Activation of canonical WNT/β-catenin signaling enhances in vitro motility of glioblastoma cells by activation of ZEB1 and other activators of epithelial-to-mesenchymal transition

Division of Stereotactic Neurosurgery, Department of General Neurosurgery, University Medical Center Freiburg, Freiburg, Germany.
Cancer letters (Impact Factor: 5.62). 05/2012; 325(1):42-53. DOI: 10.1016/j.canlet.2012.05.024
Source: PubMed


Here we show that activation of the canonical WNT/β-catenin pathway increases the expression of stem cell genes and promotes the migratory and invasive capacity of glioblastoma. Modulation of WNT signaling alters the expression of epithelial-to-mesenchymal transition activators, suggesting a role of this process in the regulation of glioma motility. Using immunohistochemistry in patient-derived glioblastoma samples we showed higher numbers of cells with intranuclear signal for β-catenin in the infiltrating edge of tumor compared to central tumor parenchyma. These findings suggest that canonical WNT/β-catenin pathway is a critical regulator of GBM invasion and may represent a potential therapeutic target.

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    • "Due to the astrocytic origin, the concept of straight EMT makes little sense in GBM, as these tumors rarely express E-cadherin [40], [41]. Nonetheless, expression of ZEB1 and other activators has been observed in GBM cells due to Wnt/β-catenin signaling [42], that increases cell motility in an epithelial-to-mesenchymal(-like) transition manner [43]. Recently, the effect of connective tissue growth factor (CTGF) has been described in glioma stem/tumor initiating cells (TIC/TSCs). "
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    ABSTRACT: Extensive infiltration of the surrounding healthy brain tissue is a critical feature in glioblastoma. Several miRNAs have been related to gliomagenesis, some of them related with the EGFR pathway. We have evaluated whole-genome miRNA expression profiling associated with different EGFR amplification patterns, studied by fluorescence in situ hybridization in tissue microarrays, of 30 cases of primary glioblastoma multiforme, whose clinicopathological and immunohistochemical features have also been analyzed. MicroRNA-200c showed a very significant difference between tumors having or not EGFR amplification. This microRNA plays an important role in epithelial-mesenchymal transition, but its implication in the behavior of glioblastoma is largely unknown. With respect to EGFR status our cases were categorized into three groups: high level EGFR amplification, low level EGFR amplification, and no EGFR amplification. Our results showed that microRNA-200c and E-cadherin expression are down-regulated, while ZEB1 is up-regulated, when tumors showed a high level of EGFR amplification. Conversely, ZEB1 mRNA expression levels were significantly lower in the group of tumors without EGFR amplification. Tumors with a low level of EGFR amplification showed ZEB1 expression levels comparable to those detected in the group with a high level of amplification. In this study we provide what is to our knowledge the first report of association between microRNA-200c and EGFR amplification in glioblastomas.
    Full-text · Article · Jul 2014 · PLoS ONE
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    • "The three major groups of transcription factors, the SNAI, TWIST, and Zinc-finger enhancer binding (ZEB) family members have been reported to be altered in GBM. Their overexpression follows the activation of WNT/β-catenin pathway and results in increased in vitro cell migration and invasion [23, 24]. It is likely that the high expression of mesenchymal genes in the mesenchymal subset of human GBMs [25] can be considered to be reminiscent of the EMT program [26] or that the aberrant activation of EMT factors during gliomagenesis can trigger the mesenchymal shift in GBM [27]. "
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    ABSTRACT: Glioblastoma (GBM) stem cells (GSCs), responsible for tumor growth, recurrence, and resistance to therapies, are considered the real therapeutic target, if they had no molecular mechanisms of resistance, in comparison with the mass of more differentiated cells which are insensitive to therapies just because of being differentiated and nonproliferating. GSCs occur in tumor niches where both stemness status and angiogenesis are conditioned by the microenvironment. In both perivascular and perinecrotic niches, hypoxia plays a fundamental role. Fifteen glioblastomas have been studied by immunohistochemistry and immunofluorescence for stemness and differentiation antigens. It has been found that circumscribed necroses develop inside hyperproliferating areas that are characterized by high expression of stemness antigens. Necrosis developed inside them because of the imbalance between the proliferation of tumor cells and endothelial cells; it reduces the number of GSCs to a thin ring around the former hyperproliferating area. The perinecrotic GSCs are nothing else that the survivors remnants of those populating hyperproliferating areas. In the tumor, GSCs coincide with malignant areas so that the need to detect where they are located is not so urgent.
    Full-text · Article · Apr 2014
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    • "Notably, an inverse relationship between N‐cadherin expression and invasion has been described (Asano et al, 2004), and the importance of cell‐cell interactions for EMT processes and plasticity has recently been discussed (Thompson & Haviv, 2011). Beta‐catenin is known to induce expression of ZEB1 (Kahlert et al, 2012; Schmalhofer et al, 2009), but we did not observe nuclear accumulation of beta‐catenin in our samples. Instead, immunoreactivity was confined to cell membranes within the tumour core, and absent at the invasion front, corroborating reduced cell–cell contacts during invasion (Supporting Information Fig S1D). "
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    ABSTRACT: Glioblastoma remains one of the most lethal types of cancer, and is the most common brain tumour in adults. In particular, tumour recurrence after surgical resection and radiation invariably occurs regardless of aggressive chemotherapy. Here, we provide evidence that the transcription factor ZEB1 (zinc finger E-box binding homeobox 1) exerts simultaneous influence over invasion, chemoresistance and tumourigenesis in glioblastoma. ZEB1 is preferentially expressed in invasive glioblastoma cells, where the ZEB1-miR-200 feedback loop interconnects these processes through the downstream effectors ROBO1, c-MYB and MGMT. Moreover, ZEB1 expression in glioblastoma patients is predictive of shorter survival and poor Temozolomide response. Our findings indicate that this regulator of epithelial-mesenchymal transition orchestrates key features of cancer stem cells in malignant glioma and identify ROBO1, OLIG2, CD133 and MGMT as novel targets of the ZEB1 pathway. Thus, ZEB1 is an important candidate molecule for glioblastoma recurrence, a marker of invasive tumour cells and a potential therapeutic target, along with its downstream effectors. Glioblastoma have a poor prognosis, mainly due to infiltrating and therapy resistant cells leading to cancer recurrence. Here, tumor formation, invasion and resistance are not independent but intertwined processes regulated by the EMT activator ZEB1.
    Full-text · Article · Aug 2013 · EMBO Molecular Medicine
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