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Adjudication committee
- First opponent: Associate Professor Magnus Tisell, University of Gothenburg
- Second opponent: Associate Professor Terje Sundstrøm, University of Bergen
- Third member and chair of the evaluation committee: Associate Professor June Myklebust, University of Oslo
Chair of the Defence
Professor Per Kristian Hol, University of Oslo
Principal supervisor
Dr. Einar O. Vik-Mo, Oslo University Hospital
Summary
Glioblastoma (GBM) is the most common primary brain tumor, and the one with
the worst outcome. The median survival is less than one year. The GBM cells can tolerate severe hypoxia, are radio- and chemo-resistant. They also have the ability to migrate long distances from the tumour core into the brain tissue. All these GBM’s features conferresistance against existing treatment options. The mechanisms that drive the invasion in GBM and how invasive properties connected with intra-tumoral hypoxia are still unknown. In the present work we have studied the two main features of GBM cells – their tolerance of hypoxia and ability to invade – by long-term video-microscopy imaging, combined with gene expression assay and transplantation of GBM cells in to immunodeficient mice.
Our data demonstrate that GBM cells that underwent partial maturation possess enhanced abilities to resist hypoxia and invade. The observation of invasion on single-cell level identified cells with distinct morphology and increased ability to migrate in to brain. Prevalence of these cells predicts the invasiveness of GBM patient derived culture. We show that invasive properties of GBMs are patient-specific and dependent on the presence of the signalling from the tumor core rather than the surrounding microenvironment. Moreover, in the absence of the core (for example after mechanical removal) the invasion was abolished. The analysis of gene expression verified several potential genes that may be responsible for chemical cues which are produced by the tumor core and repel invasive cells. Finally, animal experiments with transplantation of GBM cells identified boundaries in the brain parenchyma that are difficult for invasive cells to transverse.
Obtained data support the background for further studies to identify pathways responsible for GBM hypoxia resistance and invasion.
Additional information
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