Subcutaneous and intrahepatic growth of human hepatoblastoma in immunodeficient mice.
OBJECTIVE
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.
Schnater
J Marco
JM
Research Laboratory, Department of Pediatric Surgery, University Childrens' Hospital Basel, Hebelstrasse 20, 4031 Basel, Switzerland.
Bruder
Elisabeth
E
Bertschin
Sibylle
S
Woodtli
Thomas
T
de Theije
Chiel
C
Pietsch
Torsten
T
Aronson
Daniel C
DC
von Schweinitz
Dietrich
D
Lamers
Wouter H
WH
Köhler
Eleonore S
ES
D000818:Animals; D014408:Biomarkers, Tumor / Q000097:blood; D006528:Carcinoma, Hepatocellular / Q000097:blood / Q000473:pathology; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000473:pathology*; D004195:Disease Models, Animal; D018197:Hepatoblastoma / Q000097:blood / Q000473:pathology*; D006801:Humans; D008113:Liver Neoplasms / Q000097:blood / Q000473:pathology*; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness / Q000473:pathology*; D009362:Neoplasm Metastasis / Q000473:pathology; D009368:Neoplasm Transplantation / Q000379:methods / Q000473:pathology*; D009374:Neoplasms, Experimental / Q000473:pathology; D013160:Splenic Neoplasms / Q000473:pathology; D000509:alpha-Fetoproteins / Q000032:analysis
D014408:Biomarkers, Tumor; D000509:alpha-Fetoproteins