Dietary Immunosuppressants Do Not Enhance UV-Induced Skin Carcinogenesis, and Reveal Discordance between p53-Mutant Early Clones and Carcinomas
Dietary Immunosuppressants Do Not Enhance UV-Induced Skin Carcinogenesis, and Reveal Discordance between p53-Mutant Early Clones and Carcinomas
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DOI：
10.1158/1940-6207.capr-12-0361
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发表时间：
2013-02-01
影响因子：
3.3
通讯作者：
De Gruijl, Frank R.
中科院分区：
文献类型：
--
作者：
Voskamp, Pieter;Bodmann, Carolien A.;De Gruijl, Frank R.
免疫抑制药物被认为会导致器官移植受者暴露在阳光下的皮肤患癌的风险急剧增加。这些药物对皮肤的局部作用不同。我们调查了这种局部影响是否可以预测皮肤癌风险，从而为最大限度地降低风险提供指导。免疫抑制剂（硫唑嘌呤，环孢素，他克莫司，霉酚酸酯和雷帕霉素）进行了评估，改变紫外线诱导的细胞凋亡在人类皮肤模型和p53突变细胞克隆（假定的肿瘤前体）和随后的皮肤癌（突变p53）在无毛小鼠的皮肤。发现雷帕霉素增加细胞凋亡（三倍），而环孢霉素减少细胞凋亡（三倍）。相应地，在长期暴露于紫外线的小鼠皮肤中，分别发现过表达突变型p53的细胞簇减少1.5至5倍（P = 0.07）或增加2至3倍（P < 0.001）。然而，深度测序显示，p53热点突变（密码子270和275）的等位基因频率（类似于5%）保持不受影响。大多数具有突变的p53的细胞似乎不过度表达突变的蛋白质。出乎意料的是，高剂量的免疫抑制剂都没有加速肿瘤的发展，环孢霉素甚至使肿瘤的发生延迟了大约15%（P < 0.01）。因此，与早期研究结果相反，p53突变细胞的频率不能预测皮肤癌的发生。此外，对肿瘤发展缺乏任何加速作用表明，免疫抑制药物不是器官移植受者皮肤癌风险急剧增加的唯一原因。Cancer Prev Res; 6（2）; 129-38.（C）2012年AACR。
Immunosuppressive drugs are thought to cause the dramatically increased risk of carcinomas in sun-exposed skin of organ transplant recipients. These drugs differ in local effects on skin. We investigated whether this local impact is predictive of skin cancer risk and may thus provide guidance on minimizing the risk. Immunosuppressants (azathioprine, cyclosporine, tacrolimus, mycophenolate mofetil, and rapamycin) were assessed on altering the UV induction of apoptosis in human skin models and of p53 mutant cell clones (putative tumor precursors) and ensuing skin carcinomas (with mutant p53) in the skin of hairless mice. Rapamycin was found to increase apoptosis (three-fold), whereas cyclosporine decreased apoptosis (three-fold). Correspondingly, a 1.5- to five-fold reduction (P = 0.07) or a two-to three-fold increase (P < 0.001) was found in cell clusters overexpressing mutant p53 in chronically UV-exposed skin of mice that had been fed rapamycin or cyclosporine, respectively. Deep sequencing showed, however, that the allelic frequency (similar to 5%) of the hotspot mutations in p53 (codons 270 and 275) remained unaffected. The majority of cells with mutated p53 seemed not to overexpress the mutated protein. Unexpectedly, none of the immunosuppressants admixed in high dosages to the diet accelerated tumor development, and cyclosporine even delayed tumor onset by approximately 15% (P < 0.01). Thus, in contrast to earlier findings, the frequency of p53-mutant cells was not predictive of the incidence of skin carcinoma. Moreover, the lack of any accelerative effect on tumor development suggests that immunosuppressive medication is not the sole cause of the dramatic increase in skin cancer risk in organ transplant recipients. Cancer Prev Res; 6(2); 129-38. (C)2012 AACR.