Hutt Julie A, Vuillemenot Brian R, Barr Edward B, Grimes Marcie J, Hahn Fletcher F, Hobbs Charles H, March Thomas H, Gigliotti Andrew P, Seilkop Steven K, Finch Gregory L, Mauderly Joe L, Belinsky Steven A
Lovelace Respiratory Research Institute, Albuquerque, NM 87108, USA.
Carcinogenesis. 2005 Nov;26(11):1999-2009. doi: 10.1093/carcin/bgi150. Epub 2005 Jun 8.
Although cigarette smoke has been epidemiologically associated with lung cancer in humans for many years, animal models of cigarette smoke-induced lung cancer have been lacking. This study demonstrated that life time whole body exposures of female B6C3F1 mice to mainstream cigarette smoke at 250 mg total particulate matter/m(3) for 6 h per day, 5 days a week induces marked increases in the incidence of focal alveolar hyperplasias, pulmonary adenomas, papillomas and adenocarcinomas. Cigarette smoke-exposed mice (n = 330) had a 10-fold increase in the incidence of hyperplastic lesions, and a 4.6-fold (adenomas and papillomas), 7.25-fold (adenocarcinomas) and 5-fold (metastatic pulmonary adenocarcinomas) increase in primary lung neoplasms compared with sham-exposed mice (n = 326). Activating point mutations in codon 12 of the K-ras gene were identified at a similar rate in tumors from sham-exposed mice (47%) and cigarette smoke-exposed mice (60%). The percentages of transversion and transition mutations were similar in both the groups. Hypermethylation of the death associated protein (DAP)-kinase and retinoic acid receptor (RAR)-beta gene promoters was detected in tumors from both sham- and cigarette smoke-exposed mice, with a tendency towards increased frequency of RAR-beta methylation in the tumors from the cigarette smoke-exposed mice. These results emphasize the importance of the activation of K-ras and silencing of DAP-kinase and RAR-beta in lung cancer development, and confirm the relevance of this mouse model for studying lung tumorigenesis.
尽管多年来流行病学研究已表明香烟烟雾与人类肺癌有关，但一直缺乏香烟烟雾诱发肺癌的动物模型。本研究表明，雌性B6C3F1小鼠终生全身暴露于总颗粒物为250 mg/m³的主流香烟烟雾中，每天6小时，每周5天，可导致局灶性肺泡增生、肺腺瘤、乳头状瘤和腺癌的发生率显著增加。与假暴露小鼠（n = 326）相比，暴露于香烟烟雾的小鼠（n = 330）增生性病变的发生率增加了10倍，原发性肺肿瘤（腺瘤和乳头状瘤）增加了4.6倍，腺癌增加了7.25倍，转移性肺腺癌增加了5倍。在假暴露小鼠和香烟烟雾暴露小鼠的肿瘤中，K-ras基因第12密码子的激活点突变发生率相似（分别为47%和60%）。两组的颠换和转换突变百分比相似。在假暴露和香烟烟雾暴露小鼠的肿瘤中均检测到死亡相关蛋白（DAP）激酶和视黄酸受体（RAR）β基因启动子的高甲基化，且香烟烟雾暴露小鼠肿瘤中RAR-β甲基化频率有增加趋势。这些结果强调了K-ras激活以及DAP激酶和RAR-β沉默在肺癌发生中的重要性，并证实了该小鼠模型在研究肺肿瘤发生中的相关性。
