Toll-like receptors 2, 4, and 9 modulate promoting effect of COPD-like airway inflammation on K-ras-driven lung cancer through activation of the MyD88/NF-ĸB pathway in the airway epithelium

Abstract

IntroductionToll-like receptors (TLRs) are an extensive group of proteins involved in host defense processes that express themselves upon the increased production of endogenous damage-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs) due to the constant contact that airway epithelium may have with pathogenic foreign antigens. We have previously shown that COPD-like airway inflammation induced by exposure to an aerosolized lysate of nontypeable Haemophilus influenzae (NTHi) promotes tumorigenesis in a K-ras mutant mouse model of lung cancer, CCSPCre/LSL-K-rasG12D (CC-LR) mouse.MethodsIn the present study, we have dissected the role of TLRs in this process by knocking out TLR2, 4, and 9 and analyzing how these deletions affect the promoting effect of COPD-like airway inflammation on K-ras-driven lung adenocarcinoma.ResultsWe found that knockout of TLR 2, 4, or 9 results in a lower tumor burden, reduced angiogenesis, and tumor cell proliferation, accompanied by increased tumor cell apoptosis and reprogramming of the tumor microenvironment to one that is antitumorigenic. Additionally, knocking out of downstream signaling pathways, MyD88/NF-κB in the airway epithelial cells further recapitulated this initial finding.DiscussionOur study expands the current knowledge of the roles that TLR signaling plays in lung cancer, which we hope, can pave the way for more reliable and efficacious prevention and treatment modalities for lung cancer.

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“…Nontypeable Haemophilus influenzae (NTHi) is a risk factor for chronic obstructive pulmonary disease (COPD), which has been reported to promote lung cancer development in mice in a toll-like receptor (TLR)-dependent manner [ 88 , 89 ]. Further investigation revealed that NTHi promoted K-ras-driven lung cancer via COPD-like airway inflammation, which was mediated by the NF-κB-involved TLR2/4/9 pathway [ 89 ]. However, the correlation between NTHi and lung cancer in patients has not been fully elucidated [ 90 ], which, in turn, sheds light an opportunity for researchers to fill in this gap.…”