Genetic Regulation of Angiogenesis in Colonic Polyps

结肠息肉血管生成的遗传调控

• 批准号: 7030990
• 负责人: DANIEL C CHUNG
• 金额: $ 24.07万
• 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/7030990
• 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 在各种生理和病理过程中起着关键作用 states.特别是新血管的形成， 在肿瘤块内发展的缺氧环境对于肿瘤的生长至关重要。 晚期恶性肿瘤的生存率。然而，血管生成在血管生成中的作用是不确定的。 良性前驱病变的发病机制尚不清楚。在描述良好的 在结肠癌的进展中，血管生成在结肠癌的早期阶段开始。 癌前腺瘤性息肉在结肠上皮细胞中， 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表达上调的基础是 介绍了Wnt（APC β-连环蛋白）和K-ras信号传导的激活 在这些结肠息肉中特征性地观察到了该通路。初步 研究证实了Wnt信号转导对VEGF的新的上调。在 此外，K-ras在磷脂酰肌醇3-激酶中调节VEGF表达， 依赖的方式。此外，K-ras与Wnt协同发挥作用， 上调VEGF的途径。为了解决这些信号 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VEGF在血管生成中的重要作用， 提出了具体目标：（1）定义关键的顺式调节元件 在介导Wnt信号的VEGF启动子中。(2)来定义K-ras 调节VEGF表达的效应子途径，和（3）确定 缺氧与Wnt信号在VEGF上调中的相互作用。 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基础 专门针对血管生成来预防结肠癌 前体