Bidirectional Eph/ephrin signaling in the crosstalk at the tumor-vessel interface

Eph受体通过结合邻近细胞表达的膜结合ephrin配体介导细胞间的短程通讯。它们在各种各样的发育和成人过程中发挥作用，如细胞迁移、轴突引导和地形图绘制、节段模式、突触形态和突触可塑性、血管生成和肿瘤发生。本项目的主要目的是研究Eph和ephrin系统在肿瘤血管生成和肿瘤细胞行为中的作用。我们将研究肿瘤诱导血管形成的过程，重点是内皮细胞-内皮细胞和肿瘤细胞-内皮细胞之间的通讯。在胶质瘤和内皮细胞的血管生成实验中，Eph和ephrin介导的细胞粘附和排斥将被分析。我们计划通过从缺乏ephrinB2的条件小鼠和ephrinB2信号突变小鼠中分离内皮细胞来进行功能丧失实验。为了在体外和体内研究肿瘤细胞中Eph/ephrin信号通路对肿瘤生长和侵袭性的要求，我们将从基因工程小鼠中分离和转化星形胶质细胞，产生ephrinB2突变或缺乏ephrinB配体的小鼠胶质瘤。

Eph receptors mediate short-range cell-to-cell communication by binding membrane-bound ephrin ligands expressed by neighbouring cells. They function in an amazing variety of developmental and adult processes like cell migration, axon guidance and topographic mapping, segmental patterning, synapse morphology and synapse plasticity, angiogenesis and tumorigenesis. The main goal of this project is to study the Eph and ephrin system in the context of tumor angiogenesis and tumor cell behavior. We will study the process of tumor-induced blood vessel formation with focus on endothelial cell-endothelial cell and tumor cell- endothelial cell communication. Cell adhesion and repulsion mediated by Eph and ephrins in various angiogenesis assays involving glioma and endothelial cells will be analyzed. We plan to do loss-of-function experiments by isolating endothelial cells from conditional mice lacking ephrinB2 as well as from ephrinB2 signaling mutant mice. In order to study the requirements for Eph/ephrin signaling in the tumor cells for tumor growth and invasiveness in vitro and in vivo, murine gliomas with mutated ephrinB2 or lacking ephrinB ligands will be generated by isolation and transformation of astrocytes from genetically engineered mice.