1. Hubrecht Laboratory, Center for Biomedical Genetics, Uppsalalaan 8, 3584 CT Utrecht, The Netherlands
2. Biomedical Research Institute, Barcelona Science Park, Josep Samitier 1-5, 08028 Barcelona, Spain
3. Institució Catalana de Recerca i Estudis Avançats (ICREA), Passeig de Lluis Companys 23, 08010 Barcelona, Spain
4. Department of Pathology, Academic Medical Center, 1105 AZ Amsterdam, The Netherlands
5. Samuel Lunefeld Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, Ontario, M5G 1X5, Canada
6. Institut Municipal d'Investigació Mèdica, Dr Aiguader 80, 08003 Barcelona, Spain

Correspondence to: Hans Clevers¹ Correspondence and requests for materials should be addressed to H.C. (Email: clevers@niob.knaw.nl).

Abstract

Most sporadic colorectal cancers are initiated by activating Wnt pathway mutations¹, characterized by the stabilization of -catenin and constitutive transcription by the -catenin/T cell factor-4 (Tcf-4) complex^{2, 3}. EphB guidance receptors are Tcf4 target genes that control intestinal epithelial architecture through repulsive interactions with Ephrin-B ligands^{4, 5}. Here we show that, although Wnt signalling remains constitutively active, most human colorectal cancers lose expression of EphB at the adenoma–carcinoma transition. Loss of EphB expression strongly correlates with degree of malignancy. Furthermore, reduction of EphB activity accelerates tumorigenesis in the colon and rectum of Apc^Min/+ mice, and results in the formation of aggressive adenocarcinomas. Our data demonstrate that loss of EphB expression represents a critical step in colorectal cancer progression.

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