Induction of hepatocellular carcinoma with high metastatic potential in WS/Shi rats: discovery of an inbred strain highly susceptible to the liver carcinogen N-nitrosomorpholine.

We investigated the susceptibility of three inbred strains of rats to the hepatocarcinogen, N-nitrosomorpholine (NNM), to establish a spontaneous metastatic model of hepatocellular carcinoma (HCC). WS/Shi. SD/gShi, and F344/DuCrj rats were given 0.02% NNM in drinking water for 8 weeks and thereafter left without any treatment. The experiment ceased at week 20, because mortality markedly increased after this time point in WS/Shi rats. Liver weight was highest in WS/Shi rats among the three strains examined. The incidence of HCC was 15/15 (100%) in WS/Shi rats, 1/16 (6%) in SD/gShi rats, and 13/16 (81%) in F344/DuCrj rats surviving after NNM treatment. Metastasis to the lung was observed in HCC-bearing rats at an incidence of 13/15 (87%) in WS/Shi, 1/1 in SD/gShi, and 6/13 (46%) in F344/DuCrj. Four-week administration of NNM resulted in a significantly higher BrdU-labeling index of hepatocytes in WS/Shi rats than in the other strains. These findings indicated that WS/Shi is the most sensitive strain to NNM and may be the most suitable strain for use as a spontaneous metastatic model of HCC among the strains of rats examined in the present study.