Signal Transduction and Tumor Angiogenesis

信号转导和肿瘤血管生成

• 批准号: 7238860
• 负责人: KEVIN M PUMIGLIA
• 金额: $ 29.96万
• 依托单位: ALBANY MEDICAL COLLEGE
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-04-01 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7238860
• 关键词: Signal; Transduction; Tumor; Angiogenesis

DESCRIPTION (provided by applicant): Abundant data supports a prominent role for Vascular Endothelial Growth Factor (VEGF) in the growth and metastasis of multiple tumor types, including many of the most highly vascularized such as glioblastoma, renal cell carcinoma, angiosarcoma, and Kaposi's sarcoma. Our long-range objective is a comprehensive understanding of signal transduction initiated by VEGF and the relationship of these signals to the angiogenic phenotype. VEGF and other proangiogenic growth factors likely share many signal transduction pathways, particularly downstream from "integrators" of signal transduction such as Ras and FAK. Our initial funded studies identified Ras activation as both necessary and sufficient for the angiogenic phenotype and mapped the relationship between VEGF signaling events and biological actions. Focal Adhesion Kinase (FAK), like Ras, integrates inputs from multiple extracellular stimuli including growth factor receptors, G-protein-coupled receptors, mechanical stimuli, and integrin/matrix interactions. While many studies have correlated changes in FAK phosphorylation with changes in endothelial cell function, few studies have directly investigated the role of FAK signaling. Our preliminary data demonstrate FAK signaling is essential for cell proliferation in response to VEGF. FAK has been implicated in controlling cell proliferation in other cell types through the regulation of ERK (fibroblasts) or JNK (smooth muscle cells). Our data demonstrates activation of these cascades by VEGF is not affected by disrupting FAK signal transduction. Rather, FAK appears to control cell cycle progression through a novel induction of a cyclin-dependent kinase inhibitor. Based on these data, as well as our previous results with Ras/MAPK signaling, our hypothesis is that the regulation of FAK signal transduction and associated changes in cell phenotype will have unique and endothelial cell specific components that could ultimately be exploited to modulate the angiogenic response. Our objective in this proposal is to directly investigate the role of FAK signal transduction in integrating the biological response to VEGF, determine the mechanistic basis for the observed regulation, and to investigate the role of FAK and Ras signal transduction in modulating the angiogenic response in vivo.

描述（由申请人提供）：大量数据支持血管内皮生长因子（VEGF）在多种肿瘤类型的生长和转移中的重要作用，包括许多高度血管化的肿瘤，如胶质母细胞瘤、肾细胞癌、血管肉瘤和卡波西肉瘤。 我们的长期目标是全面了解由VEGF启动的信号转导以及这些信号与血管生成表型的关系。 VEGF和其他促血管生成生长因子可能共享许多信号转导途径，特别是信号转导的“整合子”如Ras和FAK的下游。 我们最初资助的研究确定Ras激活对于血管生成表型是必要的和充分的，并绘制了VEGF信号传导事件和生物学作用之间的关系。 与Ras一样，粘着斑激酶（FAK）整合来自多种细胞外刺激的输入，所述细胞外刺激包括生长因子受体、G蛋白偶联受体、机械刺激和整联蛋白/基质相互作用。 虽然许多研究已经将FAK磷酸化的变化与内皮细胞功能的变化相关联，但很少有研究直接研究FAK信号传导的作用。 我们的初步数据表明，FAK信号是必不可少的细胞增殖响应VEGF。 FAK通过调节ERK（成纤维细胞）或JNK（平滑肌细胞）参与控制其他细胞类型的细胞增殖。 我们的数据表明，VEGF激活这些级联反应不受干扰FAK信号转导的影响。 相反，FAK似乎通过一种新的诱导细胞周期蛋白依赖性激酶抑制剂来控制细胞周期进程。 基于这些数据，以及我们以前的Ras/MAPK信号转导的结果，我们的假设是，FAK信号转导的调节和相关的细胞表型的变化将具有独特的和内皮细胞特异性的成分，最终可以被利用来调节血管生成反应。 我们的目标是在这个建议是直接调查FAK信号转导的作用，整合VEGF的生物反应，确定所观察到的调节机制的基础上，并调查FAK和Ras信号转导在体内调节血管生成反应的作用。