The role of EphA2 receptor signaling in host-tumor interactions

描述（由申请人提供）：项目概述：肿瘤向恶性转移性疾病状态的进展涉及肿瘤细胞与宿主微环境之间的复杂相互作用。其中一个关键的相互作用涉及通过血管生成募集肿瘤血管，这为肿瘤提供了氧气，营养物质和进入循环的入口点，转移细胞可以通过该入口点移动到远处器官并定殖。EphA 2受体酪氨酸激酶在肿瘤内皮细胞中表达，是体内肿瘤血管生成的关键调节因子。通过用可溶性受体或宿主EphA 2缺陷治疗来抑制EphA 2信号传导严重损害荷瘤动物中的肿瘤新血管形成和肺转移。本研究的目的是通过研究由肿瘤细胞表达的膜锚定的肝配蛋白-A1配体激活内皮表达的EphA 2的假说，来剖析将肝配蛋白-A1配体诱导的内皮EphA 2受体激活与肿瘤血管生成偶联的分子机制 RTK，通过Vav/Rac-1依赖性机制将受体的特异性结构域与内皮细胞迁移和新血管形成的起始相连接。这项研究将加强我们对肿瘤微环境及其在恶性进展中所起作用的理解，这是NCI 2006财年的优先事项。研究将在范德比尔特-英格拉姆综合癌症中心的范德比尔特大学医学院完成，该中心的设施和以宿主-肿瘤相互作用为重点的研究环境非常适合本研究中涉及的分子、生化和遗传分析。作为第一代大学毕业生，我将在完成拟议的研究期间接受的指导培训将为我提供必要的技能，模型系统和职业发展机会，以建立一个独立的学术研究计划，并作为一个独立的研究者获得资金。 相关性：这项研究的目的是确定EphA 2的结构成分，使这种受体能够对肿瘤信号作出反应，并导致新血管定植和支持肿瘤，从而允许入侵和转移扩散，最终导致癌症死亡。识别这些成分将为分子靶向药物提供基础，这些药物旨在阻断受体功能，从而阻断血管募集，从而更有效地治疗恶性肿瘤。

DESCRIPTION (provided by applicant): Project Summary: Tumor progression toward a malignant, metastatic disease state involves complex interactions between tumor cells and the host microenvironment. One such crucial interaction involves recruitment of tumor blood vessels through angiogenesis, which provides the tumor with oxygen, nutrients, and an entry point into circulation through which metastatic cells may travel to and colonize distant organs. EphA2 receptor tyrosine kinase, which is expressed tumor endothelium, is a key regulator of tumor angiogenesis in vivo. Inhibition of EphA2 signaling through treatment with soluble receptors or host EphA2- deficiency severely impairs tumor neovascularization and lung metastasis in tumor-bearing animals. The goal of this proposal is to dissect the molecular mechanism(s) that couple ephrin-A1 ligand induced activation of endothelial EphA2 receptor to tumor angiogenesis by investigating the hypothesis that membrane anchored ephrin-A1 ligands expressed by tumor cells activate endothelial expressed EphA2 RTK, linking specific domains of the receptor to initiation of endothelial cell migration and neovascularization through a Vav/Rac-1 dependent mechanism. This research will enhance our understanding of the tumor microenvironment and the role it plays in malignant progression, an NCI priority for FY2006. Investigation will be completed at Vanderbilt University School of Medicine in the context of the Vanderbilt-lngram Comprehensive Cancer Center, with facilities and a host-tumor interaction focused research environment ideally suited for the molecular, biochemical, and genetic analyses involved in this research. As a first-generation college graduate, the mentored training I will receive during completion of the proposed research will provide me with the skills, model systems, and career development opportunities necessary to establish an independent academic research program and to secure funding as an independent investigator. Relevance: The goal of this research is to identify structural components of EphA2 that enable this receptor to respond to tumor signals and cause new blood vessels to colonize and support the tumor, permitting invasion and metastatic spread that ultimately lead to cancer death. Identifying these components will provide the foundation for molecularly-targeted drugs designed to block receptor function and therefore blood vessel recruitment, which could more effectively treat malignant cancer.