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Carcinogenesis Advance Access published online on June 8, 2005
Carcinogenesis, doi:10.1093/carcin/bgi150
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© The Author 2005. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oupjournals.org
Received February 18, 2005
Revised June 3, 2005
Accepted June 5, 2005

CARCINOGENESIS

Life-span inhalation exposure to mainstream cigarette smoke induces lung cancer in B6C3F1 mice through genetic and epigenetic pathways

Julie A. Hutt 1*, Brian R. Vuillemenot 1, Edward B. Barr 1, Marcie J. Grimes 1, Fletcher F. Hahn 1, Charles H. Hobbs 1, Thomas H. March 1, Andrew P. Gigliotti 1, Steven K. Seilkop 2, Gregory L. Finch 1, Joe L. Mauderly 1, and Steven A. Belinsky 1

1 Lovelace Respiratory Research Institute, Albuquerque, NM
2 SKS Consulting Services, Siler City, NC

* To whom correspondence should be addressed.
Julie A. Hutt, E-mail: jhutt{at}lrri.org


  Abstract

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 hours per day, 5 days a week induces marked increases in the incidence of focal alveolar hyperplasias, and 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 to 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 tumors from cigarette smoke-exposed mice (60%). The percentages of transversion and transition mutations were similar in both 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 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.

Keywords: cigarette smoke; lung cancer; methylation; K-ras mutation; mouse model.
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