Genomic progression in mouse models for liver tumors.
The principal cause of human liver cancer is infection with hepatitis viruses B and C, but tumor progression is fueled by ensuing perturbations that confer gain of function on proto-oncogenes or loss of function on tumor suppressor genes. Frequent among these perturbations is overexpression of the proto-oncogene MET. We have modeled the pathogenesis of liver tumors by expressing conditional transgenes of MET in the hepatocytes of inbred mice. The response to the MET transgene varied with both the magnitude and timing of its expression but included hyperplasia of hepatic progenitor cells, as well as benign and malignant tumors that display both phenotypic and genotypic resemblances to human counterparts. The results reveal MET to be a crucial switch in the development of the liver; dramatize how different cellular compartments within a developmental lineage can give rise to distinctive tumor stem cells; delineate rules of tumor progression; provide evidence that the experimental tumors in mice are authentic models for human tumors; and support a role for MET in the genesis of human liver tumors. The models should be useful in elucidating the mechanisms of tumorigenesis and in the preclinical testing of new therapeutics.
Tward
A D
AD
GW Hooper Foundation, University of California at San Francisco, 94143, USA.
Jones
K D
KD
Yant
S
S
Kay
M A
MA
Wang
R
R
Bishop
J M
JM
D000595:Amino Acid Sequence; D000818:Animals; D004195:Disease Models, Animal; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008114:Liver Neoplasms, Experimental / Q000209:etiology / Q000235:genetics* / Q000821:virology; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009154:Mutation; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000235:genetics; D019859:Proto-Oncogene Proteins c-met; D011519:Proto-Oncogenes; D017978:Receptors, Growth Factor / Q000235:genetics; D014162:Transfection; D051176:beta Catenin / Q000235:genetics
C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D017978:Receptors, Growth Factor; D051176:beta Catenin; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met