In vitro modeling of glioblastoma initiation using PDGF-AA and p53-null neural progenitors
Open Access
- 16 April 2020
- journal article
- research article
- Published by Oxford University Press (OUP) in Neuro-Oncology
- Vol. 22 (8), 1150-1161
- https://doi.org/10.1093/neuonc/noaa093
Abstract
Imagining ways to prevent or treat glioblastoma (GBM) has been hindered by a lack of understanding of its pathogenesis. Although overexpression of platelet derived growth factor with two A-chains (PDGF-AA) may be an early event, critical details of the core biology of GBM are lacking. For example, existing PDGF-driven models replicate its microscopic appearance, but not its genomic architecture. Here we report a model that overcomes this barrier to authenticity. Using a method developed to establish neural stem cell cultures, we investigated the effects of PDGF-AA on subventricular zone (SVZ) cells, one of the putative cells of origin of GBM. We microdissected SVZ tissue from p53-null and wild-type adult mice, cultured cells in media supplemented with PDGF-AA, and assessed cell viability, proliferation, genome stability, and tumorigenicity. Counterintuitive to its canonical role as a growth factor, we observed abrupt and massive cell death in PDGF-AA: wild-type cells did not survive, whereas a small fraction of null cells evaded apoptosis. Surviving null cells displayed attenuated proliferation accompanied by whole chromosome gains and losses. After approximately 100 days in PDGF-AA, cells suddenly proliferated rapidly, acquired growth factor independence, and became tumorigenic in immune-competent mice. Transformed cells had an oligodendrocyte precursor-like lineage marker profile, were resistant to platelet derived growth factor receptor alpha inhibition, and harbored highly abnormal karyotypes similar to human GBM. This model associates genome instability in neural progenitor cells with chronic exposure to PDGF-AA and is the first to approximate the genomic landscape of human GBM and the first in which the earliest phases of the disease can be studied directly.Funding Information
- Terry Fox Research Institute and Foundation
- Alberta Cancer Foundation
- Genome Canada (psychoceramics-1152342)
- Alberta Innovates
This publication has 26 references indexed in Scilit:
- Glioblastomas are composed of genetically divergent clones with distinct tumourigenic potential and variable stem cell-associated phenotypesActa Neuropathologica, 2013
- The Somatic Genomic Landscape of GlioblastomaCell, 2013
- Neural and Oligodendrocyte Progenitor Cells: Transferrin Effects on Cell ProliferationASN Neuro, 2013
- Chromosome Segregation Errors as a Cause of DNA Damage and Structural Chromosome AberrationsScience, 2011
- Presence of pluripotent CD133+ cells correlates with malignancy of gliomasMolecular and Cellular Neuroscience, 2010
- Phase II Study of Neoadjuvant Imatinib in Glioblastoma: Evaluation of Clinical and Molecular Effects of the TreatmentClinical Cancer Research, 2009
- Proliferation of Human Glioblastoma Stem Cells Occurs Independently of Exogenous MitogensThe International Journal of Cell Cloning, 2009
- Flow Cytometry Analysis of Neural Differentiation Markers Expression in Human Glioblastomas May Predict Their Response to ChemotherapyCellular and Molecular Neurobiology, 2009
- Oligodendrocyte and astrocyte development in rodents: An in situ and immunohistological analysis during embryonic developmentGlia, 2002
- Generation of Neurons and Astrocytes from Isolated Cells of the Adult Mammalian Central Nervous SystemScience, 1992