Aim: 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.
Conclusion: 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.
Keywords: Alpha-fetoprotein-producing gastric cancer cells; Liver cancer metastasis; Mouse with humanized liver; Urokinase-type plasminogen activator/severe combined immunodeficient mouse.