Glioma-Astrocyte Vascular Interactions

项目摘要/摘要： 原发脑瘤，神经胶质瘤，到目前为止都没有得到有效的治疗，这使它们成为一个巨大的 在临床上提出挑战。这在一定程度上是由于胶质瘤不寻常的能力渗透到周围的大脑。 使手术切除变得困难。肿瘤细胞可以通过脑实质移动，如下 白质束或沿血管。归根结底，许多胶质瘤细胞与血管相关， 大概是为了获得更多的营养物质。在最近的一项研究中，我们表明胶质瘤细胞是 通过对血管内皮细胞产生的缓激肽的反应而被吸引到脑血管 细胞。一旦与血管联系在一起，胶质瘤细胞就占据了血管系统，并最终诱导 血管萌发和血管生成。了解神经胶质瘤如何改变人的生理 现有的脑血管系统是这笔赠款的主要目标。我们假设 血管联系提供了一种内在的优势，胶质瘤积极地调节行为 相关联的血管。更具体地说，我们假设(1)血管相关胶质瘤 细胞使星形细胞的末端从血管中移位；(2)这会破坏正常的星形细胞血管。 偶联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) 星形细胞终足的移位导致血脑屏障的破坏；和(4) 附着在血管上的胶质瘤细胞通过释放血管活性物质来主动调节血管张力 化合物。这些假说将使用临床相关的胶质瘤动物模型进行验证。 采用单光子和多光子成像研究相结合的原位和活体研究。这些 研究有可能阐明干扰这些病毒破坏性生物学的新方法。 未来的致命肿瘤。

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.