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 …