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EphB receptor activity suppresses colorectal cancer progression

Nature volume 435, pages 1126–1130 (2005)Cite this article

A Corrigendum to this article was published on 11 August 2005

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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Figure 1: EPHB2 is a β-catenin/Tcf-4 target gene but it is downregulated in advanced colorectal tumours and cell lines.
Figure 2: EphB2 and EphB4 are downregulated during CRC progression.
Figure 3: EphB2 downregulation correlates with higher histological tumour grade.
Figure 4: Accelerated colorectal tumorigenesis in Apc Min/+ mice expressing Δ cy EphB2 transgene or bearing Ephb3 -null alleles.

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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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Authors and Affiliations

  1. Hubrecht Laboratory, Center for Biomedical Genetics, Uppsalalaan 8, Utrecht, 3584 CT, The Netherlands

    Eduard Batlle, Harry Begthel, Suzanne Jonkeer, Alexander Gregorieff, Maaike van de Born, Elena Sancho & Hans Clevers

  2. Biomedical Research Institute, Barcelona Science Park, Josep Samitier 1-5, 08028, Barcelona, Spain

    Eduard Batlle, Suzanne Jonkeer & Elena Sancho

  3. Institució Catalana de Recerca i Estudis Avançats (ICREA), Passeig de Lluis Companys 23, 08010, Barcelona, Spain

    Eduard Batlle

  4. Department of Pathology, Academic Medical Center, 1105 AZ, Amsterdam, The Netherlands

    Elles Boon & Steven Pals

  5. Samuel Lunefeld Research Institute, Mount Sinai Hospital, 600 University Avenue, Ontario, M5G 1X5, Toronto, Canada

    Julinor Bacani, Tony Pawson & Steven Gallinger

  6. Institut Municipal d'Investigació Mèdica, Dr Aiguader 80, 08003, Barcelona, Spain

    Núria Malats

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  1. Eduard Batlle
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Correspondence to Hans Clevers.

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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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