However, the insidious role of nicotine and its potential direct effects on neutrophils in breast cancer lung metastasis is yet poorly understood. It has also been reported that there is a significant association of cigarette smoking with increased lung metastatic burden in women with invasive breast cancer 53, 54, 55 that increased the risk by 18% and lower survival rate by 33% at diagnosis 56, 57. In addition, epidemiological studies also suggest a significant association of cigarette smoking/nicotine with an increased risk of various cancers 51, 52. Intriguingly, there is a strong indication that nicotine, a major component in cigarette smoke, significantly contributes to smoke-induced immunosuppression by attenuating NK cell activity, T-cell proliferation, macrophage antigen processing activity, and dendritic cell number 42, 43, 44, 45, 46, 47, 48, 49, 50. Furthermore, previous studies have shown that LCN2 expression is sustained in the lungs of rats and plasma of COPD patients exposed to cigarette smoke 40, 41. In contrast, cigarette smoking was found to induce EMT 36 in lung cancer through activation of signaling pathways such as STAT3, AKT, and NF-kB 37, 38, 39. Growing number of evidences indicate that long-term effects of environmental contaminants, such as cigarette smoke have pervasive effects on immunity and health of the smokers due to its adverse effects on both the innate and adaptive immune systems 32, 33, 34, 35. These conflicting observations stem from the existence of phenotypically heterogeneous and functionally versatile populations within neutrophils that govern how they respond to the environmental cues 31. In contrast, other studies linked neutrophil markers to better survival rates in various cancer patients 26, 27, 28, 29, 30. Indeed, a large meta-analysis of 8563 breast cancer patients found that an increased NLR is associated with an adverse overall- and disease-free survival, specifically within triple-negative breast cancer 25. Importantly, a high circulating neutrophil-to-lymphocyte ratio (NLR) is a robust biomarker of poor clinical outcome in various cancers 17, 18, 19, 20, 21, 22, 23, 24. However, the exact role of neutrophils in tumor progression has been a matter of debate as neutrophils were shown to possess both pro- and anti-tumor properties 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16. In recent years, they are also being recognized as a part of the immune reaction to modulate tumor growth and metastatic progression 3. They play a critical role in inflammation and in host defense against microbial infections 2. Neutrophils or polymorphonuclear leukocytes (PMNs) are the most abundant leukocyte (50–70%) in human circulation 1. 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. Moreover, natural compound, salidroside effectively abrogates nicotine-induced neutrophil polarization and consequently reduced lung metastasis of hormone receptor-negative breast cancer cells. 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). 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.
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. 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.
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