Altered body composition and increased frequency of diverse malignancies in insulin-like growth factor-II transgenic mice.
Altered body composition and increased frequency of diverse malignancies in insulin-like growth factor-II transgenic mice.
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DOI：
10.1016/s0021-9258(17)36715-7
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发表时间：
1994-05
期刊：
影响因子：
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通讯作者：
Charles E. RoglerSS;Deyun YangS;Lucian 0 Rossettin;Jeff DonohoeS;Elaine AltSll;Chee-Jen Chang;Ron RosenfeldSS;Kirk NeelySS;Ray HintzSS
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文献类型：
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作者：
Charles E. RoglerSS;Deyun YangS;Lucian 0 Rossettin;Jeff DonohoeS;Elaine AltSll;Chee-Jen Chang;Ron RosenfeldSS;Kirk NeelySS;Ray HintzSS
胰岛素样生长因子（IGF）II（IGF-II）在成人中的生理作用知之甚少。相当高的IGF-II水平在成人血清中持续存在，而在啮齿动物中，IGF-II水平非常低。为了研究成年人IGF-II持续升高的生理和致癌作用，我们生产了两种转基因小鼠，其中高水平的IGF-II（比正常水平高20或30倍）持续保持在血液中。该转基因由主要尿蛋白启动子驱动，并且在两个品系的肝脏和包皮腺中高度表达。成年转基因小鼠比对照组小，它们的身体组成也发生了改变。他们的瘦体重减少了5- 8%，而脂肪量减少了44 - 77%。表达最高水平IGF-II（30倍）的小鼠发生低血糖和低胰岛素血症，IGF-I水平正常。低表达系（IGF-II升高20倍）的小鼠在其一生中逐渐发生低血糖。来自这两个品系的小鼠在18个月大后也以比对照组更高的频率发展出多种肿瘤谱，并且最常见的肿瘤类型是肝细胞癌和淋巴瘤。鳞状细胞癌、肉瘤和甲状腺癌也发生在我们的试验组中。肿瘤出现前的长潜伏期和肿瘤类型的广泛性表明，IGF-II可能主要通过自分泌和内分泌作用机制在小鼠中作为肿瘤进展因子发挥作用。
The physiological role of insulin-like growth factor (IGF) II (IGF-II) in adult humans is poorly understood. Rather high levels of IGF-II persist in adult human serum, whereas, in rodents, IGF-II levels are very low. To investigate the physiological and carcinogenic effects of persistently elevated IGF-II in adults, we have produced two lines of transgenic mice in which high levels of IGF-II (20- or 30-fold increase above normal) are persistently maintained in the blood. The transgene is driven by the major urinary protein promoter, and it is highly expressed in the liver and perputial glands in both lines. The adult transgenic mice are smaller than controls, and their body composition is altered. Their lean body mass is reduced by 5-8%, whereas fat mass is reduced between 44 and 77%. The mice expressing the highest level of IGF-II (30x) develop hypoglycemia and hypoinsulinemia and IGF-I levels are normal. Mice in the lower expression line (20-fold elevated IGF-II) develop hypoglycemia progressively over their lifetime. Mice from both lines also develop a diverse spectrum of tumors at a higher frequency than controls after 18 months of age, and the most frequent types of tumors are hepatocellular carcinomas and lymphomas. Squamous cell carcinoma, sarcoma, and thyroid carcinomas also occurred in our test group. The long latent period before tumors arise and the wide spectrum of tumor types suggest that IGF-II may function primarily as a tumor progression factor in mice via autocrine and endocrine mechanisms of action.