Hepatocyte growth factor (HGF) is involved in malignant behavior of cancer cells by enhancing invasion and metastasis. We earlier found that NK4, a four-kringle fragment of HGF, functions as both an HGF antagonist and an angiogenesis inhibitor. We have now carried out studies to determine if hydrodynamics-based delivery and expression of the NK4 gene would inhibit liver metastasis and invasive growth of colon carcinoma cells in mice. When the naked plasmid for NK4 was introduced into mice by hydrodynamics-based gene delivery, a high level of expression of NK4 was predominant in the liver. After intrasplenic inoculation of MC-38 murine colon carcinoma cells, the cells formed numerous metastatic nodules in the liver and showed invasive growth behavior. On the other hand, when mice were given the NK4 plasmid, hepatic gene expression of NK4 inhibited the liver metastasis and subsequent growth associated with a decrease in microvessel density. Likewise, intrahepatic invasion of cancer cells was inhibited by NK4 gene expression, and this anti-invasive effect was associated with in situ inhibition of c-Met receptor tyrosine phosphorylation. Moreover, NK4 gene expression prolonged survival of these mice. Taken together with the knowledge that the majority of deaths from colon cancer are due to liver metastasis, the potential therapeutic use of hepatic gene expression of NK4 for metastatic colon cancer treatment can be given consideration.
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