Abstract
Smoking has a profound impact on tumor immunity, and nicotine, which is the major addictive component of smoke, is known to promote tumor progression despite being a non-carcinogen. In this study, we demonstrate that chronic exposure of nicotine plays a critical role in the formation of pre-metastatic niche within the lungs by recruiting pro-tumor N2-neutrophils. This pre-metastatic niche promotes the release of STAT3-activated lipocalin 2 (LCN2), a secretory glycoprotein from the N2-neutrophils, and induces mesenchymal-epithelial transition of tumor cells thereby facilitating colonization and metastatic outgrowth. Elevated levels of serum and urine LCN2 is elevated in early-stage breast cancer patients and cancer-free females with smoking history, suggesting that LCN2 serve as a promising prognostic biomarker for predicting increased risk of metastatic disease in female smoker(s). Moreover, natural compound, salidroside effectively abrogates nicotine-induced neutrophil polarization and consequently reduced lung metastasis of hormone receptor-negative breast cancer cells. Our findings suggest a pro-metastatic role of nicotine-induced N2-neutrophils for cancer cell colonization in the lungs and illuminate the therapeutic use of salidroside to enhance the anti-tumor activity of neutrophils in breast cancer patients.
Original language | American English |
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Article number | 474 |
Pages (from-to) | 474 |
Journal | Nature Communications |
Volume | 12 |
Issue number | 1 |
DOIs | |
State | Published - 2021 |
Externally published | Yes |
Keywords
- Animals
- Biomarkers, Tumor
- Breast Neoplasms/chemically induced
- Cell Line, Tumor
- Female
- Gene Expression Regulation, Neoplastic
- Humans
- Lipocalin-2/metabolism
- Lung Neoplasms/metabolism
- Lung/metabolism
- Mice
- Neoplasm Metastasis/genetics
- Neutrophil Infiltration/drug effects
- Neutrophils/metabolism
- Nicotine/adverse effects
- STAT3 Transcription Factor/genetics
- Smoking
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