RAPID DEVELOPMENT OF HEPATIC-TUMORS IN TRANSFORMING GROWTH-FACTOR A TRANSGENIC MICE ASSOCIATED WITH INCREASED CELL-PROLIFERATION IN PRECANCEROUS HEPATOCELLULAR LESIONS INITIATED BY N-NITROSODIETHYLAMINE AND PROMOTED BY PHENOBARBITAL
RAPID DEVELOPMENT OF HEPATIC-TUMORS IN TRANSFORMING GROWTH-FACTOR A TRANSGENIC MICE ASSOCIATED WITH INCREASED CELL-PROLIFERATION IN PRECANCEROUS HEPATOCELLULAR LESIONS INITIATED BY N-NITROSODIETHYLAMINE AND PROMOTED BY PHENOBARBITAL
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DOI：
10.1093/carcin/15.9.1791
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发表时间：
1994-09-01
期刊：
影响因子：
4.7
通讯作者：
WARD, JM
中科院分区：
文献类型：
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作者：
TAMANO, S;MERLINO, GT;WARD, JM
采用两阶段化学致癌方法，利用转化生长因子α转基因小鼠系MT42，研究了人转化生长因子α过表达对肿瘤的致癌和促癌作用。雄性MT42和CD-1小鼠只接受一次ip。15日龄时注射N-亚硝基二乙胺(DEN)5 mg/kg体重，4周龄开始饲喂含0.05%苯巴比妥(PB)的日粮，共35周。以DEN、PB处理和生理盐水注射各品系动物作为对照。连续处死动物3次(分别于实验第10、23、37周)。在接受DEN/PB治疗的MT42小鼠中，23周后肝细胞癌(HC)的发病率较高(100%)，而CD-1小鼠在37周后才有40%的肝癌发病率。23周后，在DEN启动的MT42小鼠中也出现了80%的人肝细胞癌，但在DEN启动的CD-1小鼠中没有观察到HCCs。37周后，PB诱发MT42小鼠癌前病变(67%)、腺瘤(33%)和肝细胞癌(33%)，而CD-1小鼠未见病变。因此，在MT42转基因小鼠中，DEN和/或PB的致癌反应加速。此外，在MT42小鼠和CD-1小鼠中分别从第10周和第23周观察到PB的促进作用。因此，PB在MT42转基因小鼠体内的促进作用也是加速的。DEN或DEN/PB处理的MT42小鼠肝细胞病灶和腺瘤的增殖细胞核抗原(PCNA)标记指数明显高于CD-1小鼠。免疫组织化学检测结果显示，MT42转基因小鼠肝组织中转化生长因子-α的表达水平高于周围实质肝细胞。总之，在DEN启动和PB促进机制中，转化生长因子-α转基因小鼠明显增强了对肝细胞癌发展的敏感性，这可能是通过在癌前病变(病灶和腺瘤)中高表达有丝分裂原转化生长因子-α而导致癌前病变(病灶和腺瘤)中肝细胞增殖增加的机制。
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.