Department of Cancer Biology, Wake Forest Baptist Medical Center, Winston-Salem, NC, USA.
Biostatistics Core, Wake Forest Baptist Medical Center, Winston-Salem, NC, USA.
Nat Commun. 2021 Jan 20;12(1):474. doi: 10.1038/s41467-020-20733-9.
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.
吸烟对肿瘤免疫有深远影响，而尼古丁是烟雾中的主要成瘾成分，尽管它不是致癌物，但已知它会促进肿瘤进展。在这项研究中，我们证明了尼古丁的慢性暴露通过招募促肿瘤 N2 中性粒细胞在肺部形成转移前生态位中起着关键作用。这个转移前生态位促进了 STAT3 激活的脂钙蛋白 2（LCN2）的释放，LCN2 是 N2 中性粒细胞的一种分泌糖蛋白，并诱导肿瘤细胞的间质上皮转化，从而促进定植和转移生长。早期乳腺癌患者和有吸烟史的无癌症女性的血清和尿液 LCN2 水平升高，表明 LCN2 可作为一种有前途的预后生物标志物，预测女性吸烟者转移疾病风险增加。此外，天然化合物红景天苷可有效阻断尼古丁诱导的中性粒细胞极化，从而减少激素受体阴性乳腺癌细胞的肺部转移。我们的研究结果表明，尼古丁诱导的 N2 中性粒细胞在促进癌细胞在肺部定植方面发挥了促转移作用，并阐明了红景天苷的治疗用途，以增强乳腺癌患者中性粒细胞的抗肿瘤活性。
