Ras activation in astrocytomas and neurofibromas.
Oncogenic mutations resulting in activated Ras Guanosine Triphosphate (GTP) are prevalent in 30% of all human cancers, but not primary nervous system tumors. Several growth factors/receptors are implicated in the pathogenesis of malignant astrocytomas including epidermal growth factor (EGFR) and platelet derived growth factor (PDGF-R) receptors, plus the highly potent and specific angiogenic vascular endothelial growth factor (VEGF). A significant proportion of these tumors also express a truncated EGFR, which is constitutively activated. Our work demonstrates that the mitogenic signals from both the normal PDGF-R and EGFR and the truncated EGFR activate Ras. Inhibition of Ras by genetic or pharmacological strategies leads to decreased astrocytoma tumorgenic growth in vitro and decreased expression of VEGF. This suggests that these agents may be potentially important as novel anti-proliferative and anti-angiogenic therapies for human malignant astrocytomas. In contrast to astrocytomas, where increased levels of activated Ras GTP results from transmitted signals from activated growth factor receptors, the loss of neurofibromin is postulated to lead to functional up-regulation of the Ras pathway in neurofibromatosis-1(NF-1). We have demonstrated that NF-1 neurofibromas and neurogenic sarcomas, compared to non-NF-1 Schwannomas, have markedly elevated levels of activated Ras GTP. Increased Ras GTP was associated with increased tumor vascularity in the NF-1 neurogenic sarcomas, perhaps related to increased VEGF secretion. The role of Ras inhibitors as potential therapy in this tumor is also under study.
Guha
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Division of Neurosurgery, Toronto Hospital, University of Toronto, Canada.
D001254:Astrocytoma / Q000235:genetics* / Q000473:pathology; D002455:Cell Division / Q000502:physiology; D016228:Endothelial Growth Factors / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology*; D011905:Genes, ras / Q000235:genetics*; D006801:Humans; D008222:Lymphokines / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000473:pathology; D009455:Neurofibroma / Q000235:genetics* / Q000473:pathology; D025542:Neurofibromin 1; D018319:Neurofibrosarcoma / Q000098:blood supply; D010524:Peripheral Nervous System Neoplasms / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D017479:Receptors, Platelet-Derived Growth Factor / Q000378:metabolism; D014407:Tumor Cells, Cultured / Q000473:pathology; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D018631:ras Proteins / Q000378:metabolism
D016228:Endothelial Growth Factors; D008222:Lymphokines; D025542:Neurofibromin 1; D011506:Proteins; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D066246:ErbB Receptors; D017479:Receptors, Platelet-Derived Growth Factor; D018631:ras Proteins