Inducible formation of liver tumors in transgenic mice.

Transgenic mice have been generated with an inducible SV40 t/T antigen construct with the aim of analysing the early changes that take place in the course of liver tumorigenesis. The strictly liver-specific human C-reactive protein (CRP) gene promoter was chosen for the control of the transgene expression because this promoter can be turned on transiently by injection of bacterial lipopolysaccharide. Among 10 independently derived CRP-Tag mouse lines five showed inducible expression of the CRP-Tag transgene in liver. However, only one had a tight control of the transgene with virtually no expression under physiological conditions and high levels of Tag expression after stimulation. Females of this line were used to analyse the progression of liver alterations upon repeated induction of the t/T antigen for different lengths of time. The first signs of transgene-induced liver alterations could be monitored by the activation of the marker enzyme gamma-glutamyltranspeptidase 30 days after the start of the induction program. After 90 days hepatocellular carcinomas were already detectable. Thus, CRP-Tag mice constitute an excellent system to analyse the sequential events that take place during liver carcinogenesis.