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GFAP promoter driven transgenic expression of PDGFB in the mouse brain leads to glioblastoma in a Trp53 null background
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
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2009 (English)In: Glia, ISSN 0894-1491, E-ISSN 1098-1136, Vol. 57, no 11, 1143-1153 p.Article in journal (Refereed) Published
Abstract [en]

Glioblastomas are the most common and malignant astrocytic brain tumors in human adults. The tumor suppressor gene TP53 is commonly mutated and/or lost in astrocytic brain tumors and the TP53 alterations are often found in combination with excessive growth factor signaling via PDGF/PDGFRalpha. Here, we have generated transgenic mice over-expressing human PDGFB in brain, under control of the human GFAP promoter. These mice showed no phenotype, but on a Trp53 null background a majority of them developed brain tumors. This occurred at 2-6 months of age and tumors displayed human glioblastoma-like features with integrated development of Pdgfralpha+ tumor cells and Pdgfrbeta+/Nestin+ vasculature. The transgene was expressed in subependymal astrocytic cells, in glia limitans, and in astrocytes throughout the brain substance, and subsequently, microscopic tumor lesions were initiated equally in all these areas. With tumor size, there was an increase in Nestin positivity and variability in lineage markers. These results indicate an unexpected plasticity of all astrocytic cells in the adult brain, not only of SVZ cells. The results also indicate a contribution of widely distributed Pdgfralpha+ precursor cells in the tumorigenic process.

Place, publisher, year, edition, pages
2009. Vol. 57, no 11, 1143-1153 p.
Keyword [en]
NEURAL STEM-CELLS, GROWTH-FACTOR-B, ALPHA-RECEPTOR EXPRESSION, AUTOCRINE STIMULATION, MALIGNANT GLIOMAS, GLIAL TUMORS, P53, MICE, CNS, PROGENITORS;
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Medical and Health Sciences
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URN: urn:nbn:se:uu:diva-124243DOI: 10.1002/glia.20837ISI: 000268438700001PubMedID: 19115382OAI: oai:DiVA.org:uu-124243DiVA: diva2:317263
Available from: 2010-05-03 Created: 2010-05-03 Last updated: 2017-12-12Bibliographically approved

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Westermark, Bengt

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