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Cell of origin contributes to the phenotypic heterogeneity of glioma initiating cells
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
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(English)Manuscript (preprint) (Other academic)
National Category
Medical and Health Sciences
Research subject
Oncology
Identifiers
URN: urn:nbn:se:uu:diva-179088OAI: oai:DiVA.org:uu-179088DiVA: diva2:543347
Available from: 2012-08-07 Created: 2012-08-07 Last updated: 2013-01-22
In thesis
1. Interplay Between Cell of Origin and Oncogenic Activation in Glioma
Open this publication in new window or tab >>Interplay Between Cell of Origin and Oncogenic Activation in Glioma
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Glioma is the most frequent primary tumor of the central nervous system. By using the RCAS/tv-a mouse glioma model, we have studied mechanisms controlling glioma development and the effect of cell of origin on these processes.

SOX5 was identified as a brain tumor locus in a retroviral insertional mutagenesis screen of PDGF-B induced mouse gliomas. Here we found that SOX5 could suppress PDGFB-induced glioma development particularly in Ink4a-/- mice. Analysis of putative PDGF-B signaling pathways revealed that the underlying mechanism could involve the activation of AKT and p27, which caused an acute cellular senescence.

When cultured in a highly selective serum free medium, glioma-initiating cells could be isolated from mouse GBMs and their self-renewal and proliferation was independent on exogenous EGF and FGF2. Addition of serum into the medium induced aberrant differentiation that was reversible. Specific depletion of viral PDGF-B demonstrated that PDGF-B was necessary for stemness and tumorigenicity of GICs by preventing them to differentiate.

Subsequently, by applying the same culture conditions, GICs of APC, NSC and OPC origins were isolated from mouse GBMs. GICs derived from NSCs exhibited higher self-renewal, faster proliferation and more potent tumorigenicity than those of APC or OPC origin. Furthermore, addition of 5% serum significantly inhibited the proliferation of APC- and OPC-derived GICs, but did not in NSC-derived GICs. Transcriptome analysis revealed that GICs of the same cell of origin displayed distinct expression profiles.

In the last study, we showed that OPCs could serve as the origin for astrocytic glioma. Results from immunostainings revealed that these tumors might belong to a different molecular subtype than the oligodendroglial tumors induced in OPCs. We also found differences in tumorigenic potential between OPCs in neonatal and adult mice, which suggest that developmental age of the cell of origin is important for its susceptibility to oncogenic transformation. 

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2012. 55 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 794
Keyword
Glioma, PDGF, cell of origin, Sox5, glioma initiating cells
National Category
Cell and Molecular Biology
Research subject
Oncology
Identifiers
urn:nbn:se:uu:diva-179093 (URN)978-91-554-8418-7 (ISBN)
Public defence
2012-09-21, Rudbecksalen, Rudbecklaboratoriet, Dag Hammarskjölds väg 20, Uppsala, 09:15 (English)
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Supervisors
Available from: 2012-08-30 Created: 2012-08-07 Last updated: 2013-01-22Bibliographically approved

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