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Is the downregulation of EphB2 receptor expression during colorectal tumorigenesis due to hypoxia?
  1. Abderrahmane Kaidi1,
  2. Morganaden Moorghen2,
  3. Ann Caroline Williams3,
  4. Christos Paraskeva3
  1. 1
    Cancer Research UK Colorectal Tumour Biology Research Group, Department of Cellular and Molecular Medicine, University of Bristol, Bristol, UK
  2. 2
    Bristol Royal Infirmary, University of Bristol, Bristol, UK
  3. 3
    Cancer Research UK Colorectal Tumour Biology Research Group, Department of Cellular and Molecular Medicine, University of Bristol, Bristol, UK
  1. Christos Paraskeva, Cancer Research UK Colorectal Tumour Biology Research Group, Department of Cellular and Molecular Medicine, University of Bristol, Bristol, BS8 1TD, UK; c.paraskeva{at}bristol.ac.uk

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Mutations in components of the Wnt pathway contribute to the aberrant activation of the β-catenin/T-cell factor-4 (TCF-4) complex and initiate most colorectal cancers.1 Upon its activation, the β-catenin/TCF-4 complex induces the expression of target genes such as c-MYC, cyclin-D1 and EPHB receptors.2 EphB receptors are receptor tyrosine kinases (RTKs) that play an important role in the coordination of cell proliferation, migration and compartmentalisation along intestinal crypts.3 4 The main effectors of these functions in the intestine are believed to be EphB2 and EphB3 receptors.5 Although EphB receptors are targets of β-catenin/TCF-4, Batlle et al. reported the unexpected downregulation of EphB2 receptor expression at the colorectal “adenoma–carcinoma” transition, despite the evident nuclear localisation of β-catenin.6 Intriguingly, EphB receptors were found to play a suppressive role in colorectal tumorigenesis as their loss promotes tumour progression in mice.6 The authors proposed the existence of a secondary, yet unknown, silencing mechanism that underlies the downregulation of EphB receptors, thus allowing colorectal tumour progression.6 Such a mechanism, we suggest, could be instigated by alterations in the tumour microenvironment. Hypoxia, the …

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