Adenoviral-mediated gene transduction of the hepatocyte growth factor (HGF) antagonist, NK4, suppresses peritoneal metastases of gastric cancer in nude mice.

The competitive inhibitory effects of NK4 (a specific hepatocyte growth factor (HGF)-antagonist) on the interaction between HGF and the c-Met/HGF receptor has been shown in HGF-mediated invasion of some distinct types of human cancer cells. Furthermore, NK4 has inhibitory effects on the angiogenic pathways driven by basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF), as well as by HGF. In this study, to evaluate the therapeutic efficacy of adenoviral-mediated NK4 gene treatment, we employed animal models of peritoneal metastasis using two gastric cancer cell lines, the strongly c-Met expressing MKN45 cell line and the weakly c-Met-expressing cell line, TMK1. In both models, the total number and weight of peritoneal tumours per mouse and ascites treated early with AxCANK4 (administered 3 times 2, 7 and 12 days after the tumour inoculation) were significantly reduced compared with those treated with phosphate-buffered solution (PBS) and AxCALacZ (P < 0.05). In Factor-VIII-related-antigen-stained sections from peritoneal metastatic tumours, the inhibition of intratumour vessels was observed in tissues from tumours of MKN45 and TMK1 treated with AxCANK4. We also compared the therapeutic effect of early AxCANK4 treatment with that of late treatment (at 7, 12 and 17 days). Peritoneal metastases and ascites treated late with AxCANK4 showed less of an improvement than those treated early with AxCANK4 in both models. In addition, the inhibitory effect of cisplatin (CDDP) on peritoneal metastasis was significantly enhanced by AxCANK4, suggesting that the combination of intraperitoneal (i.p.) chemotherapy with NK4 gene therapy might be effective, even in cases of advanced peritoneal metastasis from gastric cancer. To conclude, these results show clearly that NK4 gene therapy inhibits peritoneal metastases from gastric cancer, regardless of the level of c-Met/HGF receptor expression in the tumour cells, and especially in the early stages of peritoneal metastasis.