Subcutaneous and intrahepatic growth of human hepatoblastoma in immunodeficient mice

M.J. Schnater, E. Bruder, S. Bertschin, T. Woodtli, C.C. de Theije, T. Pietsch, D.C. Aronson, D. von Schweinitz, W.H. Lamers, S.E. Kohler

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

BACKGROUND/AIMS: Hepatoblastoma is the most frequent malignant pediatric liver tumor. Approximately 25% of hepatoblastoma patients cannot be cured with current treatment protocols. Additional treatment options must, therefore, be developed. Subcutaneous animal models for hepatoblastoma exist, but a more physiologic intrahepatic model is lacking. METHODS: The alpha-fetoprotein-expressing hepatoblastoma-cell lines HepT1, HuH6 and the childhood hepatocellular carcinoma-cell line HepG2 were injected subcutaneously and intrasplenically into NMRI nu/nu mice. Tumor growth was monitored by measuring tumor size for subcutaneous and serum human alpha-fetoprotein levels for intra-abdominal tumors. Tumors were characterized microscopically. RESULTS: Subcutaneous tumor growth occurred in 70% (7/10) of mice injected with HuH6 and 50% (5/10) of mice injected with HepG2. HepT1 did not form tumors. Accumulation of serum alpha-fetoprotein reflected tumor growth. Intrasplenic growth was seen in 50% (14/27, HuH6) and 10% (3/10, HepG2) of the mice, with only HuH6 forming intrahepatic tumors in 25% (7/27) of the mice. Growth pattern and alpha-fetoprotein production were similar at the subcutaneous and intra-abdominal location. Intrahepatic grafting occurred by metastatic spread from the spleen, produced well-defined nodules, and was accompanied by a weakened expression of the hepatocyte marker carbamoylphosphate synthetase, and the canalicular markers CD10 and cytokeratin7. The expression of cytokeratin18 and -19, active caspase3, and beta-catenin was increased. There were no lung metastases. CONCLUSIONS: We established an intrahepatic mouse model for human hepatoblastoma, in which tumor growth could be monitored by serum alpha-fetoprotein levels. Engrafting in the liver occurred by metastatic spread from the spleen and was accompanied by some loss of differentiation features.
Original languageEnglish
Pages (from-to)377-386
JournalJournal of Hepatology
Volume45
Issue number3
DOIs
Publication statusPublished - 1 Jan 2006

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