Epithelial NF- B activation promotes urethane-induced lung carcinogenesis

Chronic inflammation is linked to carcinogenesis in several organ systems. In the lungs, NFB, a central effector of inflammatory responses, is frequently activated in non-small-cell lung cancer, but its role in tumor promotion has not been studied. Several lines of evidence indicate that ethyl carbamate (urethane)-induced lung tumor formation, a prototypical mouse model of multistage lung carcinogenesis, is potentiated by inflammation. We found that mouse strains susceptible to lung tumor formation (FVB, BALB/c) exhibited early NFB activation and inflammation in the lungs after urethane treatment. However, a resistant strain (C57B6) failed to activate NFB or induce lung inflammation. In FVB mice, we identified urethaneinduced NFB activation in airway epithelium, as well as type II alveolar epithelial cells and macrophages. Using an inducible transgenic mouse model (FVB strain) to express a dominant inhibitor of NFB specifically in airway epithelial cells, we found that urethaneinduced lung inflammation was blocked and tumor formation was reduced by >50%. Selective NFB inhibition resulted in increased apoptosis of airway epithelial cells at 2 weeks after urethane treatment in association with a marked reduction of Bcl-2 expression. These studies indicate that NFB signaling in airway epithelium is integral to tumorigenesis in the urethane model and identify the NFB pathway as a potential target for chemoprevention of lung cancer.