C-met as a therapeutic target for metastatic potential of gastric cancer.

Abstract

e14568 Background: Autophosphorylation of c-met, a transmembrane tyrosine kinase, activates several signaling transduction cascades leading to cancer metastasis-cell proliferation, motility, invasion and angiogenesis. To elucidate the role of c-met activation in gastric cancer invasion and liver metastasis, we analyzed the functional expression and activation of c-met in gastric cancer cell lines and tumor tissues. Methods: Expression of c-met and activated c-met (p-met) was detected in 6 gastric cancer cell lines and 21 gastric cancer patients with liver metastasis. The effects of c-met inhibition were studied on cancer cell proliferation, migration and invasion, using a small molecule tyrosine kinase inhibitor SU-11274. Results: c-met and p-met were detected in 66.7% and 50% of gastric cancer cell lines, respectively. In gastric cancer tissues, c-met was over-expressed both in primary gastric cancer and matched liver metastasis, while activated p-met expression was more prominent in liver metastasis (p < 0.001) by immunohistochemistry. SU-11274 inhibited cell proliferation in p-met positive gastric cancer cell lines with an IC50 between 1 and 2.5 uM. Furthermore, blocking of migration in p-met positive gastric cancer cell line (Hs-746T), but not in p-met negative cell line (AGS) (p < 0.001), was observed with SU-11274 treatment. We also found abrogation of c-met activation with SU-11274 can inhibit cell invasion in Hs-746T, but not in AGS (p < 0.01). Conclusions: c-met activation is strongly associated with gastric cancer invasion and liver metastasis. Targeted therapy against c-met activation might provide a major therapeutic advance in gastric cancer invasion and metastasis. No significant financial relationships to disclose.