Abstract 2687: Toll like receptors mediated inflammatory signals mediate promotion of K-ras mutant lung cancer by chronic obstructive pulmonary disease

Abstract

Abstract Lung cancer is the leading cause of cancer death worldwide, and cigarette smoking is its main cause. However, smoker with chronic obstructive pulmonary disorder (COPD), an inflammatory disease of the lung, have an increased risk of lung cancer (3 to 10 fold) compared to smokers without COPD. Importantly, lung inflammation persists and lung function continues to deteriorate as does the increased risk of lung cancer even after cessation of cigarette smoking among former smokers. These facts suggest a strong link between COPD-related airway inflammation and lung cancer promotion, however, the precise mechanistic link is not known. We have previously developed a COPD-like mouse model of airway inflammation through repeated aerosol challenge to a lysate of nontypeable (i.e., unencapsulated) Haemophilus influenzae (NTHi). NTHi is the most common colonizing bacteria in the lower respiratory tract of patients with COPD and could be a potential cause of perpetuating and promoting airway injury and inflammation in these patients. We then showed that this type of airway inflammation promotes lung cancer in a K-ras mutant mouse model of lung cancer (CC-LR), which was associated with the activation of MyD88/NF-κB pathway and increased expression of its downstream targets in the lung. We have further shown that lack of NF-kB or MyD88 (an adaptor protein upstream to NF-κB) in the airway epithelium of CC-LR mice changes the bronchoalveolar lavage fluid cellular component of CC-LR mice and inhibits the promoting effect of COPD-like airway inflammation on lung tumorigensis. Upstream to MyD88 and NF-κB and downstream to bacterial stimuli is the toll-like receptors family (TLRs), which play critical role in the innate immune response. Among TLRs, TLR-2, TLR4, and TLR9 play critical roles in mediating inflammatory responses in lung and are required for primary epithelial response to inflammatory stimuli and activation of MyD88/NF-kB pathway in the airway epithelium. Accordingly, we further hypothesized that TLR-2, 4, and 9 mediate promoting effect of inflammtion on lung tumorigenesis in an MyD88/NF-kB dependent manner. Therefore, CC-LR mice were separately crossed to TLR-2, TLR-4 and TLR-9 knock out mice in order to test this hypothesis. We found that genetic ablation of these TLRs in CC-LR mice, causes significant reduction in lung surface tumor numbers compared to age and sex matched control CC-LR mice in the presence of COPD-like airway inflammation. This tumor reduction was associated with significant reduction in the numbers of inflammatory cells in bronchoalveolar lavage fluid of mice with lack of these TLRs. Taken these together, we conclude that promoting effect of COPD on lung cancer is mediated through TLR2, 4, 9-mediated activation of epithelial MyD88/NF-kB pathway. Citation Format: Nasim Khosravi, Nelly Torres-Garza, Soudabeh Daliri, Maria Miguelina De La Garza, Amber Cumpian, Evelyn Beltran, Misha Umer, Diana Del Bosque, Saba Akbani, Scott Evans, Seyed Javad Moghaddam. Toll like receptors mediated inflammatory signals mediate promotion of K-ras mutant lung cancer by chronic obstructive pulmonary disease [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2687. doi:10.1158/1538-7445.AM2017-2687