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 tumour progression in the Apc(Min/+) mice. In this study, we examined the expression of EphB2 in normal colon,
adenomas, primary
colorectal cancers (
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 tumour 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 tumour 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 tumour suppressor function through regulation of cell survival, adhesion and migration.