Tamano S, Merlino G T, Ward J M
Veterinary and Tumor Pathology Section, Office of Laboratory Animal Science, National Cancer Institute, Frederick, MD 21702-1201.
Carcinogenesis. 1994 Sep;15(9):1791-8. doi: 10.1093/carcin/15.9.1791.
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.
利用TGF-α转基因小鼠品系MT42，在两阶段化学致癌方案中检测了人转化生长因子α（TGF-α）过表达的致癌和促肿瘤作用。雄性MT42和CD-1小鼠在15日龄时腹腔注射一次5 mg N-亚硝基二乙胺（DEN）/kg体重，并从4周龄开始食用含0.05%苯巴比妥（PB）的饲料，持续35周。每个品系中经DEN、PB处理和注射生理盐水的动物用作对照。总共进行了三次连续处死（在实验第10、23和37周）。在接受DEN/PB处理的MT42小鼠中，23个实验周后肝细胞癌（HCC）高发（100%）且出现较早，而CD-1小鼠仅在第37周后HCC发生率为40%。在第23周后，经DEN启动的MT42小鼠中也有80%发生HCC，但在经DEN启动的CD-1小鼠中未观察到HCC。在MT42小鼠中，37周后PB诱导了癌前病灶（67%）、腺瘤（33%）和HCC（33%），但在CD-1小鼠中未发现病变。因此，MT42转基因小鼠对DEN和/或PB的致癌反应加快。此外，在MT42小鼠中从第10周开始观察到PB促进作用，在CD-1小鼠中从第23周开始观察到。因此，PB的促进作用在MT42转基因小鼠中也加快。在经DEN或DEN/PB处理的MT42小鼠中，肝细胞病灶和腺瘤的增殖细胞核抗原（PCNA）标记指数显著高于CD-1小鼠。通过免疫组织化学测定的TGF-α表达显示，这些病变中的水平高于MT42转基因小鼠周围实质肝细胞中的水平。总之，TGF-α转基因小鼠在DEN启动和PB促进方案中对肝细胞癌的发生表现出明显增强的敏感性，可能是通过癌前病变（病灶和腺瘤）中肝细胞增殖增加的机制，这是由这些病变中有丝分裂原TGF-α的高表达驱动的。
