Deciphering mechanisms of perivascular tumor cell invasion in glioblastoma

描述(申请人提供)：多形性胶质母细胞瘤(GBM)是一种原发的脑肿瘤，具有侵袭性生长特性，与血管系统紧密相连。例如，干细胞样的GBM细胞优先聚集在血管周围的壁龛中，侵袭性的GBM细胞通常通过血管基底膜分散在整个大脑中。此外，对GBM患者进行抗血管生成治疗通常会导致肿瘤细胞浸润增加，并形成致命的卫星病变。在肿瘤进展过程中和抗血管生成治疗后，GBM细胞与脑血管偶联的分子机制在很大程度上仍不清楚。在这个项目中，我们将研究GBM细胞如何利用由？V？8整合素、其潜在的转化生长因子？细胞外基质(ECM)蛋白配体和转化生长因子？受体选择性地促进脑部血管周围的生长和扩散。我们发现？V？8整合素在侵袭性基底膜细胞中表达，它介导转化生长因子？S的激活，从而驱动细胞的极性和定向迁移。此外，在抗血管生成治疗后的侵袭性GBM细胞中，？V？8整合素蛋白高表达。基于这些数据，我们假设？V？8整合素在肿瘤进展和抗血管治疗后调节黏附和促进GBM细胞侵袭的信号通路。此外，我们假设这些通路的抑制成分将减少GBM细胞的渗透。为了验证我们的假设，我们开发了一套独特的实验工具来(1)表征整合素V？8如何与血管内皮生长因子-A受体Neuropilin-1相互作用促进基底膜细胞的侵袭；(2)研究整合素激活的转化生长因子？S如何与血管内皮生长因子-A协同作用来驱动基底膜细胞的侵袭；以及(3)在临床前的基底膜小鼠模型中选择性地抑制这些途径的组成部分以阻断侵袭。总之，这些实验不仅将阐明？v？8整合素激活的转化生长因子、S和血管内皮生长因子-A受体之间的新联系，而且可能最终导致抑制肿瘤进展过程中细胞侵袭的新的治疗策略。 在进行抗血管治疗之后。

DESCRIPTION (provided by applicant): Glioblastoma multiformes (GBMs) are primary brain tumors displaying invasive growth properties that are tightly coupled to the vasculature. For example, stem-like GBM cells preferentially cluster in perivascular niches and invasive GBM cells often disperse throughout the brain via vascular basement membranes. Furthermore, anti-angiogenesis therapies administered to patients with GBM often lead to enhanced tumor cell infiltration and the formation of lethal satellite lesions. The molecular mechanisms that couple GBM cells to cerebral blood vessels during tumor progression and following anti-angiogenesis therapies remain largely unknown. In this project we will investigate how GBM cells exploit a specific cell adhesion and signaling axis comprised of ?v?8 integrin, its latent TGF? extracellular matrix (ECM) protein ligands, and TGF? receptors to selectively promote perivascular growth and dispersal in the brain. We have discovered that ?v?8 integrin is expressed in invasive GBM cells where it mediates activation of TGF?s to drive cell polarity and directional migration. In addition, ?v?8 integrin protein is highly expressed in invasive GBM cells following anti-angiogenesis treatments. Based on these data we hypothesize that ?v?8 integrin regulates adhesion and signaling pathways that promote GBM cell invasion during tumor progression and following anti-vascular therapies. Furthermore, we hypothesize that inhibiting components of these pathways will diminish GBM cell infiltration. To test our hypotheses we have developed a unique set of experimental tools to (1) characterize how ?v?8 integrin interacts with the VEGF-A receptor Neuropilin-1 to promote GBM cell infiltration; (2) investigate how integrin-activated TGF?s cooperate with VEGF-A to drive GBM cell invasiveness; and (3) selectively inhibit components of these pathways to block invasiveness in pre-clinical mouse models of GBM. Collectively, these experiments will not only elucidate novel links between ?v?8 integrin-activated TGF?s and VEGF-A receptors in GBM cells, but may eventually lead to new therapeutic strategies for inhibiting cell invasion during tumor progression and following anti-vascular therapies.