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Colorectal cancer cells use the negative feedback regulators of WNT signalling to activate epithelial–mesenchymal transition pathways
  1. Eugene Tulchinsky
  1. Department of Cancer Studies, University of Leicester, RKCSB, LRI, Leicester LE2 7LX, UK; et32@le.ac.uk
  1. Correspondence to Dr Eugene Tulchinsky, Department of Cancer Studies, University of Leicester, LKSCB, Leicester Royal Infirmary, Leicester LE2 7LX, UK; et32{at}le.ac.uk

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Epithelial–mesenchymal transition (EMT) is a reversible embryonic genetic programme pathologically activated in cancer. The EMT phenomenon has been considered in the context of distant metastases in different carcinoma types including colorectal cancer (CRC). The hallmark of EMT is dissolution of epithelial intercellular junctions and global reorganisation of the cytoskeleton leading to the loss of epithelial features and gain of mesenchymal morphology. EMT programmes are controlled by several groups of embryonic transcription factors (EMT-TFs), of which TWIST1, SNAIL1, ZEB1 and ZEB2 expression correlated with poor prognosis in patients with CRC.1 The role of EMT in cancer is not limited to enhanced invasion; a growing body of evidence implicates EMT-TFs in control of cell division, drug resistance, escape from senescence and oncogenic transformation. Activation of EMT pathways by driver oncogenic mutations was proposed to couple neoplastic transformation with the formation of quiescent circulating tumour cells (CTCs), dormant metastases and eventually early dissemination.2 In support of this theory, acquisition of mesenchymal phenotype was documented in CTCs isolated from the peripheral blood of patients with CRC.3

Accumulating evidence indicates strong association between EMT and WNT/β-catenin signalling, a pathway most commonly activated in CRC. Mutational activation of this pathway results in nuclear translocation of β-catenin in model systems. However, in central parts of colorectal tumours, cells maintain normal membranous localisation of β-catenin. Its nuclear localisation is often observed in tumour areas surrounded by the stroma due to the influence of microenvironmental factors.4 Cells at the tumour-stroma interphase are often also EMT-TFs-positive suggesting that a crosstalk between WNT and …

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