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Astrocyte-specific Expression of Activated p21-ras Results in Malignant Astrocytoma Formation in a Transgenic Mouse Model of Human Gliomas¹

Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, M5G 1X5 Canada [H. D., L. R., X. W., N. L., A. N., A. G.]; Arthur & Sonia Labatts Brain Tumor Center, Hospital for Sick Children’s Research Institute, Toronto, Ontario, M5G 1X8 Canada [H. D., L. R., N. L., A. G.]; Divisions of Neuropathology [P. S.] and Neurosurgery [A. G.], The Toronto Hospital Western Division, University Health Network, Toronto, Ontario, M5T 2S8 Canada; Ontario Cancer Institute, Toronto, Ontario, M5G 2C1 Canada [J. K., J. A. S.]; and Department of Neurology, Washington University School of Medicine, St. Louis, Missouri [D. H. G.]

Activation of the p21-ras signaling pathway from aberrantly expressed receptors promotes the growth of malignant human astrocytomas. We developed a transgenic mouse astrocytoma model using the glial fibrillary acidic protein (GFAP) promoter to express oncogenic V¹²Ha-ras, specifically in astrocytes. The development of GFAP-immunoreactive astrocytomas was directly proportional to the level of V¹²Ha-ras transgene expression. Chimeras expressing high levels of V¹²Ha-ras in astrocytes died from multifocal malignant astrocytomas 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 transgenic astrocytomas are pathologically similar to human astrocytomas, with a high mitotic index, nuclear pleomorphism, infiltration, necrosis, and increased vascularity. Derivative astrocytoma cells are tumorigenic upon inoculation in another host. The transgenic astrocytomas exhibit additional molecular alterations associated with human astrocytomas, including a decreased or absent expression of p16, p19, and PTEN as well as overexpression of EGFR, MDM2, and CDK4. Cytogenetic analysis revealed consistent clonal aneuploidies of chromosomal regions syntenic with comparable loci altered in human astrocytomas. Therefore, this transgenic mouse astrocytoma model recapitulates many of the molecular histopathological and growth characteristics of human malignant astrocytomas in a reproducible, germ-line-transmitted, and high-penetrance manner.

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