Age dependence of radiation-induced renal cell carcinomas in an Eker rat model
Age dependence of radiation-induced renal cell carcinomas in an Eker rat model
复制标题
Eker 大鼠模型中辐射诱导的肾细胞癌的年龄依赖性
DOI：
10.1111/j.1349-7006.2009.01456.x
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发表时间：
2010
期刊：
影响因子：
5.7
通讯作者：
et. Al
中科院分区：
文献类型：
--
作者：
T. Kokubo;S. Kakinuma;M. Nishimura;Y. Shimada;et. Al
（癌症科学2010；101:616-623）生命早期接触致癌物可能会导致生命后期癌症的发展。儿童在医疗过程中经历的辐射暴露量一直在增加，因此评估发育器官中癌症的辐射风险非常重要。为了实现这一目标，我们使用Eker大鼠作为肾肿瘤模型来评估发生肾细胞癌的风险。雄性Eker （tsc2突变体）和雌性F344 F1杂交大鼠分别在妊娠第15和19天和出生后第5、20和49天接受0.5或2 Gy γ射线照射。27周龄时，检查肾脏是否有增生性病变。肿瘤前病变，如表型改变的小管，在出生后照射后随着年龄的增加而增加，在围产期和出生后照射后增生大大增加。相比之下，腺瘤和腺癌的发展在围出生年龄的动物中很明显，在妊娠第19天最大。tsc2位点的LOH频率出乎意料地低——未照射对照组为0%(0 / 4)，而照射组为17%（6 / 35）。无论LOH如何，Tsc1/2复合物负调控的mTOR（哺乳动物雷帕霉素靶蛋白）通路在良性和恶性病变中都被激活，S6核糖体蛋白和4E‐BP1的磷酸化证明了这一点。这表明野生型petsc2等位基因可能在功能上失活。总之，在围产期（F344 × Eker） F1大鼠（Tsc2+/−）中，活跃生长的肾脏存在与mTOR激活相关的放射诱导肾上皮恶性转化的风险。
(Cancer Sci2010; 101: 616–623)Exposure to carcinogens early in life may contribute to cancer development later in life. The amount of radiation exposure children experience during medical procedures has been increasing, so it is important to evaluate the radiation risk of cancer in developing organs. Toward this goal, we assessed the risk of developing renal cell carcinoma using Eker rats as a kidney tumor model. F1 hybrids of male Eker (Tsc2mutant) and female F344 rats were irradiated with 0.5 or 2 Gy gamma radiation on gestation days 15 and 19, and on postnatal days 5, 20, and 49. At 27 weeks of age, kidneys were examined for proliferative lesions. Preneoplastic lesions such as phenotypically altered tubules increased after postnatal irradiation as a function of age‐at‐irradiation, and hyperplasia were greatly increased after perinatal and postnatal irradiation. In contrast, development of adenoma and adenocarcinoma were evident in animals irradiated at perinatal ages, being maximal at gestational day 19. The frequency of LOH at theTsc2locus was unexpectedly low – 0% (0 of 4) for the unirradiated control, and 17% (6 of 35) for the irradiated group. Irrespective of LOH, the mTOR (mammalian target of rapamycin) pathway, which is negatively regulated by the Tsc1/2 complex, was activated in both benign and malignant lesions, as evidenced by phosphorylation of S6 ribosomal protein and 4E‐BP1. This suggests that the wild‐typeTsc2allele may be functionally inactivated. In conclusion, actively growing kidneys in perinatal‐aged (F344 × Eker) F1 rats (Tsc2+/−) are at risk for radiation‐induced malignant transformation of the renal epithelium associated with mTOR activation.