Interaction of the Eph family of
receptor protein tyrosine kinase and its
ligand ephrin family induces bidirectional signaling via cell-cell contacts. High expression of B-type
ephrin is frequently found in various
cancer cells, and their expression levels are associated with high invasion of
tumors and poor prognosis. However, whether
ephrin-B1 actually promotes invasion of
cancer cells in vivo has not been shown. We investigated the involvement of
ephrin-B1 in regulating the invasiveness of scirrhous
gastric cancer, which is a diffusely infiltrative
carcinoma with high invasion potential. Reduction of
ephrin-B1 expression by short inter-fering
RNA or overexpression of phosphorylation-defective mutant suppressed migration and invasion of scirrhous
gastric cancer cells in vitro without affecting
tumor cell proliferation and apoptosis. Blocking of
tyrosine phosphorylation of
ephrin-B1 attenuates not only dissemination of
cancer cells injected intraperitoneally but also local invasion and dissemination of orthotopically implanted
cancer cells in the gastric wall of nude mice. Furthermore, blocking of
ephrin-B1 phosphorylation attenuated the activation of Rac1
GTPase in these invasive
gastric cancer cells. Our results suggest that
tyrosine phosphorylation of
ephrin-B1 promotes invasion of
cancer cells in vivo and is a potential therapeutic target in some types of
gastrointestinal cancers.