Reduced expression of EphB2 that parallels invasion and metastasis in colorectal tumours.
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.
Guo
Dong Li
DL
Department of Pathology, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong.
Zhang
Ji
J
Yuen
Siu Tsan
ST
Tsui
Wai Yin
WY
Chan
Annie S Y
AS
Ho
Coral
C
Ji
Jiafu
J
Leung
Suet Yi
SY
Chen
Xin
X
D000236:Adenoma / Q000235:genetics* / Q000473:pathology*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002470:Cell Survival; D002471:Cell Transformation, Neoplastic; D003106:Colon / Q000201:enzymology; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology*; D018572:Disease-Free Survival; D015536:Down-Regulation; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D008113:Liver Neoplasms / Q000556:secondary; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D011379:Prognosis; D036183:Receptor, EphB2 / Q000096:biosynthesis*
D036183:Receptor, EphB2