Reference SummaryTamano S, Carcinogenesis 1994 Sep;15(9):1791-8
Title |
Rapid development of hepatic tumors in transforming growth factor alpha transgenic mice associated with increased cell proliferation in precancerous hepatocellular lesions initiated by N-nitrosodiethylamine and promoted by phenobarbital. |
Authors |
Tamano S; Merlino GT; Ward JM |
Journal |
Carcinogenesis |
Volume |
15 |
Issue |
9 |
Year |
1994 |
Pages |
1791-8 |
Abstract |
The carcinogenic and tumor-promoting effects of human transforming growth factor alpha (TGF-alpha) overexpression were examined in a two-stage chemical carcinogenesis protocol using TGF-alpha transgenic mouse line MT42. Male MT42 and CD-1 mice received a single i.p. injection of 5 mg N-nitrosodiethylamine (DEN)/kg body wt at 15 days of age, and were placed on a diet containing 0.05% of phenobarbital (PB) from 4 weeks of age for 35 weeks. DEN-, PB-treated and saline-injected animals in each strain were used as controls. A total of three sequential sacrifices (at 10, 23 and 37 experimental weeks) was performed. Hepatocellular carcinomas (HCCs) developed earlier at high incidence (100%) after 23 experimental weeks in MT42 mice receiving DEN/PB, while CD-1 mice had a 40% incidence of HCCs only after week 37. HCCs also developed in the DEN-initiated MT42 mice at 80% incidence after week 23, but no HCCs were observed in the DEN-initiated CD-1 mice. PB induced preneoplastic foci (67%), adenomas (33%) and HCCs (33%) after 37 weeks in MT42 mice, but no lesions were found in CD-1 mice. Thus, the carcinogenic response to DEN and/or PB was accelerated in the MT42 transgenic mice. Furthermore, PB promotion was observed from week 10 in MT42 mice and week 23 in CD-1 mice. Thus, the promoting effect of PB was also accelerated in the MT42 transgenic mice. Proliferating cell nuclear antigen (PCNA) labeling indices of hepatocellular foci and adenomas in DEN- or DEN/PB-treated MT42 mice were significantly higher than those of CD-1 mice. TGF-alpha expression determined by immunohistochemistry revealed higher levels in these lesions than in hepatocytes of surrounding parenchyma of MT42 transgenic mice. In conclusion, TGF-alpha transgenic mice clearly demonstrated enhanced sensitivity to the development of hepatocellular carcinoma in the DEN initiation and PB promotion regime, possibly through a mechanism of increased hepatocyte proliferation in precancerous lesions (foci and adenomas), driven by high expression of the mitogen TGF-alpha in these lesions. |
Links |
J:20676 – MGI References 7923571 – National Library of Medicine/PubMed |
| Strain | Model Name | Treatment Agent(s) | Organ Affected | Frequency | Model Details |
|---|---|---|---|---|---|
| CD-1-Tg(MtTGFA)42Lmb | Liver - Hepatocyte foci |
|
Liver - Hepatocyte |
0 - 10 |
|
| CD-1-Tg(MtTGFA)42Lmb | Liver - Hepatocyte foci |
|
Liver - Hepatocyte |
observed |
|
| CD-1-Tg(MtTGFA)42Lmb | Liver - Hepatocyte foci |
|
Liver - Hepatocyte |
observed |
|
| CD-1-Tg(MtTGFA)42Lmb | Liver - Hepatocyte foci |
|
Liver - Hepatocyte |
0 - 67 |
|
| CD-1 | Liver - Hepatocyte foci |
|
Liver - Hepatocyte |
0 |
|
| CD-1 | Liver - Hepatocyte foci |
|
Liver - Hepatocyte |
0 - observed |
|
| CD-1 | Liver - Hepatocyte foci |
|
Liver - Hepatocyte |
0 - observed |
|
| CD-1 | Liver - Hepatocyte foci |
|
Liver - Hepatocyte |
0 |
|
| CD-1-Tg(MtTGFA)42Lmb | Liver hepatocellular adenoma |
|
Liver |
0 |
|
| CD-1-Tg(MtTGFA)42Lmb | Liver hepatocellular adenoma |
|
Liver |
0 - 100 |
|
| CD-1-Tg(MtTGFA)42Lmb | Liver hepatocellular adenoma |
|
Liver |
observed - 80 |
|
| CD-1-Tg(MtTGFA)42Lmb | Liver hepatocellular adenoma |
|
Liver |
0 - 33 |
|
| CD-1 | Liver hepatocellular adenoma |
|
Liver |
0 |
|
| CD-1 | Liver hepatocellular adenoma |
|
Liver |
0 - observed |
|
| CD-1 | Liver hepatocellular adenoma |
|
Liver |
0 - observed |
|
| CD-1 | Liver hepatocellular adenoma |
|
Liver |
0 |
|
| CD-1-Tg(MtTGFA)42Lmb | Liver hepatocellular carcinoma |
|
Liver |
0 |
|
| CD-1-Tg(MtTGFA)42Lmb | Liver hepatocellular carcinoma |
|
Liver |
0 - 100 |
|
| CD-1-Tg(MtTGFA)42Lmb | Liver hepatocellular carcinoma |
|
Liver |
0 - 100 |
|
| CD-1-Tg(MtTGFA)42Lmb | Liver hepatocellular carcinoma |
|
Liver |
0 - 33 |
|
| CD-1 | Liver hepatocellular carcinoma |
|
Liver |
0 |
|
| CD-1 | Liver hepatocellular carcinoma |
|
Liver |
0 |
|
| CD-1 | Liver hepatocellular carcinoma |
|
Liver |
0 - 40 |
|
| CD-1 | Liver hepatocellular carcinoma |
|
Liver |
0 |
|
| CD-1-Tg(MtTGFA)42Lmb | Liver tumor |
|
Liver |
0 |
|
| CD-1-Tg(MtTGFA)42Lmb | Liver tumor |
|
Liver |
100 |
|
| CD-1-Tg(MtTGFA)42Lmb | Liver tumor |
|
Liver |
90 |
|
| CD-1-Tg(MtTGFA)42Lmb | Liver tumor |
|
Liver |
17 |
|
| CD-1 | Liver tumor |
|
Liver |
0 |
|
| CD-1 | Liver tumor |
|
Liver |
observed |
|
| CD-1 | Liver tumor |
|
Liver |
observed |
|
| CD-1 | Liver tumor |
|
Liver |
0 |