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Increased expression of and sensitivity to transforming growth factor-alpha: a promotive role during rat liver
S Strömblad1, L C Eriksson, G Andersson
1Department of Pathology, Karolinska Institutet, Huddinge University Hospital, Sweden.
Abstract:
The influence of the tumor promoter 2-acetylaminofluorene (2-AAF) on cell proliferation and on the epidermal growth factor receptor (EGFR) system was assessed in normal and nodular rat livers. DNA replication in vivo was inhibited below the detection level after 8d of dietary 2-AAF treatment of previously unexposed rats. The 2-AAF-induced growth inhibition was accompanied by downregulation of the number of epidermal growth factor (EGF)-binding sites and decreased levels of EGFR transcripts, whereas no changes in the transforming growth factor-alpha (TGF-alpha) mRNA levels were observed. The persistent liver nodules generated by intermittent 2-AAF-feeding had a 30- to 35-fold higher replicating cell fraction than normal liver. Treatment with 2-AAF in vivo reduced the replicating cell fraction to one third in nodules after 14 d of 2-AAF treatment. The initial EGFR mRNA levels and number of EGF binding sites in nodules before 2-AAF administration was about 605 that of control livers and was slightly reduced by 2-AAF feeding. The levels of EGFR mRNA after 14 d of 2-AAF feeding were thus similar in the nodules and in the 2-AAF-treated control livers, whereas the fraction of proliferating cells in nodules after the 2-AAF treatment was much larger than in normal liver. The TGF-alpha mRNA level in the nodules was found to be 1.4-fold and in malignant hepatomas 1.7-fold the level in normal liver. Primary hepatocytes isolated from control livers were four to five times more sensitive to replicative stimulation with EGF than with TGF-alpha, whereas nodular cells responded at lower concentrations than control cells and equally well to both EGF and TGF-alpha. We conclude that the decreased amounts of EGFR in the nodular cells with respect to proliferative stimulation could be more than compensated for by elevated synthesis of TGF-alpha combined with an increased TGF-alpha sensitivity. Collectively, these changes implicate TGF-alpha in sustaining cell proliferation during chemically induced rat liver carcinogenesis.
Insights
Dietary 2-acetylaminofluorene (2-AAF) inhibits normal rat liver cell proliferation by downregulating epidermal growth factor receptor (EGFR). However, in liver nodules, transforming growth factor-alpha (TGF-alpha) sustains proliferation despite reduced EGFR.
Area of Science:
- Hepatocarcinogenesis research
- Molecular biology of cell growth regulation
- Toxicology and chemical carcinogenesis
Background:
- The tumor promoter 2-acetylaminofluorene (2-AAF) is used to study liver cancer development.
- Epidermal growth factor receptor (EGFR) signaling is crucial for cell proliferation.
- Transforming growth factor-alpha (TGF-alpha) is another key growth factor involved in cell regulation.
Purpose of the Study:
- To investigate the impact of 2-AAF on cell proliferation and the EGFR system in normal and nodular rat livers.
- To understand the roles of EGFR and TGF-alpha in chemically induced liver carcinogenesis.
Main Methods:
- Administration of 2-AAF to rats to induce liver changes.
- Assessment of DNA replication, EGFR expression, and TGF-alpha mRNA levels.
- Isolation and stimulation of primary hepatocytes and nodular cells with EGF and TGF-alpha.
Main Results:
- 2-AAF treatment inhibited DNA replication in normal livers by downregulating EGFR and EGF binding sites.
- Liver nodules showed higher proliferation rates and elevated TGF-alpha mRNA levels compared to normal liver.
- Nodular cells exhibited increased sensitivity to TGF-alpha, compensating for reduced EGFR signaling.
Conclusions:
- In chemically induced rat liver carcinogenesis, 2-AAF initially suppresses normal liver cell proliferation via EGFR downregulation.
- In established liver nodules, elevated TGF-alpha production and sensitivity sustain cell proliferation despite reduced EGFR.
- TGF-alpha plays a significant role in promoting cell proliferation during rat liver cancer development.