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Carcinogenesis Advance Access published online on November 4, 2005
Carcinogenesis, doi:10.1093/carcin/bgi259
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© The Author 2005. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org
Received August 8, 2005
Revised October 17, 2005
Accepted October 30, 2005

CANCER BIOLOGY

Reduced expression of EphB2 that parallels invasion and metastasis in colorectal tumors

Dong Li Guo 1 {ddagger}, Ji Zhang 2 {ddagger}, Siu Tsan Yuen 1, Wai Yin Tsui 1, Annie S. Y. Chan 1, Coral Ho 3, Jiafu Ji 4, Suet Yi Leung 1, and Xin Chen 3*

1 Department of Pathology, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong
2 Department of Biopharmaceutical Sciences, University of California, San Francisco, USA; Department of Surgery, Beijing Cancer Hospital, Peking University School of Oncology, Beijing, China
3 Department of Biopharmaceutical Sciences, University of California, San Francisco, USA
4 Department of Surgery, Beijing Cancer Hospital, Peking University School of Oncology, Beijing, China

* To whom correspondence should be addressed.
Xin Chen, E-mail: chenx{at}pharmacy.ucsf.edu


  Abstract

EphB2, a receptor tyrosine kinase regulated by the {beta}-catenin/Tcf4 complex, is expressed in the proliferative compartment of mouse intestine and regulates bidirectional migration of intestinal precursor cells in the crypt-villus axis through repulsive interaction with Ephrin-B ligands. Recently, it has been shown that reduction of EphB activity accelerates colon tumor progression in the ApcMin/+ mice. In this study, we examined the expression of EphB2 in normal colon, adenomas, primary CRCs, lymph node metastases and liver metastases using immunohistochemistry on tissue microarrays. In addition, EphB2 was overexpressed in SW480 colon cancer cells to study its effect in vitro. We found that EphB2 was expressed in 100% of normal colon crypt base cells, 78% of adenomas, 55.4% of primary CRCs, 37.8% of lymph node metastases and 32.9% of liver metastases (all differences were statistically significant at p<0.001 compared with primary CRCs). Patients with CRCs that lose EphB2 expression had more advanced tumor stage (p=0.005), poor differentiation (p<0.001), poor overall survival (p=0.005) and disease-free survival (p=0.001), with the latter being independent of tumor stage. In vitro studies showed that overexpression of EphB2 inhibited colon cancer cell growth in colony formation assay and activation of EphB2 receptor inhibited colon cancer cell adhesion and migration. Our data demonstrated a progressive loss of EphB2 expression in each critical step of colon carcinogenesis, including the onset of invasion, dedifferentiation and metastasis which are paralleled by adverse patient outcome. EphB2 may achieve its tumor suppressor function through regulation of cell survival, adhesion and migration.

{ddagger}These authors contribute equally to the work.
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