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[Cancer Research 63, 1106-1113, March 1, 2003]
© 2003 American Association for Cancer Research

Tumor Biology

Oligodendrogliomas Result from the Expression of an Activated Mutant Epidermal Growth Factor Receptor in a RAS Transgenic Mouse Astrocytoma Model1

Hao Ding, Patrick Shannon, Nelson Lau, Xiaoli Wu, Luba Roncari, Rebecca L. Baldwin, Hirohide Takebayashi, Andras Nagy, David H. Gutmann and Abhijit Guha2

Samuel Lunenfeld Research Institute, Mount Sinai Hospital [H. D., X. W., A. N.]; Division of Neuropathology [P. S.] and Division of Neurosurgery [A. G.], University Health Network, Toronto, Ontario, Canada; Department of Neurology, Washington University School of Medicine, St. Louis, Missouri [R. L. B., D. H. G.); Arthur & Sonia Labatt Brain Tumor Center, Hospital for Sick Children’s Research Institute, Toronto, Ontario, Canada [H. D., N. L., L. R., A. G.]; and Laboratory of Neural Information, National Institute for Physiological Sciences, Okazaki, Japan [H. T.]

A significant proportion of human malignant gliomas exhibit amplification, overexpression, or mutations of the epidermal growth factor receptor (EGFR). To define the functional role(s) of the EGFR in the pathogenesis of gliomas, we established transgenic mice that express both wild-type (wt) and mutant (EGFRvIII) EGFR molecules using the human glial fibrillary acidic protein (GFAP) promoter. Both GFAP-EGFRwt and GFAP-EGFRvIII transgenic mice demonstrated increased numbers of astrocytes compared with control littermates, however, developed normally without formation of gliomas. To determine whether EGFR overexpression could modify the tumor phenotype in our previously reported GFAP-V12Ha-ras transgenic mouse astrocytoma model, mice expressing both activated RAS and EGFR were developed. GFAP-V12Ha-ras;GFAP-EGFRvIII, but not GFAP-V12Ha-ras;GFAP-EGFRwt double transgenic mice, had decreased survival with fifty percent of the mice dead at 2–4 weeks from gliomas, compared with 12–16 weeks for the GFAP-V12Ha-ras mice. Furthermore, GFAP-V12Ha-ras;GFAP-EGFRvIII mice developed oligodendrogliomas and mixed oligoastrocytoma tumors, instead of the fibrillary astrocytomas observed in GFAP-V12Ha-ras mice. In addition to yielding a spontaneous model of infiltrating oligodendroglioma, this study demonstrates that astrocyte-specific expression of EGFRvIII alone is insufficient for gliomagenesis but rather contributes to glioma progression in the context of existing predisposing genetic changes.




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