Life-span inhalation exposure to mainstream cigarette smoke induces lung cancer in B6C3F1 mice through genetic and epigenetic pathways.
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.
Hutt
Julie A
JA
Lovelace Respiratory Research Institute, Albuquerque, NM 87108, USA. jhutt@lrri.org
Vuillemenot
Brian R
BR
Barr
Edward B
EB
Grimes
Marcie J
MJ
Hahn
Fletcher F
FF
Hobbs
Charles H
CH
March
Thomas H
TH
Gigliotti
Andrew P
AP
Seilkop
Steven K
SK
Finch
Gregory L
GL
Mauderly
Joe L
JL
Belinsky
Steven A
SA
D000230:Adenocarcinoma / Q000139:chemically induced / Q000235:genetics / Q000556:secondary; D000236:Adenoma / Q000139:chemically induced / Q000235:genetics / Q000473:pathology; D000280:Administration, Inhalation; D000818:Animals; D051017:Apoptosis Regulatory Proteins; D001835:Body Weight; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects; D019175:DNA Methylation; D064550:Death-Associated Protein Kinases; D005260:Female; D020868:Gene Silencing / Q000187:drug effects*; D011905:Genes, ras / Q000187:drug effects; D006965:Hyperplasia / Q000139:chemically induced / Q000235:genetics / Q000473:pathology; D015994:Incidence; D008168:Lung / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008175:Lung Neoplasms / Q000139:chemically induced* / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008815:Mice, Inbred Strains; D009929:Organ Size; D010212:Papilloma / Q000139:chemically induced / Q000235:genetics / Q000473:pathology; D017354:Point Mutation; D011401:Promoter Regions, Genetic; D011650:Pulmonary Alveoli / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018168:Receptors, Retinoic Acid / Q000235:genetics; D012907:Smoking / Q000009:adverse effects*; D015996:Survival Rate
D051017:Apoptosis Regulatory Proteins; D018168:Receptors, Retinoic Acid; C082925:retinoic acid receptor beta; D064550:Death-Associated Protein Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases