EphA2 Receptor in Endothelial Cell-Mediated Tumor Progression

描述（由申请人提供）：血管生成促进肿瘤进展并使转移成为可能。 以前的研究集中在激活内皮细胞反应的肿瘤信号的功能。 然而，直接引起肿瘤细胞反应的内皮细胞信号的功能仍然没有被表征。 该提案的目标是鉴定和表征肿瘤细胞生长和侵袭的新型内皮源性分子调节剂。 我们的初步研究表明，条件培养基从野生型，但不是EphA 2缺陷，内皮细胞促进肿瘤细胞的生长和运动的文化。 共移植的野生型，但不是EphA 2缺陷，内皮细胞增强肿瘤细胞增殖在体内血流的情况下。 野生型和EphA 2缺陷型内皮细胞的微阵列分析显示，编码slit 2的mRNA在EphA 2缺陷型内皮细胞中升高。 Slit 2是roundabout（Robo）受体家族的分泌配体，其在神经发育中起作用，并且最近显示负调节血管生成和肿瘤进展。 此外，我们观察到在大量人类乳腺癌样本中EphA 2阳性肿瘤血管中不存在slit 2蛋白，并且还发现ephA 2与人类乳腺癌患者的总体存活率呈负相关，而slit 2与人类乳腺癌患者的总体存活率呈正相关。 这使我们假设EphA 2下调slit 2配体以促进内皮细胞诱导的肿瘤细胞增殖、迁移和进展以及血管生成。 这项研究将增强我们对肿瘤周围微环境中看似正常的组织（如内皮）如何促进生长、侵袭和转移的理解，这是NCI 2010财年及以后的优先事项。 研究将在范德比尔特大学医学院的范德比尔特-英格拉姆综合癌症中心设施中完成，该设施支持宿主-肿瘤相互作用的研究环境，非常适合本研究中涉及的分子、生化、遗传和成像分析。 公共卫生相关性：我们的研究目的是探讨新的概念，即来自宿主内皮细胞的信号直接刺激肿瘤细胞的生长和侵袭，促进肿瘤细胞的扩散，最终导致癌症死亡。 识别和表征这些信号将为旨在抑制这些信号并更有效地治疗恶性肿瘤的分子靶向治疗提供基础。

DESCRIPTION (provided by applicant): Angiogenesis promotes tumor progression and enables metastatsis. Previous studies focused on the function of tumor signals that activate endothelial cell responses. However, the function of endothelial cell signals that directly elicit tumor cell responses remain uncharacterized. The goal of this proposal is to identify and characterize novel, endothelial-derived molecular regulators of tumor cell growth and invasion. Our preliminary studies showed that conditioned media from wild-type, but not EphA2-deficient, endothelial cells promotes tumor cell growth and motility in culture. Co-transplanted wild-type, but not EphA2-deficient, endothelial cells enhanced tumor cell proliferation in the absence of blood flow in vivo. Microarray analysis of wild-type and EphA2-deficient endothelial cells revealed that mRNA encoding slit2 is elevated in EphA2-deficient endothelial cells. Slit2 is a secreted ligand for the roundabout (Robo) receptor family that functions in neural development, and was more recently shown to negatively regulate angiogenesis and tumor progression. In addition we observed the absence of slit2 protein in EphA2-positive blood tumor vessels within a significant number of human breast cancer samples, and also found that ephA2 correlates negatively, while slit2 correlates positively, with overall survival in human breast cancer patients. This led us to hypothesize that EphA2 downregulates slit2 ligand to facilitate endothelial cell-induced tumor cell proliferation, migration, and progression, as well as angiogenesis. This research will enhance our understanding of how seemingly normal tissue in the microenvironment, such as endothelium, that surrounds the tumor facilitates growth, invasion, and metastasis, an NCI priority for FY2010 and beyond. Investigation will be completed at Vanderbilt University School of Medicine in the context of the Vanderbilt-Ingram Comprehensive Cancer Center facilities, which supports a host-tumor interaction focused research environment ideally suited for the molecular, biochemical, genetic, and imaging analyses involved in this research. PUBLIC HEALTH RELEVANCE: Our research objective is to investigate the novel concept that signals derived from host endothelial cells directly stimulate tumor cell growth and invasion, facilitating metastastic spread that ultimately leads to cancer death. Identifying and characterizing these signals will provide the foundation for molecularly targeted therapies designed to inhibit these signals and more effectively treat malignant cancer.