尼古丁？红景天？乳腺癌肺转移？

　　众所周知，吸烟对于肿瘤免疫具有严重影响。烟草的主要化学成分和主要致瘾成分尼古丁（俗称烟碱）属于强兴奋剂和强致命有毒物质。虽然尼古丁本身的致癌作用尚未获得国际癌症研究机构确认，故未被正式归入致癌物质，但是尼古丁能够促进肿瘤的形成、生长、转移及其血管生成，具体机制尚不明确。

　　2021年1月20日，英国《自然》旗下《自然通讯》在线发表美国威克森林大学浸会医学中心的研究报告，探讨了尼古丁促进乳腺癌肺转移的具体机制。

　　既往研究发现，白细胞的主要成分中性粒细胞可被分为抗肿瘤N1型和促肿瘤N2型。N1型中性粒细胞可抑制、杀伤肿瘤细胞；N2型中性粒细胞可释放弹性蛋白酶、基质金属蛋白酶、细胞因子、趋化因子，促进肿瘤的形成、生长、转移及其血管生成。

　　本研究证实，长期暴露于尼古丁可促进N2型中性粒细胞聚集于乳腺癌转移前肺内微环境，引起信号转导及转录激活蛋白STAT3激活N2型中性粒细胞分泌释放脂质运载蛋白LCN2，并诱导上皮→间质转化，从而加速肿瘤细胞的克隆和转移。

　　早期乳腺癌患者和有吸烟史无癌女性的血清和尿液LCN2水平升高，表明LCN2有望成为预测女性吸烟者病变转移风险增加的预后生物标志。

　　此外，天然化合物红景天苷（又称红景天甙）可有效抑制尼古丁所致N2型中性粒细胞聚集，从而减少激素受体阴性乳腺癌（例如三阴性乳腺癌）肺转移。

　　因此，该研究结果表明，尼古丁通过刺激N2型中性粒细胞聚集于肺内产生转移前微环境，从而促进乳腺癌肺转移，红景天苷具有抑制N2型中性粒细胞聚集、减少乳腺癌肺转移的治疗作用。

Nat Commun. 2021 Jan 20;12(1):474.

Nicotine promotes breast cancer metastasis by stimulating N2 neutrophils and generating pre-metastatic niche in lung.

Abhishek Tyagi, Sambad Sharma, Kerui Wu, Shih-Ying Wu, Fei Xing, Yin Liu, Dan Zhao, Ravindra Pramod Deshpande, Ralph B. D'Agostino Jr., Kounosuke Watabe.

Wake Forest Baptist Medical Center, Winston-Salem, NC, USA.

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.

DOI: 10.1038/s41467-020-20733-9