Genetic Regulation of Angiogenesis in Colonic Polyps

描述（申请人提供）：血管生成是生理和病理过程的基本特征，多种遗传和环境因素共同调控新血管的形成。在从正常结肠上皮到结肠癌的良好进展中，血管生成在良性腺瘤性息肉早期就开始了。发生在癌前阶段的K-ras和Wnt通路的遗传改变可以调节血管内皮生长因子（VEGF）的表达。当肿瘤扩大时，由于代谢需求超过血液供应，缺氧不可避免地发生。初步研究表明，K-ras可以与肿瘤微环境相互作用并产生应答。K-ras与缺氧合作，募集不需要缺氧诱导因子-1 （HIF-1）的新血管生成途径。这些包括诱导额外的血管生成因子，如白细胞介素-8 （IL-8）和c-myc的新激活以上调VEGF。此外，K-ras对促血管生成因子和抗血管生成因子之间平衡的局部变化有反应，因此当HIF-1等经典途径被阻断时，这些替代途径可以以代偿方式被激活。这种结肠肿瘤招募替代血管生成因子的能力可能解释了当仅使用单一药物进行抗血管生成治疗时可能产生的耐药性。总的来说，这些发现表明血管生成表型的维持是一个对局部环境线索高度敏感的动态过程，K-ras在这一过程中起着重要作用。为了解决通常发生在早期结肠瘤变中K-ras的改变与微环境相互作用以调节多种血管生成途径的假设，提出了以下具体目标：(1)确定K-ras在诱导结肠上皮细胞IL-8中的作用；(2)确定K-ras在结肠上皮细胞c-myc缺氧调控VEGF中的作用；(3)确定K-ras在抑制VEGF和IL-8后是否诱导其他血管生成因子的表达。更好地了解在结肠上皮中激活的血管生成途径的完整谱是合理设计和应用靶向抗血管生成方法的先决条件。

DESCRIPTION (provided by applicant): Angiogenesis is an essential feature of both physiological and pathological processes, and multiple genetic and environmental factors converge to regulate the formation of new blood vessels. In the well-described progression from normal colonic epithelium to colon cancer, angiogenesis begins early at the stage of the benign adenomatous polyp. Genetic alterations in the K-ras and Wnt pathways that occur at this premalignant stage can regulate the expression of vascular endothelial growth factor (VEGF). As tumors enlarge, hypoxia invariably develops as the metabolic demands outstrip the blood supply. Preliminary studies have revealed that K-ras can interact with and respond to the tumor microenvironment. K-ras cooperates with hypoxia to recruit novel angiogenic pathways that do not require hypoxia-inducible factor-1 (HIF-1). These include the induction of additional angiogenic factors such as interleukin-8 (IL-8) and the novel activation of c-myc to upregulate VEGF. Moreover, K-ras is responsive to local shifts in the balance between pro- and anti-angiogenic factors so that these alternative pathways can be activated in a compensatory manner when classical pathways such as HIF-1 are blocked. This ability of colon tumors to recruit alternative angiogenic factors may explain the resistance that can develop when only a single agent is used for anti-angiogenic therapy. Collectively, these findings suggest that maintenance of the angiogenic phenotype is a dynamic process that is highly responsive to local environmental cues, and there is an important role for K-ras in this process. To address the hypothesis that alterations in K-ras that typically occur in early colonic neoplasia interact with the microenvironment to regulate multiple angiogenic pathways, the following specific aims are proposed: (I) to define the role of K-ras in the induction of IL-8 in colonic epithelial cells, (II) to define the role of K-ras in the hypoxic regulation of VEGF by c-myc in colonic epithelial cells, and (III) to determine whether K-ras induces the expression of alternative angiogenic factors following inhibition of both VEGF and IL-8. A better understanding of the complete spectrum of angiogenic pathways activated in the colonic epithelium is a prerequisite for the rational design and application of targeted anti- angiogenic approaches.