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(American Journal of Pathology. 2005;167:859-867.)
© 2005 American Society for Investigative Pathology

Pathological and Molecular Progression of Astrocytomas in a GFAP:¹²V-Ha-Ras Mouse Astrocytoma Model

Patrick Shannon^*, Nesrin Sabha, Nelson Lau, Deepak Kamnasaran, David H. Gutmann and Abhijit Guha

From the Department of Neuropathology^* and the Division of Neurosurgery, Western Hospital, and the Arthur and Sonia Labatts Brain Tumor Centre, Hospital for Sick Children’s Research Institute, University of Toronto, Toronto, Canada; and the Department of Neurology, Washington University School of Medicine, St. Louis, Missouri

We previously characterized a genetically engineered mouse astrocytoma model with embryonic astrocyte-specific, activated ¹²V-Ha-RAS (GFAP-RAS) transgenesis. The GFAP-RAS line Ras-B8 appears normal at birth, but 50% of mice die by 4 months from low- and high-grade astrocytomas. We examined the development and progression of astrocytomas in the Ras-B8 genetically engineered mouse. At embryonic day 16.5 (E16.5), there were no pathological differences compared to control littermates, aside from transgene expression. Diffuse astroglial hyperplasia was the first distinguishing feature in the 1-week-old Ras-B8 mice; however, these astrocytes were not transformed in vitro or in vivo. From 3 to 8 weeks the incidence of low-grade astrocytomas progressively increased with 85% of 12-week-old mice harboring low- or high-grade astrocytomas, the latter characterized by increased proliferation, nuclear atypia, and angiogenesis. Tp53 mutations were detected in both astrocytoma grades, with high-grade astrocytomas expressing elevated levels of epidermal growth factor receptor and vascular endothelial growth factor, plus decreased levels of PTEN and p16, similar to human astrocytomas. We postulate that expression of ¹²V-Ha-RAS in astroglial precursors induces astroglial hyperplasia, but transformation and subsequent progression requires additional molecular alterations resulting from aberrant activated p21-RAS. Of interest, many of these acquired alterations occur in human astrocytomas, further validating GFAP-RAS as a useful model for studying astrocytoma development and progression.

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