Synergistic Effect of Cigarette Smoke and Bacterial Induced Chronic Obstructive Pulmonary Disease Type Airway Inflammation on Promotion of K-ras Mutant Lung Cancer

Lung cancer (LC), specifically K-ras mutant lung cancer, primarily caused by cigarette smoking (CS), is the leading cause of cancer death worldwide. Previous epidemiologic studies have shown a strong association between LC and COPD (chronic obstructive pulmonary disease), an inflammatory disease of the airways caused by CS. These facts suggest a link between COPD-related airway inflammation and LC promotion. NTHi is the most common colonizing bacteria in the lower respiratory tract of patients with COPD and could be the cause of the promoting persistent airway inflammation after CS smoking. We further studied the effect of combined CS and NTHi exposure in the induction of COPD phenotype and promotion of LC. Briefly, 6-week old C57BL/6J and K-ras mutant mice (CC-LR) were exposed to NTHi lysate once a week for 8 weeks and to cigarette smoke (CS) daily for 2 hours/day, 5 days/week for 8 weeks and studied at the age of 14 weeks. The CS caused a mild macrophage dominant airway inflammation, leading to a 2.3-fold increase in lung tumor burden. These results suggest that CS exposure and colonization of smoke-injured airways induce an inflammatory and structural COPD phenotype recapitulating Human COPD, providing a microenvironment promoting K-ras mutant LC. This project was completed with contributions from Seyed Moghaddam from the MD Anderson Cancer Center - Pulmonary Medicine.