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The corresponding TGF proteins share sequence homology and interestingly have nearly identical effects in some biological systems and opposite effects in others. The proteins are initially inactive and are activated by enzymatic cleavage of the latent form.The TGF proteins bind with high afnity to a set of receptors distinct from others discussed in this review.In these studies, levels of TGF RIII were high in higher grade glioma tissue, while lowgrade astrocytomas and gliosis cases had moderate expression of T RII. TGF IIIII were also upregulated, but not signicantly.Interestingly, immunohistochemical studies of TGF R have demonstrated that areas of neovascularization in gliomas are strongly immunoreactive. In normal endothelial cells, TGF RIII, betaglycan, and endoglin are also expressed, though T RIII have been most easily detected in vitro. Moreover, increasing levels of TGF expression has been correlated inversely with survival among malignant glioma patients. The functional signicance of increased TGF activity in glioma has also been investigated.Despite its central physiologic role as a growth inhibitor, TGF has been shown to be mitogenic for a number of glioma cell lines. The switch from TGF s inhibitory to proliferative effects may be explained by a selective resistance to TGF R through mutation of the receptor, or to a downregulation of the receptors. However, while T RIII are considerably downregulated in other extracranial neoplasms such as Pyridoxal phosphate colorectal cancer, studies to date indicate that receptor expression is upregulated in glioma, suggesting that TGF s switch from a growth inhibitor to a mitogen may be due to other growth factor mediators such as PDGF which are upregulated by TGF proteins have been shown to Farlutin induce expression of the protooncogene csis s conversion from inhibitor to mitogen may be due in part to modulation of expression of other growth factor systems.TGF s pleiotropic effects include roles in angiogenesis, but the exact nature of its participation in this process is unclear.TGF has been described as angiogenic or antiangiogenic, depending on the nature of the assay.These effects, coupled with its induction of endothelial cell quiescence, have led some to speculate that TGF takes part in the resolution phase of angiogenesis in which endothelial cells cease proliferating and functional basement membranes and ECM complexes are laid down. TGF may also participate in angiogenesis in glioma by inuencing the activity andor expression of proteins in other growth factor systems.When added at low concentrations to endothelial cells in a threedimensional collagen gel model, TGF potentiates angiogenic effects of VEGF and bFGF such as cord formation in vitro.TGF has also been shown to induce PDGFA and B chain synthesis in endothelial cells. In addition to possible regulation of the FGF and PDGF systems, TGF has also been shown to induce EGFR. Other evidence suggesting a role for the TGF system in glioma angiogenesis includes the high immunopositivity for endoglin in childhood gliomas. Endoglin, a TGF binding protein, is expressed primarily on endothelial cells and appears to be essential for angiogenesis, recently demonstrated by the defective vascular development in mice lacking the gene. Consistent with a possible role in angiogenesis, endoglin binds the TGF that have been shown to be most angiogenic in other studies.

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