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Upregulation of SOX5 can be linked to proneural glioblastoma and perturbs glioma cell proliferation
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Cancer och vaskulärbiologi.
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Cancer och vaskulärbiologi.
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
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(engelsk)Manuskript (preprint) (Annet vitenskapelig)
HSV kategori
Forskningsprogram
Experimentell patologi
Identifikatorer
URN: urn:nbn:se:uu:diva-158377OAI: oai:DiVA.org:uu-158377DiVA, id: diva2:439181
Tilgjengelig fra: 2011-09-06 Laget: 2011-09-06 Sist oppdatert: 2018-01-12
Inngår i avhandling
1. Investigations of Proneural Glioblastoma to Identify Novel Therapeutic Targets
Åpne denne publikasjonen i ny fane eller vindu >>Investigations of Proneural Glioblastoma to Identify Novel Therapeutic Targets
2011 (engelsk)Doktoravhandling, med artikler (Annet vitenskapelig)
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.

sted, utgiver, år, opplag, sider
Uppsala: Acta Universitatis Upsliensis, 2011. s. 45
Serie
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 700
Emneord
Glioma, proneural subtype, hallmarks, glioma initiating cells, S-SOX5, angiogenesis, stromal cells
HSV kategori
Forskningsprogram
Experimentell patologi
Identifikatorer
urn:nbn:se:uu:diva-158383 (URN)978-91-554-8148-3 (ISBN)
Disputas
2011-10-21, Rudbecksalen, Rudbecklaboratoriet, Dag Hammarskölds väg 20, Uppsala, 09:15 (engelsk)
Opponent
Veileder
Tilgjengelig fra: 2011-09-29 Laget: 2011-09-06 Sist oppdatert: 2011-11-03bibliografisk kontrollert

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