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Promoting effect of neutrophils on lung tumorigenesis is mediated by CXCR2 and neutrophil elastase

Gong, Lei, Cumpian, Amber M, Caetano, Mauricio S, Ochoa, Cesar E, De la Garza, Maria Miguelina, Lapid, Daniel J, Mirabolfathinejad, Seyedeh Golsar, Dickey, Burton F, Zhou, Qinghua, Moghaddam, Seyed Javad·2013·Molecular Cancer
DOI 10.1186/1476-4598-12-154
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Abstract

Background: Tumor cells produce various cytokines and chemokines that attract leukocytes. Leukocytes can amplify parenchymal innate immune responses, and have been shown to contribute to tumor promotion. 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. Results: 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 lung neutrophilic influx due to the increased level of neutrophil chemoattractant, KC. To further study the role of neutrophils in lung tumorigenesis, we depleted neutrophils in CC-LR mice using an anti-neutrophil antibody. This resulted in a significant reduction in lung tumor number. We further selectively inhibited the main receptor for neutrophil chemo-attractant KC, CXCR2. Similarly, this resulted in suppression of neutrophil recruitment into the lung of CC-LR mice followed by significant tumor reduction. Neutrophil elastase (NE) is a potent elastolytic enzyme produced by neutrophils at the site of inflammation. We crossed the CC-LR mice with NE knock-out mice, and found that lack of NE significantly inhibits lung cancer development. These were associated with significant reduction in tumor cell proliferation and angiogenesis. Conclusion: We conclude that lung cancer promotion by inflammation is partly mediated by activation of the IL-8/CXCR2 pathway and subsequent recruitment of neutrophils and release of neutrophil elastase. This provides a baseline for future clinical trials using the IL-8/CXCR2 pathway or NE inhibitors in patients with lung cancer.

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Metadata

Authors
Gong, L., Cumpian, A. M., Caetano, M. S., Ochoa, C. E., De la Garza, M. M., Lapid, D. J., Mirabolfathinejad, S. G., Dickey, B. F., Zhou, Q., & Moghaddam, S. J.
Venue
Molecular Cancer
Publisher
Springer Science and Business Media LLC
Published
2013-12
Volume
12
Issue
1
ISSN
1476-4598
DOI
10.1186/1476-4598-12-154
Cited by
150
References
4
Language
en

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