Combinations of genetic mutations in the adult neural stem cell compartment determine brain tumour phenotypes
Open accessAbstract
It has been suggested that intrinsic brain tumours originate from a neural stem/progenitor cell population in the subventricular zone of the post-natal brain. However, the influence of the initial genetic mutation on the phenotype as well as the contribution of mature astrocytes to the formation of brain tumours is still not understood. We deleted Rb/p53, Rb/p53/PTEN or PTEN/p53 in adult subventricular stem cells; in ectopically neurografted stem cells; in mature parenchymal astrocytes and in transplanted astrocytes. We found that only stem cells, but not astrocytes, gave rise to brain tumours, independent of their location. This suggests a cell autonomous mechanism that enables stem cells to generate brain tumours, whereas mature astrocytes do not form brain tumours in adults. Recombination of PTEN/p53 gave rise to gliomas whereas deletion of Rb/p53 or Rb/p53/PTEN generated primitive neuroectodermal tumours (PNET), indicating an important role of an initial Rb loss in driving the PNET phenotype. Our study underlines an important role of stem cells and the relevance of initial genetic mutations in the pathogenesis and phenotype of brain tumours.
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In NSCs, ablation of RB together with p53 triggers over-proliferation and a brain tumour phenotype.
“In NSCs, genetic ablation of RB together with p53 triggers NSC over-proliferation, resulting in a brain tumour phenotype68.”
From Molecular regulation of stem cell quiescence (2013) · cites this paper as [68]
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References 48 · Cited by 214
- Authors
- Jacques, T. S., Swales, A., Brzozowski, M. J., Henriquez, N. V., Linehan, J. M., Mirzadeh, Z., O' Malley, C., Naumann, H., Alvarez‐Buylla, A., & Brandner, S.
- Affiliations
- Great Ormond Street Hospital (GB)
- MRC Prion Unit (GB)
- UCL Queen Square Institute of Neurology (GB)
- University of California, San Francisco (US)
- Corresponding author
- Brandner, Sebastian
- Venue
- The EMBO Journal
- Published
- 2009-11-19
- Volume
- 29
- Issue
- 1
- Pages
- 222-235
- ISSN
- 0261-4189 (ISSN-L)
- 1460-2075
- PMC
- PMC2808375
- OpenAlex
- W2024791894
- Cited by
- 214
- References
- 48
- Citations by year
- 2026: 3 · 2025: 2 · 2024: 6 · 2023: 10 · 2022: 4 · 2021: 11 · 2020: 15 · 2019: 13 · 2018: 13 · 2017: 5 · 2016: 11 · 2015: 19 · 2014: 19 · 2013: 15 · 2012: 25
- FWCI
- 10.61
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- The EMBO Journal (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Funders
- Brain Research Trust
- National Institutes of Health (HD-32116)
- University of California, San Francisco
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD32116, R37HD032116, R01HD032116)
- Topics
- Health Sciences › Medicine › Genetics › Glioma Diagnosis and Treatment
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Keywords
- brain tumors, neural stem cells, subventricular zone, astrocytes, PTEN, glioma, primitive neuroectodermal tumor, tumor phenotype, carcinogenesis, genetic mutations
- MeSH terms
- Animals, Astrocytes, Brain Neoplasms, Glial Fibrillary Acidic Protein, Glioma, Mice, Transgenic, Models, Neurological, Mutation, Nerve Tissue Proteins, Neurons, Phenotype, Neoplastic Stem Cells, Genes, Tumor Suppressor, Genes, p53, Genes, Retinoblastoma, Neuroectodermal Tumors, Primitive, Mice, Knockout, PTEN Phosphohydrolase, Mice, Adult Stem Cells
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