Astrocyte-specific expression of activated p21-ras results in malignant astrocytoma formation in a transgenic mouse model of human gliomas

Activation of the p21-ras signaling pathway from aberrantly expressed recep tors promotes the growth of malignant human astrocytomas. We developed a tr ansgenic mouse astrocytoma model using the glial fibrillary acidic protein (GFAP) promoter to express oncogenic V(12)Ha-ras, specifically in astrocyte s. The development of GFAP-immunoreactive astrocytomas was directly proport ional to the level of V(12)Ha-ras transgene expression. Chimeras expressing high levels of V(12)Ha-ras in astrocytes died from multifocal malignant as trocytomas within 2 weeks, whereas those with moderate levels went to germ- line transmission. Ninety-five percent of these mice died from solitary or multifocal low- and high-grade astrocytomas within 2-6 months. These transg enic astrocytomas are pathologically similar to human astrocytomas, with a high mitotic index, nuclear pleomorphism, infiltration, necrosis, and incre ased vascularity. Derivative astrocytoma cells are tumorigenic upon inocula tion in another host. The transgenic astrocytomas exhibit additional molecu lar alterations associated with human astrocytomas, including a decreased o r absent expression of p16, p19, and PTEN as well as overexpression of EGFR , MDM2, and CDK4. Cytogenetic analysis revealed consistent clonal aneuploid ies of chromosomal regions syntenic with comparable loci altered in human a strocytomas. Therefore, this transgenic mouse astrocytoma model recapitulat es many of the molecular histopathological and growth characteristics of hu man malignant astrocytomas in a reproducible, germ-line-transmitted, and hi gh-penetrance manner.