The role of EphA2 receptor signaling in host-tumor interactions

项目概述：肿瘤向恶性转移状态发展涉及肿瘤细胞与宿主微环境之间复杂的相互作用。其中一种至关重要的相互作用包括通过血管生成募集肿瘤血管，血管生成为肿瘤提供氧气、营养物质和进入循环的入口，转移细胞可以通过循环进入并定居远端器官。EphA2受体酪氨酸激酶在体内表达肿瘤内皮，是肿瘤血管生成的关键调控因子。通过可溶性受体或宿主EphA2缺乏抑制EphA2信号通路严重损害肿瘤新生血管和肺转移。本研究的目的是通过研究肿瘤细胞表达的膜锚定ephrin-A1配体激活内皮细胞表达的EphA2的假设，剖析偶联ephrin-A1配体诱导内皮细胞EphA2受体激活肿瘤血管生成的分子机制

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.