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Investigations of Proneural Glioblastoma to Identify Novel Therapeutic Targets
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
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. , p. 45
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 700
Keyword [en]
Glioma, proneural subtype, hallmarks, glioma initiating cells, S-SOX5, angiogenesis, stromal cells
National Category
Medical and Health Sciences
Research subject
Experimental Pathology
Identifiers
URN: urn:nbn:se:uu:diva-158383ISBN: 978-91-554-8148-3 (print)OAI: oai:DiVA.org:uu-158383DiVA: diva2:439201
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
List of papers
1. PDGF-B Can sustain self-renewal and tumorigenicity of experimental glioma-derived cancer-initiating cells by preventing oligodendrocyte differentiation
Open this publication in new window or tab >>PDGF-B Can sustain self-renewal and tumorigenicity of experimental glioma-derived cancer-initiating cells by preventing oligodendrocyte differentiation
2011 (English)In: Neoplasia, ISSN 1522-8002, E-ISSN 1476-5586, Vol. 13, no 6, p. 492-503Article 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.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-158264 (URN)10.1593/neo.11314 (DOI)000295448800001 ()21677873 (PubMedID)
Available from: 2011-09-05 Created: 2011-09-05 Last updated: 2017-12-08Bibliographically approved
2. Upregulation of SOX5 can be linked to proneural glioblastoma and perturbs glioma cell proliferation
Open this publication in new window or tab >>Upregulation of SOX5 can be linked to proneural glioblastoma and perturbs glioma cell proliferation
Show others...
(English)Manuscript (preprint) (Other academic)
National Category
Cell and Molecular Biology
Research subject
Experimental Pathology
Identifiers
urn:nbn:se:uu:diva-158377 (URN)
Available from: 2011-09-06 Created: 2011-09-06 Last updated: 2018-01-12
3. Histidine-rich glycoprotein can prevent development of mouse experimental glioblastoma
Open this publication in new window or tab >>Histidine-rich glycoprotein can prevent development of mouse experimental glioblastoma
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2009 (English)In: PLoS ONE, ISSN 1932-6203, Vol. 4, no 12, p. e8536-Article in journal (Refereed) Published
Abstract [en]

Extensive angiogenesis, formation of new capillaries from pre-existing blood vessels, is an important feature of malignant glioma. Several antiangiogenic drugs targeting vascular endothelial growth factor (VEGF) or its receptors are currently in clinical trials as therapy for high-grade glioma and bevacizumab was recently approved by the FDA for treatment of recurrent glioblastoma. However, the modest efficacy of these drugs and emerging problems with anti-VEGF treatment resistance welcome the development of alternative antiangiogenic therapies. One potential candidate is histidine-rich glycoprotein (HRG), a plasma protein with antiangiogenic properties that can inhibit endothelial cell adhesion and migration. We have used the RCAS/TV-A mouse model for gliomas to investigate the effect of HRG on brain tumor development. Tumors were induced with platelet-derived growth factor-B (PDGF-B), in the presence or absence of HRG. We found that HRG had little effect on tumor incidence but could significantly inhibit the development of malignant glioma and completely prevent the occurrence of grade IV tumors (glioblastoma).

 

National Category
Cell and Molecular Biology
Research subject
Medical Cell Biology
Identifiers
urn:nbn:se:uu:diva-109484 (URN)10.1371/journal.pone.0008536 (DOI)000273180200017 ()20046875 (PubMedID)
Available from: 2009-10-15 Created: 2009-10-15 Last updated: 2018-01-12Bibliographically approved
4. Malignancy of PDGF-BB driven glioma correlates with increased infiltration of pro-angiogenic macrophages and mesenchymal cells
Open this publication in new window or tab >>Malignancy of PDGF-BB driven glioma correlates with increased infiltration of pro-angiogenic macrophages and mesenchymal cells
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(English)Manuscript (preprint) (Other academic)
National Category
Cell and Molecular Biology
Research subject
Experimental Pathology
Identifiers
urn:nbn:se:uu:diva-158378 (URN)
Available from: 2011-09-06 Created: 2011-09-06 Last updated: 2018-01-12

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