Abstract 313: K-ras- and EGFR-mediated lung tumor formation require epithelial NF-κB signaling to modulate the inflammatory microenvironment

Abstract

Abstract The transcription factor nuclear factor-κB (NF-κB) is a key mediator of the inflammatory response, and its activation correlates with poor prognosis in non-small cell lung cancer patients. Oncogenic K-ras and epidermal growth factor receptor (EGFR) mutations occur frequently in lung adenocarcinoma and are associated with an inflammatory response in lung tumors. Recent papers have shown that inhibition of epithelial NF-κB signaling in a mouse model of K-ras-mediated lung tumorigenesis decreased tumor formation. However, the mechanisms linking NF-κB signaling to tumor formation remain unclear. We hypothesize that epithelial NF-κB signaling is a common requirement for lung tumorigenesis, causing activation and/or recruitment of inflammatory cells that promote lung tumor formation. For our studies, we used mice that inducibly express oncogenic K-rasG12D or EGFRT790M+L858R as well as a dominant negative inhibitor of κB signaling (DN-IκB) specifically in the lung epithelium. Mice expressing DN-IκB together with K-rasG12D or EGFRT790M+L858R developed significantly fewer tumors than mice expressing K-rasG12D or EGFRT790M+L858R alone after two months of doxycycline administration. However, two months of K-rasG12D or EGFRT790M+L858R expression did not significantly alter total inflammatory cell numbers in bronchoalveolar lavage fluid (BAL). EGFRT790M+L858R expression led to an increase in BAL neutrophils that was lost when NF-κB signaling was inhibited, while no changes in BAL macrophage, lymphocyte, or neutrophil subpopulations were observed in K-rasG12D-expressing mice with or without NF-κB signaling. At later time points, both K-rasG12D- and EGFRT790M+L858R-expressing mice demonstrated a profound inflammatory response, which was associated with an increased tumor burden. Using a model of long term alveolar macrophage depletion by intratracheal administration of liposomal clodronate, we found that depletion of alveolar macrophages decreased tumor burden in K-rasG12D-expressing mice. Together, these results suggest that, rather than causing a profound inflammatory influx, epithelial NF-κB signaling may be important for activating resident inflammatory cell populations that aid in K-ras- and EGFR-mediated tumor formation. From these studies, we hope to broaden understanding of the role of inflammatory signaling pathways in regulation of lung carcinogenesis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 313. doi:1538-7445.AM2012-313