Molecular analysis of tumor-vessel interactions during tumor progression

转移是由肿瘤细胞（TC）与血管和淋巴管壁（EC）细胞之间复杂的双向交流引起的。转移性TC诱导血管生成、血管内渗、在循环中行进至远端部位、粘附于次级器官中的EC以最终外渗并建立远端转移。除了诱导血管生成之外，这些多种TC和EC相互作用的机制在分子水平上知之甚少。我们在以前的工作中表征了EphB 4受体酪氨酸激酶及其相应的ephrinB 2配体在肿瘤进展和血管生成过程中的表达、细胞功能和作用。这些实验已经超越了EphB/ephrinB系统对血管生成和动静脉分化的既定作用，为EphB受体和ephrinB配体在控制粘附性TC-EC相互作用中的作用提供了证据。基于这些发现和额外的初步数据，本项目的目的是在细胞和体内实验中系统地研究控制肿瘤进展和转移的肿瘤细胞和内皮细胞之间的粘附性EphB/ephrinB相互作用。这些实验旨在揭示一种新的TC-EC粘附机制。相关的细胞和体内试验的既定平台也将被利用来研究可能参与TC转移性传播的其他粘附机制。总的来说，这些实验将有助于更好地理解转移级联反应的关键步骤。

Metastasis results from an intricate bi-directional communication of tumor cells (TC) with cells of the blood and lymphatic vessel wall (EC). Metastatic TC induce angiogenesis, intravasate vessels, travel in the circulation to distant sites, adhere to EC in secondary organs to eventually extravasate and to establish distant metastases. Beyond the induction of angiogenesis, the mechanisms of these multiple TC and EC interactions are poorly understood at the molecular level. We have in previous work characterized the expression, cellular functions and the role during tumor progression and angiogenesis of the EphB4 receptor tyrosine kinase and its corresponding ephrinB2 ligand. These experiments have beyond the established roles of the EphB/ephrinB system for angiogenesis and arteriovenous differentiation provided evidence for a role of EphB receptors and ephrinB ligands in controlling adhesive TC-EC interactions. Based on these findings and additional preliminary data, the present project is aimed at systematically studying in cellular and in vivo experiments adhesive EphB/ephrinB interactions between tumor cells and endothelial cells that control tumor progression and metastasis. The experiments are aimed at shedding light into a novel TC-EC adhesion mechanism. The established platform of relevant cellular and in vivo assays will also be exploited to study other adhesive mechanisms that may be involved in TC metastatic dissemination. Collectively, the experiments will contribute to a better mechanistic understanding of a key step of the metastatic cascade.