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

• Published in: The journal of gene medicine 2010-12, Vol.12 (12), p.1002-1013
• Main Authors: Kakinoki, Kaheita, Nakamoto, Yasunari, Kagaya, Takashi, Tsuchiyama, Tomoya, Sakai, Yoshio, Nakahama, Tohru, Mukaida, Naofumi, Kaneko, Shuichi
• Format: Article
• Language: English
• Subjects: Adenovirus; Animals; Chemokine CCL2 - administration & dosage; chemokines; Ganciclovir - administration & dosage; Gene therapy; Genes, Transgenic, Suicide; Genetic Therapy - methods; Genetic Vectors - administration & dosage; hepatocellular carcinoma; Herpes simplex virus; Immunohistochemistry; Liver cancer; Liver Neoplasms, Experimental - pathology; Liver Neoplasms, Experimental - therapy; Mice; Mice, Inbred BALB C; monocytes/macrophages; Neoplasm Metastasis - prevention & control; Neoplasm Metastasis - therapy; Th1 Cells - immunology; Thymidine Kinase - administration & dosage; Treatment Outcome
• ISSN: 1099-498X; 1521-2254; 1521-2254
• DOI: 10.1002/jgm.1528

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/MLow), 3/3 (T/MHigh) and Ad‐tk/Ad‐LacZ = 3/3 (T/L) were injected into BALB/c mice. Results Intrahepatic tumor growth was significantly lower in T/MLow mice. By contrast, no tumor suppression was observed in T/MHigh mice. The tumor‐specific cytolytic activities of splenocytes from T/MLow and T/MHigh 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/MLow mice. In addition, interleukin‐12 production was elevated in these tissues. Vascular endothelial growth factor‐A expression and CD31+ microvessels were increased in T/MHigh 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.