PARTICIPATION OF HEPATOCYTE GROWTH FACTOR (HGF) AND MET AUTOCRINE/PARACRINE LOOP IN LIVER METASTASIS OF GASTRIC CANCER
Y. Yonemura1,*, Y. Endo2, E. Bandou1, T. Kawamura1, K. Kinoshita1, S. Takahashi1, K. Sugiyama3, T. Sasaki
1Surgical Department of Gastric Cancer, Shizuoka Cancer Center, Suntou-Gun, Nagaizumi-Machi, Shimo-Nagakubo, 1007, Shizuoka-Ken 411-0934, Japan, 2Experimental Therapeutics, Cancer Research Institute, Kanazawa University, Takara-Machi 13-1, Kanazawa 920-8640 3Virology Division, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuoo-Ku, Tokyo 104, Japan
Abstract. A highly metastatic to the liver gastric cancer cell line AZ-H was established by repeated intrasplenic injection of AZ-521 cells. In a Matrigel coated chamber AZ-H showed higher adhesiveness than AZ-521, and the invasiveness of AZ-H through Matrigel was significantly higher than that of AZ-521. Furthermore, AZ-H had higher metastatic potential to chicken liver than AZ-521. RT-PCR comparison of AZ-521 and AZZ-H in terms of the expression of 41 metastasis related genes showed that the expression of c-met, VEGF-C and integrin avb5 mRNAs and protein in AZ-H was higher than those in the parental cells AZ-521. Hepatocyte growth factor (HGF) expression was not found in parental AZ-521, but AZ-H showed both HGF and MET overexpression. Maspin mRNA expression in AZ-H was weaker than in AZ-521 cells. The remaining 36 genes showed no difference in the expression levels between AZ-H and AZ-521 cells. The incidence of liver metastasis in mice which had received intrasplenic infusion of anti-MET rabbit antibody treated AZ-H cells was significantly lower than that in mice, injected with normal rabbit IgG-treated AZ-H cells. Among 188 primary tumors 127 (68%) showed positive immunoreactivity for MET. Primary tumors of patients, who died of liver metastasis, exclusively showed MET immunoreaction. We conclude that liver metastasis of the AZ-H cells may be resulted from the simultaneous and concerted expression of VEGF-C, avb5 integrin, HGF and MET, and that invasion and proliferation of AZ-H cells in liver may be activated via the HGF/MET autocrine and paracrine loop.
