NTHi-promoted proliferation of K-ras-induced early lung cancer lesions is fully dependent on Toll-like receptor signaling

Introduction: Smoking is the main risk factor for the development of lung cancer and chronic obstructive lung disease (COPD). Lungs of COPD patients are frequently infected with bacterial pathogens, such as nontypeable Haemophilus influenzae (NTHi), which cause neutrophilic inflammation and exacerbations. Pulmonary adenocarcinomas are frequently associated with an activating mutation in the K-ras gene. Methods: Wild type (WT) and mice double deficient for TLR 2 and 4 (TLR-2/4-/-), both with an oncogenic K-ras allele in lung epithelium, were exposed to NTHi for 4 weeks. Results: Exposure to NTHi resulted in increased tumor proliferation and growth in WT mice, but not in TLR-2/4-/- mice. Alveolar adenomatous hyperplasia and adenocarcinoma were significantly increased in WT mice compared with TLR-2/4-/- mice. Tumor size was significantly increased in WT mice, whereas there was no difference in the number of alveolar lesions between WT and TLR-2/4-/- mice. NTHi-induced neutrophilic inflammation was strongly reduced in TLR-2/4-/- mice. Conclusion: NTHi-induced inflammation promotes the proliferation of K-ras induced early cancerous lesions in a TLR-dependent manner once a driver-mutation occurred.