准号: 6624075
• 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/6624075
• 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（由申请人提供）：血管生成的受控诱导 在多种生理和病理过程中发挥着重要作用 州。特别是响应于新血管的形成 肿瘤块内形成的缺氧环境对于肿瘤的发生至关重要 晚期恶性肿瘤的生存。然而，血管生成在 良性前驱病变的发病机制尚不清楚。在详细描述的 在结肠癌的进展过程中，血管生成在早期就开始了 癌前腺瘤性息肉。在结肠上皮细胞中，这与 关键促血管生成因子 VEGF 的上调。遗传机制 良性结肠息肉中 VEGF 上调的潜在机制很差 描述的。 Wnt（APC β-连环蛋白）和 K-ras 信号传导的激活 在这些结肠息肉中观察到了典型的通路。初步的 研究证明 Wnt 信号传导对 VEGF 具有新的上调作用。在 此外，K-ras 调节磷脂酰肌醇 3 激酶中的 VEGF 表达 依赖方式。此外，K-ras 与 Wnt 具有协同作用 上调 VEGF 的途径。为了解决这些信号传导的假设 早期结肠肿瘤中经常改变的通路也可能发挥作用 通过 VEGF 的调节在血管生成中发挥重要作用，以下 提出了具体目标：(1) 定义关键的顺式监管要素 位于介导 Wnt 信号传导的 VEGF 启动子中。 (2) 定义K-ras 调节 VEGF 表达的效应途径，以及 (3) 定义 缺氧与 Wnt 信号传导在 VEGF 上调中的相互作用。 总的来说，这些研究将强调血管生成的重要作用 癌前结肠息肉并为新策略提供基础 专门针对血管生成来预防这些结肠癌 前体。