Abstract
Lung cancer is the leading cause of cancer deaths in the United States. In addition to genetic abnormalities induced by cigarette smoke, several epidemiologic studies have found that smokers with chronic obstructive pulmonary disease (COPD), an inflammatory diseaseofthe lungs,haveanincreased riskoflung cancer(1.3-to4.9- fold) compared to smokers without COPD. This suggests a link between chronic airway inflammation and lung carcinogenesis, independent of tobacco smoke exposure. We studied this association by assaying the inflammatory impact of products of nontypeable Haemophilus influenzae, which colonizes the airways of patients with COPD, on lung cancer promotion in mice with an activated K-ras mutation in their airway epithelium. Two new mouse models of lung cancer were generated by crossing mice harboring the LSL-K- ras G12D allele with mice containing Cre recombinase inserted into the Clara cell secretory protein (CCSP) locus, with or without the neomycin cassette excised (CCSPCre and CCSPCre-Neo, respectively). Lung lesions in CCSP Cre-Neo/LSL-K-ras G12D and CCSP Cre/LSL-K- ras G12D mice appeared at 4 and 1 month of age, respectively, and were classified as epithelial hyperplasia of the bronchioles, adenoma, and adenocarcinoma. Weekly exposure of CCSP Cre/LSL-K- rasG12D mice to aerosolized nontypeable Haemophilus influenzae lysate from age 6-14 weeks resulted in neutrophil/macrophage/ CD8 T-cell-associated COPD-like airway inflammation, a 3.2-fold increase in lung surface tumor number (156 ± 9 versus 45 ± 7), and an increasein total lung tumor burden.Weconclude that COPD-like airway inflammation promotes lung carcinogenesisinabackground of a G12D-activated K-ras allele in airway secretory cells.
Original language | English (US) |
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Pages (from-to) | 443-453 |
Number of pages | 11 |
Journal | American journal of respiratory cell and molecular biology |
Volume | 40 |
Issue number | 4 |
DOIs | |
State | Published - Apr 1 2009 |
Keywords
- Inflammation
- K-ras
- Lung cancer
ASJC Scopus subject areas
- Molecular Biology
- Pulmonary and Respiratory Medicine
- Clinical Biochemistry
- Cell Biology
MD Anderson CCSG core facilities
- Research Animal Support Facility