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Ras Activation in Astrocytomas and Neurofibromas

Published online by Cambridge University Press:  18 September 2015

Abhijit Guha
Abhijit Guha*
Affiliation:
Division of Neurosurgery, The Toronto Hospital, University of Toronto, Toronto and theLunenfeld Research Institute Mt. Sinai Hospital, University of Toronto, Toronto
*
2-415 McLaughlin Pavilion, The Toronto Hospital, 399 Bathurst Street, Toronto, Ontario, Canada M5T 2S8
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Abstract:

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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.

Résumé:

RÉSUMÉ:

). Les mutations d'oncogènes provoquant une activation de Ras-GTP ont une prévalence de 30% dans tous les cancers humains, mais non dans les tumeurs primitives du système nerveux. Plusieurs facteurs de croissance / récepteurs sont impliqués dans la pathogenèse des astrocytomes malins dont le récepteur du facteur de croissance épidermique (EGF-R) et celui du facteur de croissance plaquettaire (PDGF-R), ainsi que le facteur de croissance endothélial vasculaire (VEGF), un facteur de croissance très puissant et hautement spécifique. Une grande proportion des astrocytomes malins expriment un EGF-R tronqué qui est activé constitutivement. Nos travaux démontrent que les signaux mitogènes du PDGF-R normal et du EGFR normal et du EGFR tronqué activent Ras. L'inhibition de Ras par des stratégies génétiques ou pharmacologiques provoque la diminution de la croissance tumorale astrocytaire in vitro et diminue l'expression du VEGF. Ceci indique que ces agents pourraient être importants comme traitements antipro-lifératifs et antiangiogéniques dans les astrocytomes malins humains. Contrairement aux astrocytomes où des niveaux augmentés de Ras.GTP activé résultent de signaux transmis provenant de récepteurs de facteurs de croissance activés, on pense que la perte de la neurofibromine amène une régulation fonctionnelle à la hausse de la voie Ras dans la neu-rofibromatose I (NFI). Nous avons démontré que les neurofibromes de la NFI et les sarcomes neurogéniques non-NFI ont des niveaux très élevés de Ras.GTP activé comparés aux Schwannomes. Un Ras.GTP augmenté était associé à une vascularité tumorale augmentée dans les sarcomes neurogéniques de la NFI, possiblement en relation avec une augmentation de la sécrétion du VEGF. Le rôle des inhibiteurs de Ras en tant que thérapie dans cette tumeur est aussi à l'étude présentement.

Type
Review Article
Information
Canadian Journal of Neurological Sciences , Volume 25 , Issue 4 , November 1998 , pp. 267 - 281
Copyright
Copyright © Canadian Neurological Sciences Federation 1998

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