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

Molecular Cancer

Research

Amber M Cumpian¹  Burton F Dickey¹  Maria Miguelina De la Garza¹  Seyed Javad Moghaddam¹  Daniel J Lapid¹  Seyedeh Golsar Mirabolfathinejad¹  Mauricio S Caetano¹  Cesar E Ochoa¹  Lei Gong²  Qinghua Zhou³ 

[1] Departments of Pulmonary Medicine, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 1100, 77030, Houston, TX, USA;Departments of Pulmonary Medicine, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 1100, 77030, Houston, TX, USA;Tianjin Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin Medical University, Tianjin, China;Department of Esophageal Cancer, Key Laboratory of Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, China;Tianjin Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin Medical University, Tianjin, China;

关键词: Neutrophil;    Elastase;    Lung cancer;    Inflammation;    CXCR2;    K-ras;   

DOI  :  10.1186/1476-4598-12-154

 received in 2013-08-05, accepted in 2013-11-29,  发布年份 2013

来源: Springer

【 摘 要 】

BackgroundTumor 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.ResultsWe 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.ConclusionWe 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.

【 授权许可】

Unknown   
© Gong et al.; licensee BioMed Central Ltd. 2013. This article is published under license to BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.