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Vermeulen L, De Sousa EMF, van der Heijden M et al.Wnt activity defines colon cancer stem cells and is regulated by the microenvironment. Nat Cell Biol 12:468-476

Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for Experimental Molecular Medicine (CEMM), Academic Medical Center (AMC), University of Amsterdam, 1105 AZ Amsterdam, The Netherlands.
Nature Cell Biology (Impact Factor: 20.06). 04/2010; 12(5):468-76. DOI: 10.1038/ncb2048
Source: PubMed

ABSTRACT Despite the presence of mutations in APC or beta-catenin, which are believed to activate the Wnt signalling cascade constitutively, most colorectal cancers show cellular heterogeneity when beta-catenin localization is analysed, indicating a more complex regulation of Wnt signalling. We explored this heterogeneity with a Wnt reporter construct and observed that high Wnt activity functionally designates the colon cancer stem cell (CSC) population. In adenocarcinomas, high activity of the Wnt pathway is observed preferentially in tumour cells located close to stromal myofibroblasts, indicating that Wnt activity and cancer stemness may be regulated by extrinsic cues. In agreement with this notion, myofibroblast-secreted factors, specifically hepatocyte growth factor, activate beta-catenin-dependent transcription and subsequently CSC clonogenicity. More significantly, myofibroblast-secreted factors also restore the CSC phenotype in more differentiated tumour cells both in vitro and in vivo. We therefore propose that stemness of colon cancer cells is in part orchestrated by the microenvironment and is a much more dynamic quality than previously expected that can be defined by high Wnt activity.

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Available from: Martin Sprick, Aug 28, 2015
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    • "It was reported that mesenchymal cells in breast cancer support CSCs through a signalling loop dependent on Interleukin-6 and chemokine C-X-C motif ligand 7 (CXCL7) (Liu et al., 2011). Also, in colon cancer, myofibroblasts support the CSCs through hepatocyte growth factor (Vermeulen et al., 2010). "
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    Experimental and Molecular Pathology 02/2015; 98(2). DOI:10.1016/j.yexmp.2015.02.002 · 2.88 Impact Factor
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    • "In these niches, the secreted factors and the activation of related signaling would regulate the conversion between CSCs and non-CSCs. For instance , hepatocyte growth factor (HGF), vascular endothelial growth factor (VEGF) or transforming growth factor-β (TGF-β) secreted from myofibroblast could activate Wnt signaling or Zeb1 promoter transcription , which would induce dedifferentiation of non-CSCs to CSCs [22] [40] [41]. On the contrary, when the Wnt or Notch signaling was downregulated, miR-27 was upregulated or cells were activated by BMP4, CSCs tend to differentiate to non-CSCs (Fig. 2) [42] [43]. "
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    ABSTRACT: Accumulating evidence suggests that cancer stem cells (CSCs) are heterogeneous populations and their phenotypes are unstable. A number of intrinsic and extrinsic mechanisms contribute to CSC phenotypic variation. The existence of various CSC subpopulations which would lead to a rapid relapse after primary treatments might pose a problem for CSC targeted therapeutics. In order to develop more effective approaches to cancer therapeutics, more CSC-related surface markers or targeting molecules, as well as some novel targeting strategies should be explored. This review summarized the origin and performance of heterogeneity in CSCs and discussed their therapeutic implications. Copyright © 2014. Published by Elsevier Ireland Ltd.
    Cancer Letters 11/2014; 357(1). DOI:10.1016/j.canlet.2014.11.040 · 5.62 Impact Factor
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    • "This indicates that the 'constitutively active' Wnt signalling caused by APC/CTNNB1 mutations is actually still modulated by tumour cell intrinsic and/or extrinsic factors (Fodde and Brabletz, 2007). This results in high levels of Wnt signalling specifically in cells at the invasive front, which underlies the cancer stem cell properties and metastatic potential of these cells (Vermeulen et al, 2010). What these Wnt modulating factors are remains unknown but these nuclear b-catenin expressing cells at the invasive front only arise after an adenoma becomes a carcinoma and in the proximity of the stroma and are thought to be the result of an interaction between tumour cell intrinsic and extrinsic factors. "
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    ABSTRACT: Background:Constitutive Wnt activation is essential for colorectal cancer (CRC) initiation but also underlies the cancer stem cell phenotype, metastasis and chemosensitivity. Importantly Wnt activity is still modulated as evidenced by higher Wnt activity at the invasive front of clonal tumours termed the β-catenin paradox. SMAD4 and p53 mutation status and the bone morphogenetic protein (BMP) pathway are known to affect Wnt activity. The combination of SMAD4 loss, p53 mutations and BMP signalling may integrate to influence Wnt signalling and explain the β-catenin paradox.Methods:We analysed the expression patterns of SMAD4, p53 and β-catenin at the invasive front of CRCs using immunohistochemistry. We activated BMP signalling in CRC cells in vitro and measured BMP/Wnt activity using luciferase reporters. MTT assays were performed to study the effect of BMP signalling on CRC chemosensitivity.Results:Eighty-four percent of CRCs with high nuclear β-catenin staining are SMAD4 negative and/or p53 aberrant. BMP signalling inhibits Wnt signalling in CRC only when p53 and SMAD4 are unaffected. In the absence of SMAD4, BMP signalling activates Wnt signalling. When p53 is lost or mutated, BMP signalling no longer influences Wnt signalling. The cytotoxic effects of 5-FU are influenced in a similar manner.Conclusions:The BMP signalling pathway differentially modulates Wnt signalling dependent on the SMAD4 and p53 status. The use of BMPs in cancer therapy, as has been proposed by previous studies, should be targeted to individual cancers based on the mutational status of p53 and SMAD4.British Journal of Cancer advance online publication, 13 November 2014; doi:10.1038/bjc.2014.560 www.bjcancer.com.
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