Signal Transduction and Tumor Angiogenesis

描述(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发挥重要作用，包括许多血管密度最高的肿瘤，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血管内皮生长因子启动的信号转导以及这些信号与血管生成表型的关系。血管内皮生长因子和其他促血管生成生长因子可能共享许多信号转导途径，特别是在RAS和FAK等信号转导整合因子的下游。我们最初资助的研究发现RAS的激活是血管生成表型的必要条件和充分条件，并绘制了血管内皮生长因子信号事件和生物学作用之间的关系。粘着斑激酶(FAK)和RAS一样，整合了多种细胞外刺激的信息，包括生长因子受体、G蛋白偶联受体、机械刺激和整合素/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联系在一起，但很少有研究直接研究FAK信号的作用。我们的初步数据表明，FAK信号对细胞的增殖是必不可少的，以响应血管内皮生长因子。FAK通过调节成纤维细胞(ERK)或平滑肌细胞(JNK)来控制其他细胞类型的细胞增殖。我们的数据表明，血管内皮生长因子激活这些级联通路不受干扰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的激酶抑制物来控制细胞周期进程。基于这些数据，以及我们之前对RAS/MAPK信号的研究结果，我们的假设是，FAK信号转导的调控和相关的细胞表型变化将具有独特的内皮细胞特异性成分，最终可能被用来调节血管生成反应。我们的目标是直接研究FAK信号转导在整合对血管内皮生长因子的生物反应中的作用，确定观察到的调控的机制基础，并研究FAK和RAS信号转导在体内调节血管生成反应中的作用。

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.