VEGF SIGNAL TRANSDUCTION AND TUMOR ANGIOGENESIS

不断增长的肿瘤的增殖和侵袭性，最终 病理后果，在很大程度上取决于它的能力 经历一次“血管生成转换”。随着这种表型的变化， 肿瘤的生长特性受到其后天能力的关键帮助 以刺激毛细血管供血的侵入和新的生长。 血管内皮细胞生长因子是血管生成所必需的细胞因子 发育和血管生成(13，27)。它是针对血管的。 内皮是一种强有力的有丝分裂原，它能增加内皮细胞 通透性，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)。这些行为最终都会调节血管生成反应。 血管内皮生长因子现在被认为是肿瘤血管生成的关键介质，并且 这一因子通过细胞转化和 在生长的肿瘤中发现的低氧条件。血管内皮生长因子的调节失调 生产现在被认为是血管瘤的致病因素， 冯·希佩尔-林道病患者的肾细胞癌。 血管生成的信号转导机制 对此的回应在很大程度上仍不得而知。这项研究的目的是 研究RAS及RAS相关信号转导在 介导了一些已知的与血管生成相关的血管生长因子的作用。 这些实验将使用可诱导的、异位表达的突变体 信号分子在基因上操纵信号转导 原代内皮细胞中的通路。信号转导途径 这些似乎对血管生成反应至关重要的血管内皮生长因子 在体外，也将在体内肿瘤血管生成模型中进行测试 使用依赖血管内皮生长因子的肾细胞癌的异种移植。这 将为从分子水平上理解血管生成提供一个绿洲 级别，并最终将允许设计新的方法来 在治疗上以肿瘤生长为目标。

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.