title: Oligodendrogliomas result from the expression of an activated mutant epidermal growth factor receptor in a RAS transgenic mouse astrocytoma model.
abstract: 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-EGFR(wt) 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-V(12)Ha-ras transgenic mouse astrocytoma model, mice expressing both activated RAS and EGFR were developed. GFAP-V(12)Ha-ras;GFAP-EGFRvIII, but not GFAP-V(12)Ha-ras;GFAP-EGFR(wt) 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-V(12)Ha-ras mice. Furthermore, GFAP-V(12)Ha-ras;GFAP-EGFRvIII mice developed oligodendrogliomas and mixed oligoastrocytoma tumors, instead of the fibrillary astrocytomas observed in GFAP-V(12)Ha-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.
authors.affiliation: Samuel Lunenfeld Research Institute, Mount Sinai Hospital, USA.
authors.forename: Hao
authors.initials: H
authors.lastname: Ding
authors.forename: Patrick
authors.initials: P
authors.lastname: Shannon
authors.forename: Nelson
authors.initials: N
authors.lastname: Lau
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Wu
authors.forename: Luba
authors.initials: L
authors.lastname: Roncari
authors.forename: Rebecca L
authors.initials: RL
authors.lastname: Baldwin
authors.forename: Hirohide
authors.initials: H
authors.lastname: Takebayashi
authors.forename: Andras
authors.initials: A
authors.lastname: Nagy
authors.forename: David H
authors.initials: DH
authors.lastname: Gutmann
authors.forename: Abhijit
authors.initials: A
authors.lastname: Guha
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000378:metabolism / Q000502:physiology; D001254:Astrocytoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D066246:ErbB Receptors / Q000096:biosynthesis* / Q000235:genetics; D005904:Glial Fibrillary Acidic Protein / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009837:Oligodendroglioma / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D014183:Transplantation, Heterologous; D018631:ras Proteins / Q000096:biosynthesis / Q000235:genetics*
chemical_list: D005904:Glial Fibrillary Acidic Protein; C410723:epidermal growth factor receptor VIII; D066246:ErbB Receptors; D018631:ras Proteins