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

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