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

恶性脑肿瘤中小胶质细胞和血管之间的相互作用——对脑肿瘤血管生成、血管调节和脑肿瘤生长的意义

• 批准号: 22033510
• 负责人: Professor Dr. Peter Vajkoczy
• 金额: --
• 依托单位: Klinik für Neurochirurgie mit Arbeitsbereich Pädiatrische Neurochirurgie (CVK)
• 依托单位国家: 德国
• 项目类别: Priority Programmes
• 财政年份: 2006
• 资助国家: 德国
• 起止时间: 2005-12-31 至 2012-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/22033510?language=en
• 关键词: Interaction; between; microglia; blood; vessels

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.

恶性脑肿瘤的病理特点是在血管和肿瘤细胞之间的界面上存在多细胞相互作用。例如，血管壁的细胞成分在血管生成过程中不断相互作用，并与肿瘤细胞相互作用。此外，血管周围空间是肿瘤局部扩散的首选途径，同时肿瘤细胞对大脑皮层或血管腔的侵袭受到限制。由于引导分子ephrinB2和EphB4在脑肿瘤细胞和血管壁细胞中表达，并在细胞/细胞相互作用时被激活，影响细胞的粘附和迁移，我们假设它们在血管-肿瘤细胞界面的细胞相互作用中起核心作用。为了验证这一点，我们将首先扩展我们之前关于血管ephrinB2/EphB4信号在肿瘤血管形态发生中的作用的研究。血管ephrinB2反向信号将通过体内逆转录病毒方法和条件内皮细胞特异性ephrinB2缺陷小鼠来操纵。我们还将分析血管ephrinB2/EphB4信号是否参与肠套接性血管生长，因此可能代表这一迄今尚未完全了解的血管生成过程的新介质。其次，我们将研究肿瘤细胞ephrinB2/Eph4信号在脑肿瘤细胞迁移和侵袭中的作用，并验证ephrinB2/EphB4可能作为脑肿瘤细胞的区室化因子，引导它们进入首选的血管周围局部传播途径的假设。为了验证这一点，我们将用EphB4变体转染肿瘤细胞或通过siRNA敲除EphB4的表达，并研究其对肿瘤细胞迁移/侵袭的影响。第三，我们将探讨肿瘤细胞ephrinB2/Eph4信号通路对肿瘤血管表型的影响。因此，我们将异种移植EphB4操纵的肿瘤细胞，并研究由此产生的肿瘤血管系统的形态和结构以及血管壁的组成。通过结合体外实验和体内成像技术，我们将对ephrinB2/EphB4信号在恶性脑肿瘤血管-肿瘤细胞界面中的作用提供独特的见解。