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Snail depletes the tumorigenic potential of glioblastoma
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research. Uppsala University, Science for Life Laboratory, SciLifeLab.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research. Uppsala University, Science for Life Laboratory, SciLifeLab.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research. Uppsala University, Science for Life Laboratory, SciLifeLab.
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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.

Place, publisher, year, edition, pages
2013. Vol. 32, no 47, 5409-5420 p.
Keyword [en]
BMP, glioblastoma multiforme, glioma initiating cells, invasiveness, Snail
National Category
Cell and Molecular Biology
Identifiers
URN: urn:nbn:se:uu:diva-182944DOI: 10.1038/onc.2013.67ISI: 000327177600004PubMedID: 23524585OAI: oai:DiVA.org:uu-182944DiVA: diva2:561507
Available from: 2012-10-19 Created: 2012-10-19 Last updated: 2017-12-07Bibliographically approved
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)
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Supervisors
Available from: 2012-11-23 Created: 2012-10-31 Last updated: 2013-07-22

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Caglayan, DemetCaja, LaiaTzavlaki, KalliopiBergström, TobiasJiang, YiwenUhrbom, LeneForsberg-Nillson, KarinWestermark, BengtHeldin, Carl-HenrikFerletta, MariaMoustakas, Aristidis

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Caglayan, DemetCaja, LaiaTzavlaki, KalliopiBergström, TobiasJiang, YiwenUhrbom, LeneForsberg-Nillson, KarinWestermark, BengtHeldin, Carl-HenrikFerletta, MariaMoustakas, Aristidis
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Ludwig Institute for Cancer ResearchScience for Life Laboratory, SciLifeLabCancer and Vascular BiologyDepartment of Immunology, Genetics and PathologyDepartment of Medical Biochemistry and Microbiology
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