RRC ID 53977
Author Sumiyoshi K, Koso H, Watanabe S.
Title Spontaneous development of intratumoral heterogeneity in a transposon-induced mouse model of glioma.
Journal Cancer Sci
Abstract Glioma is the most common form of malignant brain cancer in adults. The Sleeping Beauty (SB) transposon-based glioma mouse model allows for effective in vivo analysis of candidate genes. In the present study, we developed a transposon vector that encodes the triple combination of platelet-derived growth factor subunit A (PDGFA), and shRNAs against Nf1 and Trp53 (shNf1/shp53). Initiation and progression of glioma in the brain were monitored by expression of a fluorescent protein. Transduction of the vector into neural progenitor and stem cells (NPC) in the subventricular zone (SVZ) of the neonatal brain induced proliferation of oligodendrocyte precursor cells, and promoted formation of highly penetrant malignant gliomas within 2-4 months. Cells isolated from the tumors were capable of forming secondary tumors. Two transposon vectors, encoding either PDGFA or shNf1/shp53 were co-electroporated into NPC. Cells expressing PDGFA or shNf1/shp53 were labeled with unique fluorescent proteins allowing visualization of the spatial distribution of cells with different genetic alterations within the same tumor. Tumor cells located at the center of tumors expressed PDGFA at higher levels than those located at the periphery, indicating that intratumoral heterogeneity in PDGFA expression levels spontaneously developed within the same tumor. Tumor cells comprising the palisading necrosis strongly expressed PDGFA, suggesting that PDGFA signaling is involved in hypoxic responses in glioma. The transposon vectors developed are compatible with any genetically engineered mouse model, providing a useful tool for the functional analysis of candidate genes in glioma.
Volume 109(5)
Pages 1513-1523
Published 2018-5-1
DOI 10.1111/cas.13579
PMID 29575648
PMC PMC5980157
MeSH Animals Brain Neoplasms / etiology* Brain Neoplasms / genetics Brain Neoplasms / pathology Cell Hypoxia Cell Proliferation DNA Transposable Elements / genetics* Disease Models, Animal* Glioma / etiology* Glioma / genetics Glioma / pathology Mice Mice, Inbred ICR NIH 3T3 Cells Neurofibromin 1 / genetics Platelet-Derived Growth Factor / genetics Platelet-Derived Growth Factor / physiology Signal Transduction Tumor Suppressor Protein p53 / genetics
IF 4.966
Times Cited 3
DNA material pMXs-SB11-IRES-puro (RDB16060) pT2/CMV-PDGFA-IRES-DsRed (RDB16061) pT2/shp53/shNf1/SV40-GFP (RDB16062) pT2/shp53/shNf1/CMV-PDGFA-IRES-DsRed (RDB16063)