Perivascular Invasion of GBMs

描述（申请人提供）：胶质母细胞瘤（GBM）利用不同的和独特的解剖结构侵入正常的脑实质。尽管人们对GBM通过细胞外基质渗透的浸润性侵袭性给予了很多关注，但对GBM细胞在血管外沿血管周围空间移动并分散到脑实质的血管周围侵袭性知之甚少。这种表型是高级胶质瘤特有的。血管周围浸润至少需要两种细胞类型：形成血管的内皮细胞和肿瘤细胞。该项目将验证以下假设：星形细胞瘤特异性因子和脑特异性血管成分的相互作用精心策划了GBM在血管周围的传播，血管生成的开始限制了这种侵入性过程。其中一个影响血管生成和血管周围侵袭平衡的因素是MMP-9，这将是Aim 2的重点。

DESCRIPTION (provided by applicant): Glioblastomas (GBM) use different and distinct anatomical structures to invade the normal brain parenchyma. Although a lot of attention has been given to the infiltrating invasiveness of GBM percolating through the extracellular matrix, still very little is known about perivascular invasion in which GBM cells travel on the outside of blood vessels in the perivascular space dispersing significant distances into the brain parenchyma. This phenotype is specific for high-grade gliomas. Perivascular invasion requires at least two cell types: the endothelial cells that form the vascular tubes and the tumor cells. This project will test the hypothesis that perivascular GBM dissemination is orchestrated by the interaction of astrocytoma-specific factors and brain-specific blood vessel components, and that the onset of angiogenesis restricts this invasive process. One such factor that impacts the balance of angiogenesis and perivascular invasion is MMP-9, which will be the focus of Aim 2. AIM1: REVEAL THE CRITERIA FOR PERIVASCULAR GBM DISSEMINATION. AIM 1.1: Determine to which extent astrocyte-specific criteria are necessary AIM 1.2: Determine to which extent brain-specific vascular aspects are essential, and whether angiogenesis impacts perivascular invasion. AIM2: STUDY METALLOPROTEINASE MMP-9 IN GBM DISSEMINATION We hypothesize that MMP-9 has two functional roles in GBM progression dependent on its location. Tumor cells at the invading front use MMP-9 to cleave the extracellular matrix and infiltrate into the brain matrix as single cells. MMP-9 in host cells (macrophages, endothelial cells, and bone marrow), however, initiates angiogenesis and thereby restricts perivascular GBM invasion. AIM2.1: Identify the exact cell sources of MMP-9 production in GBM. AIM2.2: Reveal function of host cell-produced MMP-9 in angiogenesis and invasion. AIM2.3: Elicit function of tumor cell-produced MMP-9 in angiogenesis and invasion.