Perivascular Invasion of GBMs

描述(申请人提供)：胶质母细胞瘤(GBM)使用不同和不同的解剖结构侵犯正常的脑实质。尽管人们对GBM通过细胞外基质渗透的侵袭性给予了很大的关注，但对GBM细胞在血管周围空间的血管外走行并向脑实质扩散的血管周围侵袭知之甚少。这种表型是高级别胶质瘤特有的。血管周围的侵袭至少需要两种细胞类型：形成血管的内皮细胞和肿瘤细胞。该项目将检验这样一种假设，即星形细胞瘤特异性因子和脑特异性血管成分的相互作用协调了血管周围GBM的扩散，并且血管生成的开始限制了这一侵袭过程。其中一个影响血管生成和血管周围侵袭平衡的因素是基质金属蛋白酶-9，它将是目标2的重点。 目的：揭示血管周围基底膜扩散的标准。 目标1.1：确定星形胶质细胞特有标准的必要性 目的1.2：确定脑特异性血管方面在多大程度上是必需的，以及血管生成是否影响血管周围的侵袭。 目的：研究基质金属蛋白酶-9在基底膜播散中的作用 我们假设，基质金属蛋白酶-9在基底膜发生发展中有两个功能作用，这取决于它的位置。侵袭前沿的肿瘤细胞使用基质金属蛋白酶-9裂解细胞外基质，并以单个细胞的形式渗透到脑基质中。然而，宿主细胞(巨噬细胞、内皮细胞和骨髓)中的MMP-9启动血管生成，从而限制血管周围GBM的侵袭。 目的：确定基底膜产生基质金属蛋白酶-9的确切细胞来源。 目的：揭示宿主细胞产生的基质金属蛋白酶-9在血管生成和侵袭中的作用。 目的：探讨肿瘤细胞产生的基质金属蛋白酶-9在血管生成和侵袭中的作用。

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.