Carcinogenesis Advance Access originally published online on June 8, 2005
Carcinogenesis 2005 26(11):1999-2009; doi:10.1093/carcin/bgi150
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Carcinogenesis vol.26 no.11 © Oxford University Press 2005; all rights reserved.
Life-span inhalation exposure to mainstream cigarette smoke induces lung cancer in B6C3F1 mice through genetic and epigenetic pathways
Lovelace Respiratory Research Institute, 2425 Ridgecrest Drive SE, Albuquerque, NM 87108, USA, 1 SKS Consulting Services, Siler City, 3942 Rives Chapel Church Road, Siler City, NC 27344, USA and 2 Pfizer Global Research and Development, Groton Laboratories, Mount Eastern Point Road, Groton, CT 06340, USA
* To whom correspondence should be addressed. Tel: +1 505 348 9567; Fax: +1 505 348 8567; Email: jhutt{at}lrri.org
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/m3 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)-ß gene promoters was detected in tumors from both sham- and cigarette smoke-exposed mice, with a tendency towards increased frequency of RAR-ß 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-ß in lung cancer development, and confirm the relevance of this mouse model for studying lung tumorigenesis.
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