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PROBLEM:
Malignant gliomas are the most common and most malignant primary brain tumours in adults and associated with poor prognosis. Recent evidence supports the involvement of canonical and non‐canonical Wnt signalling in glioma development and malignant progression. However, insights into the mechanism behind Wnt signalling in glioma and the identification of druggable targets that can be addressed to inhibit both signalling branches have been lacking.
RESULTS:
We here describe strong, WHO grade‐independent overexpression of Evi/Wls/GPR177 in human astrocytic glioma suggesting an involvement of Evi in the earliest stages of glioma tumourigenesis. Evi/GPR177 is an essential Wnt ligand secretion factors. Depletion of Evi expression by RNAi in glioma cells and primary glioblastoma‐derived cancer stem‐like cells led to reduced proliferation, cell cycle arrest and increased apoptosis. Correspondingly, transcriptome profiling identified a strong transcriptional downregulation of interleukins and genes associated with cell cycle regulation after Evi silencing. Migration experiments revealed a reduced capacity for migration of glioma cells upon Evi silencing and Evi depletion also reduced tumour growth of human glioma cells after xenotransplantation in mice.
IMPACT:
Our data established a functional role of Evi/GPR177 in the molecular pathogenesis of human astrocytic gliomas. Evi regulates both canonical and non‐canonical Wnt signalling in glioma cells with both branches likely contributing to malignancy. With its GPCR‐like structural features Evi may serve an attractive novel target for therapeutic interventions.
INTRODUCTION
Malignant astrocytomas are the largest group of primary brain tumours. Glioblastoma, the most common and most aggressive form, is characterized by marked cellular heterogeneity, high proliferative activity, aberrant microvascular proliferation, presence of necrosis and highly invasive growth (Riemenschneider & Reifenberger, 2009). They most commonly arise de novo (‘primary glioblastoma’) or develop by progression from pre‐existing lower grade tumours (‘secondary glioblastoma’) (Ohgaki & Kleihues, 2007; Wettenhall & Smyth, 2004). Glioblastomas are characterized by complex genetic and epigenetic aberrations that differ between primary and secondary glioblastomas but affect a similar set of pathways, in particular receptor tyrosine kinase/Ras, phosphoinositol 3‐kinase, p53 and pRb signalling (TCGA, 2008). Despite highly aggressive multimodal therapy, including surgical resection followed by combined radio‐ and chemotherapy, the median survival of glioblastoma patients has remained as low as 12–14 months throughout the past decade (Furnari et al, 2007; Holland, 2001).
Aberrant...