Prevention of intrahepatic metastasis of liver cancer by suicide gene therapy and chemokine ligand 2/monocyte chemoattractant protein‐1 delivery in mice

Background The prognosis of patients with hepatocellular carcinoma (HCC) remains poor, largely as a result of intrahepatic metastasis. Using a mouse model of intrahepatic metastasis, we investigated whether chemokine ligand 2/monocyte chemoattractant protein‐1 (CCL2/MCP‐1) could potentiate the antitumor effects of the herpes simplex virus thymidine kinase/ganciclovir (HSV‐tk/GCV) system. Methods Mouse hepatoma cells infected with recombinant adenovirus vectors expressing HSV‐tk, CCL2/MCP‐1 and LacZ at multiplicities of infection of Ad‐tk/Ad‐MCP1 = 3/0.03 (T/M Low ), 3/3 (T/M High ) and Ad‐tk/Ad‐LacZ = 3/3 (T/L) were injected into BALB/c mice. Results Intrahepatic tumor growth was significantly lower in T/M Low mice. By contrast, no tumor suppression was observed in T/M High mice. The tumor‐specific cytolytic activities of splenocytes from T/M Low and T/M High mice were comparable. Immunohistochemical analysis of liver tissues showed similar infiltration by Mac‐1 + and T cells in these animals, whereas the proportions of classical activated (M1) monocytes/macrophages were significantly higher in T/M Low mice. In addition, interleukin‐12 production was elevated in these tissues. Vascular endothelial growth factor‐A expression and CD31 + microvessels were increased in T/M High mice. Conclusions Collectively, these results demonstrate that an adequate amount of CCL2/MCP‐1, together with the HSV‐tk/GCV system, may induce T helper 1‐polarized antitumor effects without inducing tumor angiogenesis in the microenvironment of intrahepatic HCC progression. Copyright © 2010 John Wiley & Sons, Ltd.