A mouse model for glioma: Biology, pathology, and therapeutic opportunities

The epidermal growth factor receptor (EGFR) gene is amplified or mutated in 30-50% of human glioblastoma multiforme. These mutations are usually assoc iated with deletions of the INK4a-ARF locus, which encodes 2 gene products (p16(INK4a) and p19(ARF)) involved in cell cycle arrest and apoptosis. We h ave investigated the role of EGFR mutation in gliomagenesis using avian ret roviral vectors to transfer a mutant EGFR gene to glial precursors and astr ocytes in transgenic mice. These mice express rv-a, a gene encoding the ret rovirus receptor TVA, which is under the control of brain cell type-specifi c promoters. We demonstrate that expression of a constitutively active, mut ant form of EGFR in cells in the glial lineage can induce lesions with many similarities to human gliomas, including increased cell density, vascular proliferation, and immunohistochemical staining for glial fibrillary acidic protein (GFAP) and nestin. We also demonstrate that primary astrocytes cul tured from transgenic mice expressing tv-a from the GFAP promoter are effic iently infected in culture, and such genetically modified cell cultures can be tumorigenic in nude mice. The combinations of genetic lesions (eg, muta ted EGFR, INK4a-/-) leading to tumor formation in these 2 mouse systems are similar to those found in human gliomas. These genetically defined animal models for gliomas will allow for the resting of therapies that are targete d specifically at the gene products involved in the pathogenesis of gliomas .