Glioma-Astrocyte Vascular Interactions

描述(申请人提供)：原发脑瘤，胶质瘤，到目前为止，逃避有效的治疗，使他们在临床上是一个巨大的挑战。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，使得手术切除变得困难。肿瘤细胞可以沿着白质束或血管在脑实质中移动。最终，许多胶质瘤细胞与血管联系在一起，可能是为了获得更多的营养物质。在最近的一项研究中，我们发现胶质瘤细胞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。一旦与血管联系在一起，胶质瘤细胞就会选择血管系统，最终诱导血管萌发和血管生成。了解胶质瘤如何改变现有脑血管的生理学是这项拨款的主要目标。我们假设血管关联提供了一种内在优势，而胶质瘤积极调节相关血管的行为。更具体地说，我们假设(1)血管相关的胶质瘤细胞从血管中移位星形细胞终足；(2)这破坏了正常的星形细胞-血管偶联，因为星形细胞衍生的血管活性分子无法到达血管平滑肌细胞；(3)星形细胞端足的移位导致血脑屏障的破坏；以及(4)胶质瘤细胞一旦附着在血管上，就会通过释放血管活性化合物来主动调节血管张力。这些假说将通过临床上相关的胶质瘤动物模型进行验证，该模型采用了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未来干扰这些致命肿瘤的破坏性生物学的新方法。

DESCRIPTION (provided by applicant): 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. Tumr 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.