Combined gene therapy with oncolytic adenovirus and NK-4 against tumor growth and invasion in hepatocellular carcinoma

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The many past approaches used to treat hepatocellular carcinoma (HCC) patients have been less than satisfactory. Accumulating evidence has shown that carcinoma cell invasion and metastasis are inhibited by NK4, an antagonist for hepatocyte growth factor (HGF), and that gene therapy using replication-competent adenovirus is an effective treatment for cancer. HCC, approximately 70% of which can produce u-fetoprotein (AFP), is considered as a candidate disease for the development of a novel treatment using different genes and different vectors. To develop a rational basis for effective anticancer therapy, inhibitory effects of treatment with an AFP-promoter-driven adenovirus deficient of the E1B-55k gene (AdAFP/Rep) and an adenoviral vector expressing NK4 (AdCMV.NK4, provided by Prof. T. Nakamura, Osaka University, and Prof. T. Nukiwa, Tohoku University) to target AFP-producing HCC cells on the tumor growth and invasion were examined in vivo and in vitro. AdAFP/Rep was able to lyse all th … More e AFP-producing HCC cell line (HuH7, HepG2) and not to lyse normal human hepatocytes in primary culture. AdCMV.NK4 played an inhibitory role in the proliferation of the AFP-producing HCC cells, but not normal hepatocytes. Invasion of AFP-producing HCC cells through Matrigel basement membrane components and into collagen gels was inhibited by treatment with AdCMV.NK4. Treatment with AdAFP/Rep or AdCMV.NK4 in nude mice implanted AFP-producing HCC cells resulted in an inhibition in the tumor growth. AdCMV.NK4 treatment decreased mRNA expressions of vascular endothelial growth factor (VEGF) and CD31 as well as matrix metalloproteinase(MMP)-2 and MMP-9 in the HCC cells and implanted subcutaneous tumors. Although AdCMV.NK4 alone did not have a more potent stimulatory effect on apoptosis than that of AdAFP/Rep, the combined treatment with AdAFP/Rep and AdCMV.NK4 induced synergic pro-apoptotic action in the cells and tumors, and inhibited growth and metastasis of invisible HCC much more than each treatment. These findings clearly showed that the combination of AdAFP/Rep and AdCMV.NK4 can inhibit tumor growth, invasion and metastasis of HCC cells in laboratory animals. It may therefore offer a more effective gene therapy for HCC. Less