Distinct pathways of genomic progression to benign and malignant tumors of the liver.
We used several of the genetic lesions commonly associated with human liver tumors to reconstruct genetic progression to hepatocellular carcinoma and adenoma in mouse models. We initiated tumorigenesis with a transgene of the protooncogene MET or by hydrodynamic transfection of MET in combination with other genes into the livers of adult animals. Hepatocellular carcinoma in both instances arose from cooperation between MET and constitutively active versions of beta-catenin. In contrast, adenomas were produced by cooperation between MET and defective signaling through the transcription factor HNF1alpha. Prompted by these findings, we uncovered a coincidence between activation of the protein-tyrosine kinase encoded by MET and activating mutations of beta-catenin in a subset of human hepatocellular carcinomas. Inactivation of MET transgenes led to regression of hepatocellular carcinomas despite the persistence of activated beta-catenin. The tumors eventually recurred in the absence of MET expression, however, presumably after the occurrence of one or more events that cooperated with activated beta-catenin in lieu of MET. These results offer insight into hepatic tumorigenesis, provide mouse models that should be useful in the further study of hepatic tumorigenesis and for preclinical testing, and identify a subset of human hepatocellular carcinomas that may be susceptible to combination therapy directed against Met and the Wnt signaling pathway.
Tward
Aaron D
AD
G. W. Hooper Foundation and Department of Microbiology and Immunology, University of California, San Francisco, CA 94143, USA. atward@partners.org
Jones
Kirk D
KD
Yant
Stephen
S
Cheung
Siu Tim
ST
Fan
Sheung Tat
ST
Chen
Xin
X
Kay
Mark A
MA
Wang
Rong
R
Bishop
J Michael
JM
D018248:Adenoma, Liver Cell / Q000209:etiology / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000209:etiology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D015972:Gene Expression Regulation, Neoplastic; D051538:Hepatocyte Nuclear Factor 1-alpha / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008114:Liver Neoplasms, Experimental / Q000209:etiology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D011233:Precipitin Tests; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics; D017422:Sequence Analysis, DNA; D014162:Transfection; D019076:Transgenes; D051176:beta Catenin / Q000235:genetics