Abstract
Glioblastoma (GBM) is the most aggressive brain tumor and its diffuse infiltration in to the normal
brain tissue is one of the main causes for poor prognosis, making complete surgical removal virtually
impossible. The main aim of the research described in this thesis was to investigate the possible involvement
of differentiation of GBM cells in the invasive behavior of GBM. First, we discovered that two important
microenvironmental factors in GBM, namely TGF-β and hypoxia, induced a mesenchymal transdifferentiation
in GBM cells thereby enhancing its invasive potential. The transcription factors ZEB1 was identified as a
critical regulator of this process. Second, the involvement of the differentiation state in GBM in determining
their invasive capacity was examined. Interestingly, differentiated GBM cells appeared more invasive than the
undifferentiated GBM (stem) cells. Further we showed that differentiated cells could also revert back and gain
many of the properties associated with stem cells hence sustaining tumorigenicity. These novel findings
indicate that mesenchymal transition and differentiation enhance the invasive capacity of GBM cells. Inhibition
of the identified pathways contribute to heterogeneity and provide potential therapeutic targets to reduce
the infiltrating behavior of this aggressive and lethal brain tumor.
brain tissue is one of the main causes for poor prognosis, making complete surgical removal virtually
impossible. The main aim of the research described in this thesis was to investigate the possible involvement
of differentiation of GBM cells in the invasive behavior of GBM. First, we discovered that two important
microenvironmental factors in GBM, namely TGF-β and hypoxia, induced a mesenchymal transdifferentiation
in GBM cells thereby enhancing its invasive potential. The transcription factors ZEB1 was identified as a
critical regulator of this process. Second, the involvement of the differentiation state in GBM in determining
their invasive capacity was examined. Interestingly, differentiated GBM cells appeared more invasive than the
undifferentiated GBM (stem) cells. Further we showed that differentiated cells could also revert back and gain
many of the properties associated with stem cells hence sustaining tumorigenicity. These novel findings
indicate that mesenchymal transition and differentiation enhance the invasive capacity of GBM cells. Inhibition
of the identified pathways contribute to heterogeneity and provide potential therapeutic targets to reduce
the infiltrating behavior of this aggressive and lethal brain tumor.
| Translated title of the contribution | De rol van differentiatie bij het invasieve gedrag van glioblastomen (hersentumoren) |
|---|---|
| Original language | English |
| Qualification | Doctor of Philosophy |
| Awarding Institution |
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| Supervisors/Advisors |
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| Award date | 11-May-2015 |
| Place of Publication | [Groningen] |
| Publisher | |
| Print ISBNs | 978-90-367-7856-5 |
| Electronic ISBNs | 978-90-367-7855-8 |
| Publication status | Published - 2015 |