VEGF SIGNAL TRANSDUCTION AND TUMOR ANGIOGENESIS

生长中的肿瘤的增殖和侵袭性， 病理后果，很大程度上取决于它的能力， 进行“血管生成转换”。 随着这种表型的变化， 肿瘤的生长特性在很大程度上取决于其获得的能力 以刺激毛细血管供血的侵入和新的生长。 血管内皮生长因子是血管内皮细胞生长所必需的细胞因子， 发展和血管生成（13，27）。 对血管有特异性 内皮细胞，在那里它是一种有效的有丝分裂原， 渗透性，刺激内皮细胞迁移，诱导 分化，并作为内皮细胞存活因子（25， 126）。 这些作用最终都调节血管生成反应。 现在认为VEGF是肿瘤血管生成的关键介质， 该因子被细胞转化和细胞增殖显著上调。 在生长的肿瘤中发现的缺氧条件。VEGF失调 现在，该产物被认为是血管瘤的致病因子， 患有von Hippel-Lindau病的患者的肾细胞癌。 负责血管生成的信号转导机制 反应仍然很大程度上未知。 正在进行这项研究， 研究Ras和Ras相关信号转导在 介导VEGF与血管生成相关的几种已知作用。 这些实验将使用突变体的诱导性异位表达， 信号分子来遗传操纵信号转导 原代内皮细胞中的信号通路。 信号转导途径 这似乎是至关重要的血管生成反应，血管内皮生长因子， 也将在肿瘤血管生成的体内模型中进行测试 采用VEGF依赖性肾细胞癌的异种移植物。 这 将为理解分子水平上的血管生成提供一片绿洲， 并最终将允许设计新的方法， 治疗靶向肿瘤生长。

The proliferation and invasive nature of a growing tumor, and ultimately the pathologic consequence, is largely governed by its ability to undergo an "angiogenic switch". With this change in phenotype, the tumors growth properties are critically aided by its acquired ability to stimulate the invasion and new growth of a capillary blood supply. Vascular Endothelial Growth Factor is a cytokine essential for vascular development and angiogenesis (13, 27). It is specific for vascular endothelium, where it is a potent mitogen, increases endothelial cell permeability, stimulates endothelial cell migration, induces differentiation, and acts as an endothelial cell survival factor (25, 126). These actions all ultimately regulate the angiogenic response. VEGF is now believed to be a critical mediator of tumor angiogenesis and this factor is markedly upregulated by cellular transformation and by the hypoxic conditions found in growing neoplasms. Dysregulation of VEGF production is now implicated as a causative agent in the hemangiomas and renal cell carcinomas of patients who have von Hippel-Lindau disease. The signal transduction mechanisms responsible for the angiogenic response remain largely unknown. This study is being undertaken to investigate the role of Ras and Ras-related signal transduction in mediating several of the known actions of VEGF related to angiogenesis. These experiments will use inducible, ectopic expression of mutant signaling molecules to genetically manipulate signal transduction pathways in primary endothelial cells. Signal transduction pathways that appear to be critical for the angiogenic responses to VEGF in vitro, will also be tested in an in vivo model of tumor angiogenesis employing xenografts of a VEGF-dependent renal cell carcinoma. This will provide a oasis for understanding angiogenesis at the molecular level and ultimately will allow for designing new approaches to therapeutically target tumor growth.