A recombinant lentiviral PDGF-driven mouse model of proneural glioblastoma
| Autor: | Gilbert J. Rahme, Mark A. Israel, Bryan W. Luikart, Chao Cheng |
|---|---|
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Genetically modified mouse Cancer Research PDGFB Brain Neoplasms Transgene Biology medicine.disease Small hairpin RNA Disease Models Animal Mice 03 medical and health sciences 030104 developmental biology Oncology CDKN2A Glioma Basic and Translational Investigations Stereotactic injection Cancer research medicine Animals Neurology (clinical) Glioblastoma Proneural Glioblastoma |
| Zdroj: | Neuro-Oncology. 20:332-342 |
| ISSN: | 1523-5866 1522-8517 |
| DOI: | 10.1093/neuonc/nox129 |
| Popis: | Background Mouse models of glioblastoma (GBM), the most aggressive primary brain tumor, are critical for understanding GBM pathology and can contribute to the preclinical evaluation of therapeutic agents. Platelet-derived growth factor (PDGF) signaling has been implicated in the development and pathogenesis of GBM, specifically the proneural subtype. Although multiple mouse models of PDGF-driven glioma have been described, they require transgenic mice engineered to activate PDGF signaling and/or impair tumor suppressor genes and typically represent lower-grade glioma. Methods We designed recombinant lentiviruses expressing both PDGFB and a short hairpin RNA targeting Cdkn2a to induce gliomagenesis following stereotactic injection into the dentate gyrus of adult immunocompetent mice. We engineered these viruses to coexpress CreERT2 with PDGFB, allowing for deletion of floxed genes specifically in transduced cells, and designed another version of this recombinant lentivirus in which enhanced green fluorescent protein was coexpressed with PDGFB and CreERT2 to visualize transduced cells. Results The dentate gyrus of injected mice showed hypercellularity one week post-injection and subsequently developed bona fide tumors with the pathologic hallmarks of GBM leading to a median survival of 77 days post-injection. Transcriptomic analysis of these tumors revealed a proneural gene expression signature. Conclusion Informed by the genetic alterations observed in human GBM, we engineered a novel mouse model of proneural GBM. While reflecting many of the advantages of transgenic mice, this model allows for the facile in vivo testing of gene function in tumor cells and makes possible the rapid production of large numbers of immunocompetent tumor-bearing mice for preclinical testing of therapeutics. |
| Databáze: | OpenAIRE |
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