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Demonstration of direct lineage between hepatocytes and hepatocellular carcinoma in diethylnitrosamine‐treated rats
Author(s) -
Bralet MariePierre,
Pichard Virginie,
Ferry Nicolas
Publication year - 2002
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1053/jhep.2002.35540
Subject(s) - hccs , hepatocellular carcinoma , hepatocyte , biology , transgene , cancer research , nuclear localization sequence , nls , liver regeneration , gene , microbiology and biotechnology , regeneration (biology) , genetics , in vitro
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 β‐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 β‐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.