EphA2 Receptor in Endothelial Cell-Mediated Tumor Progression

描述(申请人提供)：血管生成促进肿瘤进展并使转移成为可能。以前的研究主要集中在激活内皮细胞反应的肿瘤信号的功能上。然而，直接引发肿瘤细胞反应的内皮细胞信号的功能仍未确定。这项建议的目标是识别和表征肿瘤细胞生长和侵袭的新型内皮衍生分子调控因子。我们的初步研究表明，来自野生型但不是EphA2缺陷的内皮细胞的条件培养液在培养中促进肿瘤细胞的生长和运动。共同移植的野生型但不是EphA2缺陷的内皮细胞在体内没有血流的情况下促进了肿瘤细胞的增殖。对野生型和EphA2缺陷内皮细胞的微阵列分析表明，编码Slit2的mRNA在EphA2缺陷内皮细胞中上调。Slit2是环行交叉口(Robo)受体家族的一种分泌配体，在神经发育中发挥作用，最近被证明对血管生成和肿瘤进展具有负面调节作用。此外，我们还观察到在相当数量的人类乳腺癌样本中，EphA2阳性的血管中没有Slit2蛋白，并且还发现，在人类乳腺癌患者中，EphA2与总的生存期呈负相关，而Slit2与总的生存期呈正相关。这导致我们假设EphA2下调SLIT2配体以促进内皮细胞诱导的肿瘤细胞的增殖、迁移和进展，以及血管生成。这项研究将加强我们对肿瘤周围微环境中看似正常的组织(如内皮细胞)如何促进生长、侵袭和转移的理解，这是2010财年及以后NCI的优先事项。研究将在范德比尔特大学医学院范德比尔特-英格拉姆综合癌症中心设施的背景下完成，该中心设施支持以宿主-肿瘤相互作用为重点的研究环境，非常适合进行这项研究中涉及的分子、生化、遗传和成像分析。 公共卫生相关性：我们的研究目标是探索来自宿主内皮细胞的信号直接刺激肿瘤细胞生长和侵袭，促进转移扩散，最终导致癌症死亡的新概念。识别和表征这些信号将为分子靶向治疗提供基础，旨在抑制这些信号并更有效地治疗恶性肿瘤。

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.