Interaction between the microglia and blood vessels in malignant brain tumors - significance for brain tumor angiogenesis, vascular modulation, and brain tumor growth

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The pathology of malignant brain tumors is characterized by multiple cellular interactions at the interface between blood vessels and tumor cells. For example, the cellular components of the vessel wall continuously interact with each other and with tumor cells during angiogenesis. Furthermore, the perivascular space is the preferred route of local tumor spread while, at the same time, tumor cells are restricted from invading the cerebral cortex or vascular lumen. Since the guidance molecules ephrinB2 and EphB4 are expressed by brain tumor cells as well as by cells of the vessel wall, and are activated upon cell/cell-interaction to affect cell adhesion and migration, we hypothesize that they play a central role in these cellular interactions at the blood vessel-tumor cell interface. To test this, we will first extend our previous studies on the role of vascular ephrinB2/EphB4 signaling for vascular morphogenesis in tumors. Vascular ephrinB2 reverse signaling will be manipulated by an in vivo retroviral approach and by using a conditional, endothelial cell-specific ephrinB2-deficient mouse. We will also analyze whether vascular ephrinB2/EphB4 signaling is involved in intussusceptive blood vessel growth and may, thereby, represent a novel mediator of this hitherto incompletely understood angiogenic process. Second, we will study the role of tumor cellular ephrinB2/Eph4 signaling for brain tumor cell migration and invasion and we will test the hypothesis that ephrinB2/EphB4 may act as a compartmentalization factor for brain tumor cells, directing them into their preferred perivascular route of local dissemination. To test this we will transfect tumor cells with EphB4 variants or knock-down EphB4 expression by siRNA and study the consequences on tumor cell migration/invasion. Third, we will address the effects of tumor cellular ephrinB2/Eph4 signaling on the tumor vascular phenotype. Therefore, we will xenograft the EphB4 manipulated tumor cells and study the resultant morphology and architecture of the tumor vascular system as well as the composition of the blood vessel wall. By applying our versatile combination of in vitro assays and in vivo imaging techniques, we will provide a unique insight into the role of ephrinB2/EphB4 signaling at the blood vessel - tumor cell interface of malignant brain tumors.