Demonstration of direct lineage between hepatocytes and hepatocellular carcinoma in diethylnitrosamine-treated rats.
The question whether hepatocellular carcinoma (HCC) arises from dedifferentiation of mature hepatocytes or from proliferation of liver stem cells is still debated. In the present study, we used retroviral-mediated genetic labeling to investigate the fate of mature hepatocytes in rats after administration of diethylnitrosamine (DEN). Mature hepatocytes were genetically labeled by intravenous injection of retroviral vectors containing the Escherichia coli beta-galactosidase gene coupled to a nuclear localization signal (nls-LacZ) 1 day after partial hepatectomy. Liver biopsies performed after completion of hepatic regeneration showed that 18.3% of hepatocytes expressed the nls-LacZ transgene. Rats were then treated with DEN in drinking water for 12 weeks and sacrificed between 98 and 151 days after the onset of DEN administration. Clones of beta-galactosidase positive cells were observed, half of which (53%) also expressed the placental form of glutathione-S-transferase (GSTp), a marker of preneoplastic cells. HCCs of various sizes expressing GSTp were present in all animals. Careful examination of 90 HCCs revealed that 16 (17.7%) also expressed nls-LacZ. This figure precisely matched the proportion of labeled hepatocytes before DEN treatment (18.3%). In conclusion, a random clonal origin of HCC from mature hepatocytes is seen in the DEN model of hepatocarcinogenesis.
Département de Pathologie, Hôpital Henri Mondor, AP-HP, Créteil; and Laboratoire de Thérapie Génique, INSERM ERM 01-05, Centre Hospitalier Universitaire de Nantes, Nantes, France.
Marie-Pierre
MP
Bralet
Virginie
V
Pichard
Nicolas
N
Ferry
D000477:Alkylating Agents; D000818:Animals; D030801:Animals, Genetically Modified; D006528:Carcinoma, Hepatocellular / Q000139:chemically induced / Q000473:pathology*; D002454:Cell Differentiation; D019070:Cell Lineage; D004052:Diethylnitrosamine; D005260:Female; D017930:Genes, Reporter; D005822:Genetic Vectors; D006498:Hepatectomy; D022781:Hepatocytes / Q000166:cytology*; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced / Q000473:pathology*; D008115:Liver Regeneration; D008297:Male; D051381:Rats; D012190:Retroviridae / Q000235:genetics; D001616:beta-Galactosidase / Q000235:genetics
D000477:Alkylating Agents; D004052:Diethylnitrosamine; D001616:beta-Galactosidase