Growth factor receptors are marked by asterisks and are shown in greater detail in the inset.Growth factor binding may lead to cell proliferation, upregulation of key proteases, andor initiation of signaling leading to VEGF transcription in tumor cells or endothelial cells.Neuropilins and were recently shown to be the newest members of the VEGF receptor family and may be involved in glioma angiogenesis.Proposed growth factormediated signaling pathways leading to VEGF transcription in tumor cells or endothelial cells.EGF, TGF; the ligands, which are dimerized, bind to tyrosine transreceptor subunits and induce dimerization.The details of TGF again binding as a dimer binds to only the RII subunit, and binding induces recruitment of the RI Citric acid subunit and transphosphorylation of RI by the constitutively phosphorylated RII.Thus FGF secreted by tumor cells may induce angiogenesis in a paracrine fashion, acting on endothelial cells directly as well as stimulating tumor cells in an D-Cycloserine autocrine and paracrine fashion to synthesize VEGF.Studies such as these have established that FGF and FGF may modulate endothelial cell activity directly and indirectly.While high levels of these growth factors have been detected in gliomas, functional roles for these proteins in glioma angiogenesis have also been investigated directly.Direct evidence for the role of FGF in glioma angiogenesis is given by in vivo studies in which intracranially implanted UMG tumors showed a signi cantly lower degree of neovascularization after treatment with an antiFGF antibody as compared to untreated tumors. Additionally, endothelial tube formation stimulated by the presence of glioma cells in a threedimensional collagen was markedly inhibited after incubation with an antiFGF antibody. Increased neovascularization accompanies the mitotic and pleiomorphic cellular changes in the malignant progression of gliomas.Immunohistochemical studies on primary glioma specimens showing that FGF is expressed in human gliomas also showed that FGF levels are increased in high grade as compared to lowgrade gliomas. Additional studies have also reported increasing FGF levels with glioma grade, noting that FGF expression correlates with glioma vascularity. Endothelial cells from CSF that contained FGF were more proliferative when compared with controls; the degree of endothelial cell stimulation correlated with FGF levels; and the level of FGF correlated with microvessel density.Most strikingly, patients with CSF containing FGF recurred earlier, with earlier tumor recurrence correlating with increased microvessel density.Interestingly, while a number of different types of brain tumors were included in this study, the highest level of FGF was detected in a pilocytic astrocytoma.Studies from our laboratory have supported the importance of microvessel density as a prognostic indicator of postoperative survival of patients with astroglial brain tumors. Research to date has focused on the involvement of FGF and FGF.A recent study provided evidence that FGF may also participate in glioma angiogenesis. The expression of these proteins was undetectable in control nonneoplastic tissue.Moreover, the expression of FGF and its receptors correlated with histological grade, tumor type, microvessel count, and cell density.These observations were corroborated by in vitro studies in which UMG, UMG, and UMG glioma cell lines were shown to secrete FGF.Additional studies showed that FGF could regulate VEGF expression and the formation of new blood vessels.

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