Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
, 36 (3), 623-30

Demonstration of Direct Lineage Between Hepatocytes and Hepatocellular Carcinoma in Diethylnitrosamine-Treated Rats

Affiliations

Demonstration of Direct Lineage Between Hepatocytes and Hepatocellular Carcinoma in Diethylnitrosamine-Treated Rats

Marie-Pierre Bralet et al. Hepatology.

Abstract

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.

Similar articles

See all similar articles

Cited by 21 PubMed Central articles

See all "Cited by" articles

Publication types

MeSH terms

Feedback