Perivascular Invasion of GBMs

描述（由申请人提供）：胶质母细胞瘤（GBM）使用不同且独特的解剖结构侵入正常脑实质。 尽管已经对GBM通过细胞外基质的浸润侵袭性给予了很多关注，但是对于血管周围侵袭仍然知之甚少，其中GBM细胞在血管周围空间中的血管外侧上行进，显著地分散到脑实质中。 这种表型是高级别胶质瘤特有的。 血管周围浸润需要至少两种细胞类型：形成血管的内皮细胞和肿瘤细胞。 该项目将检验血管周围GBM传播是由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的假设，并且血管生成的发生限制了这种侵入性过程。 影响血管生成和血管周围侵袭平衡的一个这样的因素是MMP-9，这将是目标2的焦点。 目的1：揭示血管周围GBM播散的标准。 目的1.1：确定星形胶质细胞特异性标准的必要性 目的1.2：确定在何种程度上脑特异性血管方面是必不可少的，以及血管生成是否影响血管周围浸润。 目的2：研究金属蛋白酶MMP-9在GBM播散中的作用 我们假设MMP-9在GBM进展中具有两种功能作用，这取决于其位置。 位于侵袭前沿的肿瘤细胞利用MMP-9切割细胞外基质并作为单细胞浸润到脑基质中。 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侵袭。 目标2.1：确定GBM中MMP-9产生的确切细胞来源。 AIM2.2：揭示宿主细胞产生的MMP-9在血管生成和侵袭中的功能。 AIM2.3：激发肿瘤细胞产生的MMP-9在血管生成和侵袭中的功能。

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.