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Abstract
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.
Highlights
Tumor cells produce various cytokines and chemokines that attract leukocytes
Two groups (N = 8) of 10week-old CC-LR mice were treated with mLy-6G Ab for 4 weeks, with one of these groups exposed to the non-typeable Haemophilus influenzae (NTHi) lysate once a week for 4 weeks for induction of a COPDtype inflammatory lung phenotype
We and others have shown that expression of KrasG12D within the airway epithelium of mice induces the production of chemokines which leads to the accumulation of inflammatory cells, macrophages and neutrophils, within the lung [15,17,18]
Summary
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. We showed that this type of airway inflammation promotes lung cancer in a K-ras mutant mouse model of lung cancer (CCLR) [15]. This was associated with severe neutrophilic influx due to an increased level of neutrophil chemoattractant, KC, which was partially inhibited by using a natural non-specific anti-inflammatory agent, curcumin, and resulted in significant tumor suppression [16]. Neutrophil depletion, CXCR2 inhibition, and lack of neutrophil elastase (NE) all resulted in significant tumor reduction in our K-ras mutant mouse model of lung cancer
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