title: Pathological and molecular progression of astrocytomas in a GFAP:12 V-Ha-Ras mouse astrocytoma model.
abstract: We previously characterized a genetically engineered mouse astrocytoma model with embryonic astrocyte-specific, activated (12)V-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. Tp 53 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 (12)V-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.
authors.affiliation: Department of Neuropathology, The University of Toronto, Toronto, Ontario, Canada, M5T-2S8.
authors.forename: Patrick
authors.initials: P
authors.lastname: Shannon
authors.forename: Nesrin
authors.initials: N
authors.lastname: Sabha
authors.forename: Nelson
authors.initials: N
authors.lastname: Lau
authors.forename: Deepak
authors.initials: D
authors.lastname: Kamnasaran
authors.forename: David H
authors.initials: DH
authors.lastname: Gutmann
authors.forename: Abhijit
authors.initials: A
authors.lastname: Guha
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000473:pathology; D001254:Astrocytoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D002478:Cells, Cultured; D016543:Central Nervous System Neoplasms / Q000235:genetics* / Q000473:pathology*; D004195:Disease Models, Animal; D018450:Disease Progression; D015870:Gene Expression; D011905:Genes, ras; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics*; D006133:Growth Substances / Q000378:metabolism; D006965:Hyperplasia; D051379:Mice; D008813:Mice, Inbred ICR; D008822:Mice, Transgenic / Q000235:genetics*; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000172:deficiency; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
chemical_list: D005904:Glial Fibrillary Acidic Protein; D006133:Growth Substances; D009419:Nerve Tissue Proteins; D016159:Tumor Suppressor Protein p53