Ty Abel
Faculty Member
Last active: 3/27/2014

Cell of origin determines tumor phenotype in an oncogenic Ras/p53 knockout transgenic model of high-grade glioma.

Ghazi SO, Stark M, Zhao Z, Mobley BC, Munden A, Hover L, Abel TW
J Neuropathol Exp Neurol. 2012 71 (8): 729-40

PMID: 22805776 · PMCID: PMC3407564 · DOI:10.1097/NEN.0b013e3182625c02

Human high-grade gliomas (HGGs) are known for their histologic diversity. To address the role of cell of origin in glioma phenotype, transgenic mice were generated in which oncogenic Ras and p53 deletion were targeted to neural stem/progenitor cells (NSPCs) and mature astrocytes. The hGFAP-Cre/Kras/p53 mice develop multifocal HGGs that vary histopathologically and with respect to the expression of markers associated with NSPCs. One HGG pattern strongly expressed markers of NSPCs and arose near the subventricular zone. Additional nonoverlapping patterns that recapitulate human HGG variants were present simultaneously in the same brain. These neoplastic foci were more often cortical or leptomeningeal based, and the neoplastic cells lacked expression of NSPC markers. To determine whether cell of origin determines tumor phenotype, astrocytes and NSPCs were harvested from neonatal mutant pups. Onorthotopic transplantation, early-passage astrocytes and NSPCs formed tumors that differed in engraftment rates, latency to clinical signs, histopathology, and protein expression. Astrocyte-derivedtumors were more aggressive, had giant-cell histology, and glial fibrillary acidic protein expression. The NSPC-derived tumors retained NSPC markers and showed evidence of differentiation along astrocytic, oligodendroglial, and neuronal lineages. These results indicate that identical tumorigenic stimuli produce markedly different glioma phenotypes, depending on the differentiation status of the transformed cell.

MeSH Terms (18)

Animals Astrocytes Blotting, Western Brain Neoplasms Cell Lineage Fluorescent Antibody Technique Genes, p53 Glial Fibrillary Acidic Protein Glioma Immunohistochemistry Mice Mice, Knockout Mice, Transgenic Neoplasm Transplantation ras Proteins Real-Time Polymerase Chain Reaction Recombination, Genetic Survival Analysis

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