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Novel Regulators of Brain Tumor Development: – From neural stem cell differentiation to in vivo models
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Malignant brain tumors are diseases with poor prognosis and/or severe long-term side effects of treatment. This thesis aimed to discover novel regulators in brain tumor development, based on studying neural stem cell and progenitor cell (NSPC) differentiation and using animal models to introduce new insights to mechanisms of human brain tumors.

The enzyme heparanase (HPSE) that degrades heparan sulfate (HS) is active in cell signaling and ECM remodeling. In paper I, we found an enhanced differentiation to oligodendrocytes in ES cell-derived NSPCs overexpressing HPSE. Further analysis suggested that this enhanced formation of oligodendrocytes was associated with alterations in receptor tyrosine kinase signaling, and that HPSE might also exert anti-apoptotic functions.

Subsequently, in paper II we studied the involvement of HPSE in glioma development. We observed that high HPSE levels associated with poor survival in glioma patients. In experimental models, we found that HPSE promoted glioma growth, and that an inhibitor of HPSE reduced glioma progression both in vitro and in vivo.

We hypothesize that regulators in NSPC differentiation could have a potential role in brain tumor development. In paper III, we explored the function of NRBP2, a pseudokinase that is up-regulated during NSPC differentiation. We found low expression of NRBP2 in brain tumors, in comparison to normal brain. In medulloblastoma, in particular, low NRBP2 expression is linked to poor prognosis. Overexpression of NRBP2 in medulloblastoma cells led to impaired cell growth and migration, concomitant with an increased cell death.

In paper IV, we searched for novel glioma susceptibility genes by sequencing dog breeds from the same ancestor but with different glioma incidence. In this way we identified three new glioma-associated genes. Two of these are significantly regulated in human glioma and one of those might have a role in glioblastoma stem cell differentiation.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2015. , 66 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1155
Keyword [en]
glioma, medulloblastoma, neural stem cell, heparanase, NRBP2, dog models, susceptibility
National Category
Cell and Molecular Biology Cancer and Oncology
Identifiers
URN: urn:nbn:se:uu:diva-264470ISBN: 978-91-554-9394-3 (print)OAI: oai:DiVA.org:uu-264470DiVA: diva2:865280
Public defence
2015-12-15, Rudbecksalen, Rudbecklaboratoriet, Dag Hammarskjöld vag 20, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2015-11-23 Created: 2015-10-13 Last updated: 2016-01-13
List of papers
1. Heparanase confers a growth advantage to differentiating embryonic stem cells, and enhances their differentiation into oligodendrocytes
Open this publication in new window or tab >>Heparanase confers a growth advantage to differentiating embryonic stem cells, and enhances their differentiation into oligodendrocytes
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(English)Manuscript (preprint) (Other academic)
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:uu:diva-265309 (URN)
Available from: 2015-10-26 Created: 2015-10-26 Last updated: 2016-01-13
2. Heparanase promotes glioma progression and is inversely correlated with patient survival
Open this publication in new window or tab >>Heparanase promotes glioma progression and is inversely correlated with patient survival
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(English)Manuscript (preprint) (Other academic)
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-265305 (URN)
Available from: 2015-10-26 Created: 2015-10-26 Last updated: 2016-01-13
3. Nuclear Receptor Binding Protein 2 is down-regulated in Medulloblastoma, and reduces tumor cell survival when overexpressed in Medulloblastoma cells in vitro
Open this publication in new window or tab >>Nuclear Receptor Binding Protein 2 is down-regulated in Medulloblastoma, and reduces tumor cell survival when overexpressed in Medulloblastoma cells in vitro
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(English)Manuscript (preprint) (Other academic)
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-265306 (URN)
Available from: 2015-10-26 Created: 2015-10-26 Last updated: 2016-01-13
4. Genome-Wide Association Mapping of Canine Glioma Followed by Targeted Massive Parallel Sequencing Identifies CAMKK2, P2RX7 and DENR as Novel Candidate Genes for Canine and Human Glioma
Open this publication in new window or tab >>Genome-Wide Association Mapping of Canine Glioma Followed by Targeted Massive Parallel Sequencing Identifies CAMKK2, P2RX7 and DENR as Novel Candidate Genes for Canine and Human Glioma
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(English)Manuscript (preprint) (Other academic)
National Category
Medical Genetics Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-264864 (URN)
Available from: 2015-10-19 Created: 2015-10-19 Last updated: 2016-01-13

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