Plateletderived growth factor secretion by activated endothelial cells recruits pericytes to the site of newly sprouting vessels to aid in establishment of a new basement membrane.Of the four PDGF family members, A and B are the two expressed by gliomas; whereas of the PDGF tyrosine kinase receptors, PDGFR is expressed by glioma cells, suggesting a role in autocrine growth, whereas PDGFR is expressed by glioma endothelium and pericytes, particularly the latter, suggesting its importance in the migration of pericytes into newly formed tumor blood vessels.The Fostamatinib ability of a selective inhibitor of PDGFR to block glioma growth and reduce vessel density suggests the importance of pericytes in glioma vessel stability.The summation of these proand antiangiogenic forces modulated by tissue hypoxia and genetic alterations establish the socalled angiogenic switch favoring glioma angiogenesis.The most potent activator of angiogenic mechanisms in brain tumors is tissue hypoxia.One well studied pathway is the HIFVEGFA pathway, which leads to endothelial cell proliferation and migration.In addition to VEGF, another well studied proangiogenic molecule in brain tumors is basic broblast growth factor.In glioma, FGF is expressed by tumor cells as well as in blood vessels.Once the balance tips towards proangiogenic, the tumor begins neovascularization.Sources of proangiogenic stimuli are glioma cells, endothelium, and microglia.Sources of antiangiogenic stimuli are glioma cells and endothelium.VEGFA is primarily induced by tissue hypoxia via the HIF pathway.Interleukin is also highly expressed in pseudopalisading cells in GBM, consistent with the hypothesis that hypoxia induces its expression.Recent work indicates that the tumor suppressor protein ING regulates interleukin mediated angiogenesis in glioma via the transcription factor NFB.SDF and its receptor CXCR are also found in glioma, with the highest levels of expression in areas of necrosis and the vascular endothelium, and the levels correlate tightly with those of HIF.In addition, in vitro experiments have shown that SDF has a signicant Ospemifene effect on glioma cell migration and proliferation.The best studied of this group of proteins in the context of tumor angiogenesis is the semaphorins, which signal via neuropilins and plexins.Neuropilins are found on vascular endothelial cells and function as receptors for VEGF.The deltalike ligand is a selective inhibitor of VEGF via its action on VEGFR and its coreceptor neuropilin, although its exact role in brain tumor angiogenesis is not well understood.Tenascin also promotes VEGF expression and focal adhesion kinase phosphorylation, which are both important to ongoing angiogenesis.Consistent with its role in tumor biology, a phase II trial of antitenascinC antibody in GBM patients showed an increase in median survival.Another example of an ECM protein involved in angiogenesis is bronectin.A number of antiangiogenic factors have been described and play an important role in tumor angiogenesis.Perhaps the best understood endogenous antiangiogenic protein is angiostatin.Although not yet demonstrated to be a native cleavage product of thrombospondin, kringle domain has been shown to promote several antiangiogenic processes via binding to glucoseregulated protein, a heat shock protein family member found on the cell surface of endothelial cells.Expression of kringle domain in mouse glioma has been shown to decrease tumor angiogenesis.TSP is made by platelets, endothelial cells, and smooth muscle cells in normal tissue.

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