Targeting determinants of aggressiveness in malignant brain tumors: the role of hDRR-1 in glioma invasion and Wnt signaling in medulloblastoma biology.

摘要

Despite advances in neuro-oncological research and treatment strategies, malignant brain tumors remain diseases with devastating outcome. Glioblastoma multiforme (GBM) is the most common malignant brain tumor in the adult population, whereas medulloblastoma (MB) is the most prevalent brain tumor in the pediatric population. This thesis explored determinants of aggressive tumor behaviour in these tumors.;While glioma invasion is analogous to neural progenitor cell motility, MB tumorigenesis has been associated with deregulation of signaling pathways known to control neural progenitor development in the cerebellum. In the final chapter, we explore the role of the Wnt pathway in the biology of MB. Our results showed that activation of the canonical Wnt pathway was not mitogenic in the context of MB cell lines. We demonstrate that cells that undergo nuclear translocation of β-catenin exhibited striking cell morphology changes from rounded cell clusters to single cells with protrusions. Using a candidate gene approach, we show that these morphological changes are associated with upregulation of the neuronal marker Microtubule-associated-protein 2 (MAP-2). Our studies provide the first in vitro evidence that Wnt3a is not mitogenic in the context of MB cells and we suggest a mechanism that may explain the existent correlation between nuclear β-catenin immunoreactivity and good prognosis in MB. Moreover, we identify MAP-2 as a novel target of Wnt3a. Targeting the translocation of β-catenin into the nucleus may be a strategy to improve clinical outcome in the treatment of MB.;The main determinant of morbidity and mortality in GBM is the invasion of glioma cells into healthy brain parenchyma. Glioma cell invasion recapitulates the cell motility mode of neural precursor cells. In order to further understand glioma invasion, our group has performed a functional screening assay to identify effectors of glioma invasion. In chapter 2, we biologically validate one of the candidate genes identified in the aforementioned screen: downregulated in renal cell carcinoma-1 (drr-1). Results from invasion assays performed in the 3D collagen matrix model show that hDRR-1 overexpression in glioma cells leads to a hyperinvasive phenotype, whereas downregulation of hDRR-1 causes hypoinvasion of these cells. We show that hDRR-1 is highly expressed at the edge of invasive gliomas. Interestingly, hDRR-1 knock-down prevents cell rear retraction by affecting focal adhesion disassembly. Taken together, these results identify hDRR-1 as a novel effector of glioma cell invasion and a potential therapeutic target in the field of glioma oncology.