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PDGF-B Can sustain self-renewal and tumorigenicity of experimental glioma-derived cancer-initiating cells by preventing oligodendrocyte differentiation
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
2011 (English)In: Neoplasia, ISSN 1522-8002, E-ISSN 1476-5586, Vol. 13, no 6, 492-503 p.Article in journal (Refereed) Published
Abstract [en]

According to the cancer stem cell (CSC)/cancer-initiating cell hypothesis, glioma development is driven by a sub-population of cells with unique tumor-regenerating capacity. We have characterized sphere-cultured glioma-derived cancer-initiating cells (GICs) from experimental gliomas induced by platelet-derived growth factor-B (PDGF-B) in neonatal Gtv-a Arf(-/-) mice. We found that the GICs can maintain their stem cell-like characteristics in absence of exogenous epidermal growth factor and fibroblast growth factor 2 and that this culture condition was highly selective for tumor-initiating cells where as few as five GICs could induce secondary tumor formation after orthotopic transplantation. Addition of FBS to the medium caused the GICs to differentiate into cells coexpressing glial fibrillary acidic protein and Tuj1, and this differentiation process was reversible, suggesting that the GICs are highly plastic and able to adapt to different environments without losing their tumorigenic properties. On inhibition of virally transduced PDGF-B by small interfering RNA treatment, the GICs stopped proliferating, lost their self-renewal ability, and started to uniformly express CNPase, a marker of oligodendrocyte precursor cells and mature oligodendrocytes. Most importantly, PDGF-B depletion completely abrogated the tumor-initiating capacity of the GICs. Our findings suggest that interfering with PDGF-controlled differentiation could be a therapeutic avenue for patients diagnosed with the PDGF-driven proneural subtype of human glioblastoma.

Place, publisher, year, edition, pages
2011. Vol. 13, no 6, 492-503 p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-158264DOI: 10.1593/neo.11314ISI: 000295448800001PubMedID: 21677873OAI: oai:DiVA.org:uu-158264DiVA: diva2:438889
Available from: 2011-09-05 Created: 2011-09-05 Last updated: 2017-12-08Bibliographically approved
In thesis
1. Investigations of Proneural Glioblastoma to Identify Novel Therapeutic Targets
Open this publication in new window or tab >>Investigations of Proneural Glioblastoma to Identify Novel Therapeutic Targets
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Malignant glioma is a highly lethal and destructive disease with no proper cure. We have investigated some of the hallmarks of cancer in connection to glioma and found ways to disrupt these and prevent tumor growth. The work is done within the context of a glioma subtype distinguished by activation of PDGF signaling termed the proneural subtype. In two of the studies we have investigated mechanisms regulating the glioma cells themselves, and in the other two we have focused on the tumor stroma.

In the first study, glioma-initiating cells were isolated in defined serum free culture medium from PDGF-B driven murine glioma and shown to be independent of EGF and FGF2 for self-renewal and proliferation. When cultured in serum the GICs displayed an aberrant differentiation pattern that was reversible. Specific depletion of the transduced PDGF-B caused a loss of self-renewal and tumorigenicity and induced oligodendrocyte differentiation.

The transcription factor S-SOX5 has previously been shown to have a tumor suppressive effect on PDGF-B induced murine glioma, and to induce cellular senescence in PDGF-B stimulated cells in vitro. We found that S-SOX5 had a negative effect on proliferation of newly established human glioma cells cultured under stem cell conditions. We also revealed a connection between alterations causing up-regulation of SOX5 with the proneural subgroup and a tendency towards co-occurrence with PDGFRA alterations.

Angiogenesis, the formation of new blood vessels from existing ones, is an important hallmark for glioma malignancy. We found that the anti-angiogenic protein HRG had a negative effect on glioma progression in PDGF-B induced experimental tumors and that HRG was able to completely prevent formation of glioblastomas.

Subsequently it was shown that HRG could skew pro-tumorigenic tumor associated macrophages into an anti-tumorigenic phenotype. Stromal cells had not previously been fully investigated in gliomas. We observed a correlation between tumor malignancy and increased numbers of tumor-associated macrophages as well as pericytes in PDGF-B induced gliomas. There was also a correlation between tumor grade and vessel functionality that had not previously been shown.

Our results offer further understanding of gliomagenesis and present possible future therapies.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsliensis, 2011. 45 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 700
Keyword
Glioma, proneural subtype, hallmarks, glioma initiating cells, S-SOX5, angiogenesis, stromal cells
National Category
Medical and Health Sciences
Research subject
Experimental Pathology
Identifiers
urn:nbn:se:uu:diva-158383 (URN)978-91-554-8148-3 (ISBN)
Public defence
2011-10-21, Rudbecksalen, Rudbecklaboratoriet, Dag Hammarskölds väg 20, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2011-09-29 Created: 2011-09-06 Last updated: 2011-11-03Bibliographically approved
2. 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)
Opponent
Supervisors
Available from: 2012-08-30 Created: 2012-08-07 Last updated: 2013-01-22Bibliographically approved

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