MOLECULAR STUDIES OF VPF/VEGF

该提案的长期目标是确定 肿瘤相关血管生成的机制， 降低相关疾病发病率和死亡率的治疗方法 与人类癌症有关。血管通透性因子/血管内皮 生长因子（VPF/VEGF）已被鉴定为内皮生长因子， 该因子在重要的人类癌症中广泛表达，包括 多形性胶质母细胞瘤，胃肠腺癌，卡波西氏病 肉瘤、乳腺癌和肾细胞癌。VPF/VEGF的表达 也发生在其他人类疾病中， 增殖和高渗透性;即，类风湿性关节炎， 牛皮癣和糖尿病视网膜病变。该提案将解决两个基本问题 问题：1. VPF/VEGF在肿瘤相关性 血管生成和肿瘤生长2. VPF/VEGF在血管生成中起什么作用？ 正常发育的原发性血管生成VPF/VEGF在肿瘤中的作用 相关的血管生成将直接在啮齿动物肿瘤中进行体内测试 模型将产生过表达VPF/VEGF的肿瘤细胞或其 VPF/VEGF的表达受到抑制。几种肿瘤细胞系 在低氧条件下表达不同水平的VPF/VEGF，这是一个重要的 这是肿瘤进展过程中出现的现象。令人惊讶的是， 不同类型的肿瘤细胞通过诱导 VPF/VEGF的产生与其在裸鼠体内的成瘤性直接相关 小鼠表达增加或减少的稳定转染的肿瘤细胞 将VPF/VEGF水平植入体内并测定肿瘤生长速率， VPF/VEGF及VPF/VEGF表达与组织学、血管化 将对受体进行评估。这些肿瘤模型将定义 VPF/VEGF在肿瘤发展中的作用，特别是解决 VPF/VEGF的表达是影响肿瘤的关键细胞因子， 生长和血管生成。VPF/VEGF在正常原发性肝癌中的作用 将在体内评价哺乳动物发育中发生的血管生成 通过开发转基因动物模型， VPF/VEGF。这些转基因株系将有助于阐明 VPF/VEGF与所需的时间和空间事件的关系 适当的脂肪组织和器官发育总的来说，这些 实验将确定VPF/VEGF在肿瘤生长中的功能， 正常的血管生成，并将确定VPF/VEGF是否是一个适当的 用于人类病理学如癌症中治疗性干预靶点。

The long-term objectives for this proposal are to identify the molecular mechanisms of tumor-related angiogenesis with the purpose of developing therapeutic approaches to reducing the morbidity and mortality associated with human cancers. Vascular permeability factor/vascular endothelial growth factor (VPF/VEGF) has been identified as an endothelial growth factor which is widely expressed in important human cancers including glioblastoma multiforme, gastrointestinal adenocarcinoma, Kaposi's sarcoma, breast carcinoma and renal cell carcinoma. Expression of VPF/VEGF also occurs in other human diseases which demonstrate vascular proliferation and hyperpermeability; namely, rheumatoid arthritis, psoriasis and diabetic retinopathy. This proposal will address two basic questions: 1. What is the role of VPF/VEGF in tumor-associated angiogenesis and tumor growth? 2. What role does VPF/VEGF play in the primary angiogenesis of normal development? The role of VPF/VEGF in tumor- related angiogenesis will be tested directly in vivo with rodent tumor models. Tumor cells will be developed that overexpress VPF/VEGF or whose expression of VPF/VEGF has been inhibited. Several tumor cell lines express variable levels of VPF/VEGF under hypoxic conditions, an important phenomenon occurring during tumor progression. Surprisingly, the ability of different tumor cell types to respond to hypoxia by induction of VPF/VEGF production directly correlates to their tumorigenicity in nude mice. Stable transfected tumor cells expressing increased or reduced levels of VPF/VEGF will be implanted in vivo and tumor growth rate, histology, vascularization and expression of VPF/VEGF and VPF/VEGF receptors will be evaluated. These tumor models will define the role of VPF/VEGF in tumor development, particularly addressing whether the expression of VPF/VEGF is a key cytokine which positively affects tumor growth and angiogenesis. The role of VPF/VEGF in normal primary angiogenesis occurring in mammalian development will be evaluated in vivo by developing transgenic animal models which either repress or overexpress VPF/VEGF. These transgenic lines will help to delineate the function of VPF/VEGF in relation to both temporal and spatial events required for proper adipose tissue and organ development. Collectively, these experiments will define the function of VPF/VEGF in tumor growth and normal angiogenesis and will determine whether VPF/VEGF is an appropriate target for therapeutic intervention in human pathologies such as cancer.