title: Prevention of intrahepatic metastasis of liver cancer by suicide gene therapy and chemokine ligand 2/monocyte chemoattractant protein-1 delivery in mice.
abstract: 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.
authors.affiliation: Disease Control and Homeostasis, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan.
authors.forename: Kaheita
authors.initials: K
authors.lastname: Kakinoki
authors.forename: Yasunari
authors.initials: Y
authors.lastname: Nakamoto
authors.forename: Takashi
authors.initials: T
authors.lastname: Kagaya
authors.forename: Tomoya
authors.initials: T
authors.lastname: Tsuchiyama
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Sakai
authors.forename: Tohru
authors.initials: T
authors.lastname: Nakahama
authors.forename: Naofumi
authors.initials: N
authors.lastname: Mukaida
authors.forename: Shuichi
authors.initials: S
authors.lastname: Kaneko
mesh_terms: D000818:Animals; D018932:Chemokine CCL2 / Q000008:administration & dosage; D015774:Ganciclovir / Q000008:administration & dosage; D041722:Genes, Transgenic, Suicide; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage*; D007150:Immunohistochemistry; D008114:Liver Neoplasms, Experimental / Q000473:pathology / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D009362:Neoplasm Metastasis / Q000517:prevention & control* / Q000628:therapy; D018417:Th1 Cells / Q000276:immunology; D013937:Thymidine Kinase / Q000008:administration & dosage; D016896:Treatment Outcome
chemical_list: D018932:Chemokine CCL2; D013937:Thymidine Kinase; D015774:Ganciclovir