title: A novel animal model for in vivo study of liver cancer metastasis.
abstract: OBJECTIVE
  To establish an animal model with human hepatocyte-repopulated liver for the study of liver cancer metastasis.
  
  
  METHODS
  Cell transplantation into mouse livers was conducted using alpha-fetoprotein (AFP)-producing human gastric cancer cells (h-GCCs) and h-hepatocytes as donor cells in a transgenic mouse line expressing urokinase-type plasminogen activator (uPA) driven by the albumin enhancer/promoter crossed with a severe combined immunodeficient (SCID) mouse line (uPA/SCID mice). Host mice were divided into two groups (A and B). Group A mice were transplanted with h-GCCs alone, and group B mice were transplanted with h-GCCs and h-hepatocytes together. The replacement index (RI), which is the ratio of transplanted h-GCCs and h-hepatocytes that occupy the examined area of a histological section, was estimated by measuring h-AFP and h-albumin concentrations in sera, respectively, as well as by immunohistochemical analyses of h-AFP and human cytokeratin 18 in histological sections.
  
  
  RESULTS
  The h-GCCs successfully engrafted, repopulated, and colonized the livers of mice in group A (RI = 22.0% ± 2.6%). These mice had moderately differentiated adenocarcinomatous lesions with disrupted glandular structures, which is a characteristics feature of gastric cancers. The serum h-AFP level reached 211.0 ± 142.2 g/mL (range, 7.1-324.2 g/mL). In group B mice, the h-GCCs and h-hepatocytes independently engrafted, repopulated the host liver, and developed colonies (RI = 12.0% ± 6.8% and 66.0% ± 12.3%, respectively). h-GCC colonies also showed typical adenocarcinomatous glandular structures around the h-hepatocyte-colonies. These mice survived for the full 56 day-study and did not exhibit any metastasis of h-GCCs in the extrahepatic regions during the observational period. The mice with an h-hepatocyte-repopulated liver possessed metastasized h-GCCs and therefore could be a useful humanized liver animal model for studying liver cancer metastasis in vivo.
  
  
  CONCLUSIONS
  A novel animal model of human liver cancer metastasis was established using the uPA/SCID mouse line. This model could be useful for in vivo testing of anti-cancer drugs and for studying the mechanisms of human liver cancer metastasis.
authors.affiliation: Clinical Research Center, National Hospital Organization Nagasaki Medical Center and Division of Hepatology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan. gearorange@nmc-research.jp
authors.forename: Shinsuke
authors.initials: S
authors.lastname: Fujiwara
authors.forename: Hikaru
authors.initials: H
authors.lastname: Fujioka
authors.forename: Chise
authors.initials: C
authors.lastname: Tateno
authors.forename: Ken
authors.initials: K
authors.lastname: Taniguchi
authors.forename: Masahiro
authors.initials: M
authors.lastname: Ito
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ohishi
authors.forename: Rie
authors.initials: R
authors.lastname: Utoh
authors.forename: Hiromi
authors.initials: H
authors.lastname: Ishibashi
authors.forename: Takashi
authors.initials: T
authors.lastname: Kanematsu
authors.forename: Katsutoshi
authors.initials: K
authors.lastname: Yoshizato
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D022781:Hepatocytes / Q000637:transplantation; D006801:Humans; D008114:Liver Neoplasms, Experimental / Q000473:pathology / Q000556:secondary*; D051379:Mice; D016513:Mice, SCID; D008822:Mice, Transgenic; D009368:Neoplasm Transplantation; D013274:Stomach Neoplasms; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D014568:Urokinase-Type Plasminogen Activator / Q000235:genetics
chemical_list: D014568:Urokinase-Type Plasminogen Activator