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Induction of Glioblastoma Multiforme and Gliomatosis Cerebri with a Sleeping Beauty gene transfer system, implications for T regulatory cell involvement during glioma formation.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
Department of Genetics, Cell biology and Development, Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota. .
Department of Genetics, Cell biology and Development, Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota. .
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

Glioblastoma Multiforme (GBM), the most malignant and common  neoplasm of the central nervous system (CNS), has been classified into subgroups with gene-expression profile as the basis for categorization. Among these the mesenchymal subgroup is most greatly associated with inflammatory infiltrates and increased expression of inflammatory associated genes. GBMs exhibit T cell infiltration to a varying degree and today the degree of infiltration is not used in prognostics. The Sleeping Beauty (SB) system was used to introduce AKT, a mutant variant of NRAS and a shp53 coupled to green fluorescent protein (GFP) into mice that are fully immunocomptetent, lack mature T cells or have reduced regulatory T (Treg) cell function respectively. We report, for the first time, the induction of Gliomatosis Cerebri with the SB system. Tumors that originated were either GBM or Gliomatosis Cerebri with a similar incidence. There was no difference in survival, grade or incidence of induced tumors in wild type mice and mice that lack mature T cells.

Keyword [en]
: brain tumors, Sleeping Beauty, T cells, AKT, NRAS, shp53
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-183668OAI: oai:DiVA.org:uu-183668DiVA: diva2:563740
Available from: 2012-10-31 Created: 2012-10-31 Last updated: 2013-02-11
In thesis
1. Molecular and Cellular Complexity of Glioma: Highlights on the Double-Edged-Sword of Infiltration Versus Proliferation and the Involvement of T Cells
Open this publication in new window or tab >>Molecular and Cellular Complexity of Glioma: Highlights on the Double-Edged-Sword of Infiltration Versus Proliferation and the Involvement of T Cells
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Glioblastoma multiforme (GBM), the most common and malignant brain tumor, is characterized by high molecular and cellular heterogeneity within and among tumors. Parameters such as invasive growth, infiltration of immune cells and endothelial proliferation contribute in a systemic manner to maintain the malignancy.

Studies in this thesis show that the expression of Sox2 is correlated with Sox21 in human gliomas. We demonstrate that an upregulation of Sox21 induces loss of proliferation, apoptosis and differentiation in glioma cells in vitro and in vivo and seems to correlate with decreased Sox2 expression. Induced expression of Sox21 in vivo significantly reduces the tumor size and increase the survival extensively, suggesting that Sox21 can act as a tumor suppressor Our studies indicate that the balance of Sox21-Sox2 in glioma cells is decisive of either a proliferative or a non-proliferative state.

Several TGFß family members have an important role in glioma development. TGFß promotes proliferation and tumorigenicity whereas BMPs mostly inhibit proliferation. We demonstrate that BMP7 can induce the transcription factor Snail in glioma cells and that this reduces the tumorigenicity with a concomitant increase in invasiveness. Thus, we have identified a mechanism to the double-edged sword of proliferation versus invasiveness in GBM, the latter contributing to relapse in patients.

Experimental gliomas were induced with the Sleeping Beauty (SB) model in mice with different immunological status of their T cells. The tumors that developed were either GBMs or highly diffuse in their growth, reminiscent of gliomatosis cerebri (GC). GC is a highly uncommon form of glioma characterized by extensive infiltrative growth in large parts of the brain. It is an orphan disease and today there is practically a total lack of relevant experimental models. The SB system would constitute a novel experimental model to study the mechanisms behind the development of diffusely growing tumors like GC. The presence or absence of T cells did not affect tumor development.

The work in this thesis demonstrates that the proliferative and the invasive capacities of glioma cells can be dissociated and that the SB model constitutes an excellent model to study the highly proliferative cells in GBMs versus the highly invasive cells in diffuse tumors like .GC.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2012. 79 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 838
Keyword
glioma, Sox2, Sox21, Snail, Bone morphogenetic protein, Sleeping Beauty, Gliomatosis Cerebri, T lymphocytes, T regulatory lymphocytes
National Category
Cell and Molecular Biology Cell Biology Cancer and Oncology
Research subject
Oncology; Biology
Identifiers
urn:nbn:se:uu:diva-183669 (URN)978-91-554-8530-6 (ISBN)
Public defence
2012-12-14, Rudbecksalen, Rudbecklaboratoriet, Dag Hammarskjöldsväg 20, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2012-11-23 Created: 2012-10-31 Last updated: 2013-07-22

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