Eph receptor tyrosine kinases in tumor angiogenesis

Eph受体酪氨酸激酶在肿瘤血管生成中的作用

• 批准号: 6579569
• 负责人: Jin Chen
• 金额: $ 30.24万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-05-01 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6579569
• 关键词: angiogenesis; apoptosis; biological signal transduction; cell adhesion; cell migration; disease /disorder model; flow cytometry; gene targeting; genetically modified animals; growth factor receptors; integrins; laboratory mouse; ligands; metastasis; mitogen activated protein kinase; neoplasm /cancer blood supply; neoplastic process; protein protein interaction; protein tyrosine kinase; receptor expression; terminal nick end labeling; transfection /expression vector; vascular endothelial growth factors; western blottings

DESCRIPTION (provided by applicant): Angiogenesis, the sprouting of new blood vessels from existing vasculature, is a critical step in the progression and metastasis of solid tumors. The long-term goal of our research is to dissect the molecular mechanisms of tumor angiogenesis. The purpose of the proposed research is to investigate how the Eph family of receptor tyrosine kinases regulate the growth of new blood vessels in tumors. Receptor tyrosine kinases represent a major class of cell-surface molecules that regulate tumor neovascularization. Members of Eph receptors and ligands are required in embryonic vascular development, yet their functions in postnatal angiogenesis remains unclear. Our preliminary results now show that ephrinA1 ligand and EphA2 receptor are expressed in two types of murine tumors and associated vasculature. A soluble EphA2 receptor abrogates islet tumor neovascularization in a vascular window assay, inhibits the formation of angiogenic islets in RIP-Tag transgenic mice, and suppresses 4T1 breast cancer growth and angiogenesis in vivo. To dissect the mechanisms of EphA receptor-mediated angiogenesis, we found that VEGF induces ephrinA1 expression and phosphorylation of EphA2 receptor in endothelial cells, and blocking EphA receptor activation inhibits VEGF-, but not FGF-induced endothelial cell survival, migration, sprouting, and corneal angiogenesis. Taken together, these data support a hypothesis that EphA RTKs and their ligands, ephrinAs, play a critical role in tumor neovascularization, and actions of ephrinA lignads on endothelial cells are required, at least in part, for VEGF-induced angiogenesis. To test this hypothesis, we will (1) determine whether activation of EphA2 receptor mediates VEGF-induced endothelial responses, (2) dissect the mechanisms of interactions between VEGF and the EphA/ephrinA signaling in angiogenesis, and (3) investigate whether EphA receptor activation is necessary and sufficient to promote tumor growth and angiogenesis in vivo using RIP-Tag transgenic tumor model. Each of these specific aims represents a different, but complementary, approach to understand the role of Eph receptor tyrosine kinases in tumor angiogenesis. These studies at the molecular, cellular, and whole animal level will make significant advances to the understanding of how different angiogenic factors are coordinated to promote tumor angiogenesis, and may identify novel targets to inhibit neovascularization in cancer.

描述（由申请人提供）：血管生成，即从现有脉管系统中长出新血管，是实体瘤进展和转移的关键步骤。我们研究的长期目标是剖析肿瘤血管生成的分子机制。本研究的目的是研究受体酪氨酸激酶 Eph 家族如何调节肿瘤中新血管的生长。受体酪氨酸激酶代表调节肿瘤新血管形成的一类主要细胞表面分子。 Eph受体和配体的成员是胚胎血管发育所必需的，但它们在出生后血管生成中的功能仍不清楚。我们的初步结果现在表明 ephrinA1 配体和 EphA2 受体在两种类型的小鼠肿瘤和相关脉管系统中表达。可溶性 EphA2 受体在血管窗测定中消除胰岛肿瘤新生血管形成，抑制 RIP-Tag 转基因小鼠中血管生成胰岛的形成，并抑制体内 4T1 乳腺癌生长和血管生成。为了剖析EphA受体介导的血管生成的机制，我们发现VEGF诱导内皮细胞中ephrinA1表达和EphA2受体磷酸化，并且阻断EphA受体激活会抑制VEGF而非FGF诱导的内皮细胞存活、迁移、出芽和角膜血管生成。总而言之，这些数据支持这样的假设：EphA RTK 及其配体 ephrinAs 在肿瘤新生血管形成中发挥关键作用，并且 ephrinA 配体对内皮细胞的作用是 VEGF 诱导的血管生成所必需的，至少部分是必需的。为了检验这一假设，我们将（1）确定EphA2受体的激活是否介导VEGF诱导的内皮反应，（2）剖析血管生成中VEGF与EphA/ephrinA信号传导之间相互作用的机制，以及（3）使用RIP-Tag转基因肿瘤模型研究EphA受体激活是否是促进体内肿瘤生长和血管生成所必需和充分的。这些具体目标中的每一个都代表了一种不同但互补的方法来了解 Eph 受体酪氨酸激酶在肿瘤血管生成中的作用。这些在分子、细胞和整体动物水平上的研究将在理解不同血管生成因子如何协调以促进肿瘤血管生成方面取得重大进展，并可能确定抑制癌症中新血管形成的新靶点。