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.
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.
Tamano
S
S
Veterinary and Tumor Pathology Section, Office of Laboratory Animal Science, National Cancer Institute, Frederick, MD 21702-1201.
Merlino
G T
GT
Ward
J M
JM
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D003043:Cocarcinogenesis; D004052:Diethylnitrosamine / Q000633:toxicity*; D015870:Gene Expression / Q000187:drug effects; D007150:Immunohistochemistry; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced* / Q000235:genetics* / Q000473:pathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D010634:Phenobarbital / Q000633:toxicity*; D011230:Precancerous Conditions / Q000139:chemically induced* / Q000235:genetics* / Q000473:pathology; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis; D016211:Transforming Growth Factor alpha / Q000032:analysis / Q000235:genetics* / Q000502:physiology*
D018809:Proliferating Cell Nuclear Antigen; D016211:Transforming Growth Factor alpha; D004052:Diethylnitrosamine; D010634:Phenobarbital