Genetic Regulation of Angiogenesis in Colonic Polyps

结肠息肉血管生成的遗传调控

• 批准号: 6472121
• 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/6472121
• 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 在各种生理和病理学中都起着至关重要的作用 国家。特别是在响应于新血管的形成 在肿瘤质量内发展的低氧环境对于 晚期恶性肿瘤的生存。但是，血管生成在 良性前体病变的发病机理尚不清楚。在描述良好的中 结肠癌的进展，血管生成始于 预呼应症状息肉。在结肠上皮细胞中，这与 随着关键的促血管生成因子VEGF的上调。遗传机制 良性结肠息肉中VEGF的这种上调的基础很差 描述。 Wnt（APCβ-catenin）和K-RAS信号的激活 在这些结肠息肉中观察到途径。初步的 研究证明了通过Wnt信号传导对VEGF的新上调。在 补充，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协同起作用 上调VEGF的途径。解决这些信号的假设 早期结肠肿瘤中经常改变的途径也可能发挥作用 通过调节VEGF在血管生成中的重要作用，以下 提出了具体目的：（1）定义关键的顺式调节元件 在介导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，（3）定义 VEGF上调中缺氧与Wnt信号传导的相互作用。 总的来说，这些研究将突出血管生成的重要作用 在结肠前息肉中，为新颖策略奠定了基础 专门针对预防这些结肠癌的血管生成 前体。