Demonstration of direct lineage between hepatocytes and hepatocellular carcinoma in diethylnitrosamine-treated rats
- 1 September 2002
- journal article
- Published by Ovid Technologies (Wolters Kluwer Health) in Journal of Hepatology
- Vol. 36 (3), 623-630
- https://doi.org/10.1053/jhep.2002.35540
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 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.This publication has 21 references indexed in Scilit:
- Cytotoxic Immune Response Blunts Long-Term Transgene Expression after Efficient Retroviral-Mediated Hepatic Gene Transfer in RatMolecular Therapy, 2002
- Genetic mechanisms of hepatocarcinogenesisOncogene, 2002
- In VivoRetrovirus-Mediated Gene Transfer to the Liver of Dogs Results in Transient Expression and Induction of a Cytotoxic Immune ResponseHuman Gene Therapy, 1999
- Bone Marrow as a Potential Source of Hepatic Oval CellsScience, 1999
- Cellular origin of cancer: dedifferentiation or stem cell maturation arrest?Environmental Health Perspectives, 1993
- Retroviral lineage studies: some principals and applicationsCurrent Opinion in Genetics & Development, 1993
- The role of the stages of initiation and promotion in phenotypic diversity during hepatocarcinogenesis in the ratCarcinogenesis: Integrative Cancer Research, 1992
- Enzyme histochemical and immunohistochemical characterization of oval and parenchymal cells proliferating in livers of rats fed a choline-deficient/DL-ethionine-supplemented dietCarcinogenesis: Integrative Cancer Research, 1991
- A precursor—product relationship exists between oval cells and hepatocytes in rat liverCarcinogenesis: Integrative Cancer Research, 1987
- Phenotypic diversity in experimental hepatomas: the concept of partially blocked ontogeny. The 10th Walter Hubert LectureBritish Journal of Cancer, 1978