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High-Grade Glioma Formation Results from Postnatal Pten Loss or Mutant Epidermal Growth Factor Receptor Expression in a Transgenic Mouse Glioma Model

¹ Arthur & Sonia Labatt Brain Tumour Research Centre and ² Mouse Imaging Centre, The Hospital for Sick Children; ³ Division of Neuropathology and Neurosurgery, University Health Network, Toronto, Ontario, Canada; ⁴ Department of Neurology, Washington University of Medicine, St. Louis, Missouri; and ⁵ The Wistar Institute, Philadelphia, Pennsylvania

Requests for reprints: Abhijit Guha, Fellow of the Royal College of Surgeons of Canada, 4W-446 Toronto Western Hospital, 399 Bathurst Street, Toronto, Ontario, Canada M5T 2S8. Phone: 416-603-5740; Fax: 416-603-5298; E-mail: Abhijit.Guha{at}uhn.on.ca.

High-grade gliomas are devastating brain tumors associated with a mean survival of <50 weeks. Two of the most common genetic changes observed in these tumors are overexpression/mutation of the epidermal growth factor receptor (EGFR) vIII and loss of PTEN/MMAC1 expression. To determine whether somatically acquired EGFRvIII expression or Pten loss accelerates high-grade glioma development, we used a previously characterized RasB8 glioma-prone mouse strain, in which these specific genetic changes were focally introduced at 4 weeks of age. We show that both postnatal EGFRvIII expression and Pten inactivation in RasB8 mice potentiate high-grade glioma development. Moreover, we observe a concordant loss of Pten and EGFR overexpression in nearly all high-grade gliomas induced by either EGFRvIII introduction or Pten inactivation. This novel preclinical model of high-grade glioma will be useful in evaluating brain tumor therapies targeted to the pathways specifically dysregulated by EGFR expression or Pten loss. (Cancer Res 2006; 66(15): 7429-37)

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