Glioma-Astrocyte Vascular Interactions

项目概要/摘要： 原发性脑肿瘤，神经胶质瘤，迄今为止一直逃避有效的治疗，使他们成为巨大的 临床挑战这部分是由于神经胶质瘤不寻常的能力，渗透周围的大脑 使得手术切除变得困难。肿瘤细胞可以通过脑实质移动， 白色物质束或沿着血管。最终，许多胶质瘤细胞与血管结合， 大概是为了获得更多的营养。在最近的一项研究中，我们发现神经胶质瘤细胞 通过响应血管内皮细胞产生的缓激肽而被吸引到脑血管， 细胞一旦与血管相连，胶质瘤细胞就会占据脉管系统，并最终诱导 血管发芽和血管生成。了解神经胶质瘤如何改变脑组织的生理机能 现有的脑血管系统是这项赠款的主要目标。我们假设 血管关联提供了内在优势，并且胶质瘤主动调节行为， 相关的血管。更具体地说，我们假设（1）血管相关胶质瘤 细胞从血管中置换星形胶质细胞的终足;（2）这破坏了正常的星形胶质细胞-血管 偶联，因为星形胶质细胞衍生的血管活性分子不能到达血管平滑肌细胞;（3） 星形胶质细胞终足的移位导致血脑屏障的破坏;以及（4）一旦 胶质瘤细胞附着在血管上，通过释放血管活性物质来主动调节血管张力。 化合物.这些假设将使用临床相关的神经胶质瘤动物模型进行检验 采用单光子和多光子成像研究的组合在原位和体内。这些 研究有可能阐明新的方法来干扰这些破坏性的生物学。 未来致命的肿瘤。

Project Summary/Abstract: Primary brain tumors, gliomas, have thus far evaded effective treatment making them a tremendous challenge clinically. This is in part due to the unusual ability of gliomas to infiltrate surrounding brain making surgical resection difficult. Tumor cells can move through the brain parenchyma, following white matter tracts or along blood vessels. Ultimately many glioma cells associate with blood vessels, presumably to gain enhanced access to nutrients. In a recent study, we show that glioma cells are attracted to cerebral vessels by responding to bradykinin which is produced by vascular endothelial cells. Once associated with blood vessels, glioma cells co-opt the vasculature and eventually induce vessel sprouting and angiogenesis. Understanding how gliomas alter the physiology of the existing cerebral vasculature is the primary objective of this grant. We hypothesize that the vascular association provides an intrinsic advantage and that gliomas actively regulate the behavior of the associated blood vessel. More specifically we hypothesize that (1) vessel associated glioma cells displace astrocytic endfeet from the blood vessels; (2) this disrupts normal astrocyte-vascular coupling as astrocyte-derived vasoactive molecules fail to reach vascular smooth muscle cells; (3) displacement of astrocytic endfeet leads to a breakdown of the blood-brain barrier; and (4) once attached to vessels, glioma cells actively regulate vascular tone through the release of vasoactive compounds. These hypotheses will be tested using a clinically relevant animal model of glioma employing a combination of single- and multi-photon imaging studies in situ and in vivo. These studies have the potential to elucidate novel ways to interfere with the destructive biology of these deadly tumors in the future.