MOLECULAR STUDIES OF VPF/VEGF

这项提议的长期目标是确定分子 肿瘤相关血管生成机制的研究进展 减少相关发病率和死亡率的治疗方法 与人类癌症有关。血管通透因子/血管内皮细胞 生长因子(VPF/VEGF)是一种血管内皮细胞生长因子 在重要的人类癌症中广泛表达的因子，包括 多形性胶质母细胞瘤、胃肠腺癌、卡波西 肉瘤、乳腺癌和肾癌。血管内皮生长因子/血管内皮生长因子的表达 也发生在其他人类疾病中，这些疾病表现为血管 增殖和高通透性；即类风湿性关节炎， 牛皮癣和糖尿病视网膜病变。这项提案将解决两个基本问题 问题：1.血管内皮生长因子/血管内皮生长因子在肿瘤相关疾病中的作用 血管生成与肿瘤生长？2.血管内皮生长因子/血管内皮生长因子在肿瘤生长中的作用 正常发育的原发血管生成？血管内皮生长因子/血管内皮生长因子在肿瘤中的作用 相关血管生成将在啮齿动物肿瘤中直接进行体内测试 模特们。肿瘤细胞将发展为过表达VPF/VEGF或其 血管内皮生长因子/血管内皮生长因子的表达受到抑制。几种肿瘤细胞系 在低氧条件下表达不同水平的VPF/VEGF，这是一种重要的 肿瘤进展过程中出现的现象。令人惊讶的是，这种能力 不同肿瘤细胞类型对低氧的反应 VPF/VEGF的产生与其在裸鼠体内的致瘤性直接相关 老鼠。稳定表达的肿瘤细胞表达增加或减少 VPF/VEGF的体内植入水平和肿瘤生长速度， VPF/VEGF和VPF/VEGF的组织学、血管化及表达 将对受体进行评估。这些肿瘤模型将定义 血管内皮生长因子/血管内皮生长因子在肿瘤发展中的作用 血管内皮生长因子/血管内皮生长因子的表达是影响肿瘤的关键细胞因子 生长和血管生成。血管内皮生长因子/血管内皮生长因子在正常肺组织中的作用 在哺乳动物发育中发生的血管生成将在体内进行评估 通过开发抑制或过度表达的转基因动物模型 VPF/血管内皮生长因子。这些转基因品系将有助于阐明其功能 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。总而言之，这些 实验将确定VPF/VEGF在肿瘤生长和生长中的作用 并将决定VPF/VEGF是否是合适的 癌症等人类病理治疗干预的靶标。

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.