Abstract
Most sporadic colorectal cancers are initiated by activating Wnt pathway mutations1, characterized by the stabilization of β-catenin and constitutive transcription by the β-catenin/T cell factor-4 (Tcf-4) complex2,3. EphB guidance receptors are Tcf4 target genes that control intestinal epithelial architecture through repulsive interactions with Ephrin-B ligands4,5. 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 ApcMin/+ 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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Acknowledgements
We thank A. Ziemiecki for EphB4 antiserum, and A. García de Herreros and C. Francí for help with mouse experiments.
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Supplementary information
Supplementary Methods
Detailed immunohistochemistry and in situ hybridisation protocols. (PDF 20 kb)
Supplementary Figure Legends
Legends for Supplementary Figures S1-S11. (PDF 74 kb)
Supplementary Figure S1
Example of loss of EphB2 expression in CRC liver metastasis. (PDF 206 kb)
Supplementary Figure S2
Examples of colorectal lesions classified in each EphB group. (PDF 306 kb)
Supplementary Figure S3
Statistical analysis of EphB2 expression in CRC lesions. (PDF 31 kb)
Supplementary Figure S4
Statistical analysis of EphB4 expression in CRC lesions. (PDF 30 kb)
Supplementary Figure S5
Statistical analysis of the correlation between EphB2 and EphB4 expression in CRC lesions. (PDF 11 kb)
Supplementary Figure S6
Example of colorectal tumour with downregulated EphB2 protein but high levels of EphB2 mRNA. (PDF 243 kb)
Supplementary Figure S7
Examples of in situ hybridisation with EphB2 and EphB3 probes on carcinomas with different histological grade. (PDF 149 kb)
Supplementary Figure S8
EphB4 expression in intestine of EphB2 and -B3 knock-out mice. EphB4 mRNA levels in CRC cell lines upon induction of dominant negative TCF factors. (PDF 177 kb)
Supplementary Figure 9
Examples of EphB4 expression patterns in CRC lesions at different stages. (PDF 313 kb)
Supplementary Figure S10
Nuclear β-catenin accumulation and expression of EphB2 and EphB4 in colonic microlesions of APCmin/+ mice. (PDF 205 kb)
Supplementary Figure S11
Features of δcyEphB2;ApcMin/+ tumours including nuclear β-catenin accumulation. (PDF 197 kb)
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Batlle, E., Bacani, J., Begthel, H. et al. EphB receptor activity suppresses colorectal cancer progression. Nature 435, 1126–1130 (2005). https://doi.org/10.1038/nature03626
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DOI: https://doi.org/10.1038/nature03626
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