Oligodendrogliomas result from the expression of an activated mutant epidermal growth factor receptor in a RAS transgenic mouse astrocytoma model

• Published in: Cancer research (Chicago, Ill.) Ill.), 2003-03, Vol.63 (5), p.1106-1113
• Main Authors: HAO DING, SHANNON, Patrick, LAU, Nelson, XIAOLI WU, RONCARI, Luba, BALDWIN, Rebecca L, TAKEBAYASHI, Hirohide, NAGY, Andras, GUTMANN, David H, GUHA, Abhijit
• Format: Article
• Language: English
• Subjects: Animals; Astrocytes - cytology; Astrocytes - metabolism; Astrocytes - physiology; Astrocytoma - genetics; Astrocytoma - metabolism; Astrocytoma - pathology; Biological and medical sciences; Cell physiology; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Cell Transformation, Neoplastic - genetics; Cell Transformation, Neoplastic - metabolism; Disease Models, Animal; Fundamental and applied biological sciences. Psychology; Glial Fibrillary Acidic Protein - biosynthesis; Glial Fibrillary Acidic Protein - genetics; Humans; Mice; Mice, Transgenic; Molecular and cellular biology; Mutation; Oligodendroglioma - genetics; Oligodendroglioma - metabolism; Oligodendroglioma - pathology; ras Proteins - biosynthesis; ras Proteins - genetics; Receptor, Epidermal Growth Factor - biosynthesis; Receptor, Epidermal Growth Factor - genetics; Transplantation, Heterologous
• ISSN: 0008-5472; 1538-7445

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.