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Molecular and Cellular Complexity of Glioma: Highlights on the Double-Edged-Sword of Infiltration Versus Proliferation and the Involvement of T Cells
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology. (Bengt Westermark)
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 [en]
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: urn:nbn:se:uu:diva-183669ISBN: 978-91-554-8530-6 (print)OAI: oai:DiVA.org:uu-183669DiVA: diva2:563754
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
List of papers
1. Forced expression of Sox21 inhibits Sox2 and induces apoptosis in human glioma cells
Open this publication in new window or tab >>Forced expression of Sox21 inhibits Sox2 and induces apoptosis in human glioma cells
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2011 (English)In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 129, no 1, 45-60 p.Article in journal (Refereed) Published
Abstract [en]

Numerous studies support a role for Sox2 to keep stem cells and progenitor cells in an immature and proliferative state. Coexpression of Sox2 and GFAP has been found in regions of the adult brain where neural stem cells are present and in human glioma cells. In our study, we have investigated the roles of Sox2 and its counteracting partner Sox21 in human glioma cells. We show for the first time that Sox21 is expressed in both primary glioblastoma and in human glioma cell lines. We found that coexpression of Sox2, GFAP and Sox21 was mutually exclusive with expression of fibronectin. Our result suggests that glioma consists of at least two different cell populations: Sox2+/GFAP+/Sox21+/FN- and Sox2-/GFAP-/Sox21-/FN1+. Reduction of Sox2 expression by using siRNA against Sox2 or by overexpressing Sox21 using a tetracyclineregulated expression system (Tet-on) caused decreased GFAP expression and a reduction in cell number due to induction of apoptosis. We suggest that Sox21 can negatively regulate Sox2 in glioma. Our findings imply that Sox2 and Sox21 may be interesting targets for the development of novel glioma therapy.

Keyword
Glioma, brain tumor, Sox2, Sox21, GFAP
National Category
Cell and Molecular Biology
Research subject
Medical Cell Biology
Identifiers
urn:nbn:se:uu:diva-151784 (URN)10.1002/ijc.25647 (DOI)000289987300005 ()20824710 (PubMedID)
Available from: 2011-04-18 Created: 2011-04-18 Last updated: 2017-12-11Bibliographically approved
2. Sox21 inhibits glioma progression in vivo by reducing Sox2 and stimulating aberrant differentiation
Open this publication in new window or tab >>Sox21 inhibits glioma progression in vivo by reducing Sox2 and stimulating aberrant differentiation
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2013 (English)In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 133, no 6, 1345-1356 p.Article in journal (Refereed) Published
Abstract [en]

Sox2 is a transcription factor in neural stem cells and keeps the cells immature and proliferative. Sox2 is expressed in primary human glioma such as glioblastoma multiforme (GBM), primary glioma cells and glioma cell lines and is implicated in signaling pathways in glioma connected to malignancy. Sox21, the counteracting partner of Sox2, has the same expression pattern as Sox2 in glioma but in general induces opposite effects. In this study, Sox21 was overexpressed by using a tetracycline-regulated expression system (tet-on) in glioma cells. The glioma cells were injected subcutaneously into immunodeficient mice. The control tumors were highly proliferative, contained microvascular proliferation and large necrotic areas typical of human GBM. Induction of Sox21 in the tumor cells resulted in a significant smaller tumor size, and the effect correlated with the onset of treatment, where earlier treatment gave smaller tumors. Mice injected with glioma cells orthotopically into the brain survived significantly longer when Sox21 expression was induced. Tumors originating from glioma cells with an induced expression of Sox21 exhibited an increased formation of Sox2:Sox21 complexes and an upregulation of S100β, CNPase and Tuj1. Sox21 appears to decrease the stem-like cell properties of the tumor cells and initiate aberrant differentiation of glioma cells in vivo. Taken together our results indicate that Sox21 can function as a tumor suppressor during gliomagenesis mediated by a shift in the balance between Sox2 and Sox21. The wide distribution of Sox2 and Sox21 in GBM makes the Sox2/Sox21 axis a very interesting target for novel therapy of gliomas.

Keyword
brain tumors, glioma, Sox2, Sox21, S100
National Category
Medical and Health Sciences Cell and Molecular Biology
Research subject
Medical Science
Identifiers
urn:nbn:se:uu:diva-182943 (URN)10.1002/ijc.28147 (DOI)
Available from: 2012-10-19 Created: 2012-10-19 Last updated: 2017-12-07Bibliographically approved
3. Snail depletes the tumorigenic potential of glioblastoma
Open this publication in new window or tab >>Snail depletes the tumorigenic potential of glioblastoma
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2013 (English)In: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 32, no 47, 5409-5420 p.Article in journal (Refereed) Published
Abstract [en]

Glioblastoma multiforme (GBM) is an aggressive brain malignancy characterized by high heterogeneity and invasiveness. It is increasingly accepted that the refractory feature of GBM to current therapies stems from the existence of few tumorigenic cells that sustain tumor growth and spreading, the so-called glioma-initiating cells (GICs). Previous studies showed that cytokines of the bone morphogenetic protein (BMP) family induce differentiation of the GICs, and thus act as tumor suppressors. Molecular pathways that explain this behavior of BMP cytokines remain largely elusive. Here, we show that BMP signaling induces Smad-dependent expression of the transcriptional regulator Snail in a rapid and sustained manner. Consistent with its already established promigratory function in other cell types, we report that Snail silencing decreases GBM cell migration. Consequently, overexpression of Snail increases GBM invasiveness in a mouse xenograft model. Surprisingly, we found that Snail depletes the GBM capacity to form gliomaspheres in vitro and to grow tumors in vivo, both of which are important features shared by GICs. Thus Snail, acting downstream of BMP signaling, dissociates the invasive capacity of GBM cells from their tumorigenic potential.

Keyword
BMP, glioblastoma multiforme, glioma initiating cells, invasiveness, Snail
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-182944 (URN)10.1038/onc.2013.67 (DOI)000327177600004 ()23524585 (PubMedID)
Available from: 2012-10-19 Created: 2012-10-19 Last updated: 2017-12-07Bibliographically approved
4. Induction of Glioblastoma Multiforme and Gliomatosis Cerebri with a Sleeping Beauty gene transfer system, implications for T regulatory cell involvement during glioma formation.
Open this publication in new window or tab >>Induction of Glioblastoma Multiforme and Gliomatosis Cerebri with a Sleeping Beauty gene transfer system, implications for T regulatory cell involvement during glioma formation.
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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
: brain tumors, Sleeping Beauty, T cells, AKT, NRAS, shp53
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-183668 (URN)
Available from: 2012-10-31 Created: 2012-10-31 Last updated: 2013-02-11

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