Abstract 4977: An essential role for neutrophils in lung cancer promotion .

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Abstract Lung cancer is the leading cause of cancer death worldwide, and cigarette smoking is the principal cause of it. Cigarette smoke-induced lung cancer is characterized by a deregulated inflammatory tumor microenvironment. Tumor cells produce various cytokines and chemokines that attract leukocytes. Leukocytes (innate and adaptive immune cells) can amplify parenchymal innate immune responses, and have been shown to contribute to tumor promotion. In addition, smokers with chronic obstructive pulmonary disease (COPD), an inflammatory disease of the lung, have an increased risk of lung cancer compared to smokers without COPD. These facts suggest a strong link between COPD-type inflammation and lung cancer promotion. In histopathologic specimens of lung and in bronchoalveolar lavage fluid (BALF) from COPD patients, neutrophils and macrophages are prominent. Neutrophils are among the first cells to arrive at sites of inflammation, and the increased number of tumor-associated neutrophils is linked to poorer outcome in patients with lung cancer. We have previously shown that COPD-like airway inflammation promotes lung cancer in a K-ras mutant mouse model of lung cancer (CC-LR). This was associated with severe neutrophilic influx due to increased level of neutrophil chemoattractant, KC, which was partially inhibited by using a natural non-specific anti-inflammatory agent, curcumin 1% in diet, and resulted in significant tumor suppression. To further study the role of neutrophil in lung tumorigenesis, we depleted neutrophils in CC-LR mice using an anti-neutrophil antibody, mLy6G, 5mg/kg twice a week by intraperitoneal injection. This resulted in complete lung neutrophil depletion and 68% (3.2-fold) reduction in lung surface tumor number. Neutrophil elastase (NE) is a potent elastolytic enzyme produced by neutrophils at the site of inflammation. It participates actively in COPD development and might contribute to tumor progression by activating proteolytic cascades. The concentration of NE in tumor extracts was also found to be linked to the invasiveness of lung cancer. Therefore, we crossed the CC-LR mice with NE knock out (KO) mice. We have found that lack of NE significantly inhibited lung cancer development by 43% (1.7-fold) without changing the BALF inflammatory cell component of the CC-LR mice. We further inhibited the main receptor for neutrophil chemo-attractant KC, CXCR2, using a selective inhibitor, SB332235Z, 50 mg/kg orally twice daily by gavage. Similarly, this also resulted in significant suppression of neutrophil recruitment into the lung of CC-LR mice followed by significant (∼64%, 2.8-fold) tumor reduction. We conclude that lung cancer promotion by inflammation partly mediated by activation of IL-8/CXCR2 pathway and subsequent recruitment of neutrophils and release of neutrophil elastase. This provides a baseline for future clinical trails using IL-8/CXCR2 pathway or NE inhibitors in patients with lung cancer. Citation Format: Lei Gong, Amber C. Cumpian, Cesar E. Ochoa, Daniel J. Lapid, Seyedeh Golsar Mirabolfathinejad, Maria Miguelina De la Garza, Seyed Javad Moghaddam. An essential role for neutrophils in lung cancer promotion . [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4977. doi:10.1158/1538-7445.AM2013-4977