中性粒细胞大约占白细胞总数的60%～70%，是人体免疫系统的重要成分。中性粒细胞周围存在大量包裹着颗粒蛋白的染色质脱氧核糖核酸（DNA）细丝，由中性粒细胞释放，能够诱捕细菌、病毒、真菌等微生物，故被称为中性粒细胞外陷阱或诱捕网。既往研究发现，中性粒细胞外DNA还参与了小鼠癌症的转移。不过，中性粒细胞外DNA对于人类癌症转移的作用和临床意义尚不明确。
2020年6月11日，全球自然科学三大旗舰期刊之一英国《自然》正刊在线发表中山大学孙逸仙纪念医院杨林槟、刘强、陈嘉宁、李嘉倩、陈菲、苏士成、中山大学中山医学院院长和中国科学院院士宋尔卫等学者的研究报告，发现中性粒细胞外DNA通过卷曲螺旋结构跨膜蛋白CCDC25可以促进乳腺癌等癌症转移。
该研究对544例乳腺癌患者的原发灶和转移灶进行分析，结果发现中性粒细胞外陷阱高浓度聚集于肝转移灶，而血清中性粒细胞外陷阱可以预测早期乳腺癌患者肝转移的发生。
小鼠模型表明，中性粒细胞外陷阱DNA不仅是癌细胞的“陷阱”，而且是吸引癌细胞的趋化因子，能够在肝脏或肺部吸引癌细胞形成远处转移灶。
机制分析表明，卷曲螺旋结构跨膜蛋白CCDC25是癌细胞的中性粒细胞外陷阱DNA受体，可以感知细胞外DNA，随后激活整合蛋白连接激酶ILK→β肌动结合蛋白信号传导通路，继而增强癌细胞的活动和转移能力。敲除癌细胞的CCDC25基因，即可阻断中性粒细胞外陷阱引起的转移。
临床分析表明，原发癌细胞的CCDC25表达水平越高，患者的长期生存结局越差。
因此，该研究结果表明，跨膜DNA受体CCDC25是中性粒细胞外陷阱促进乳腺癌等癌症转移的关键靶点，靶向抑制CCDC25有望成为防止乳腺癌等癌症转移的治疗策略。
对此，英国伦敦弗朗西斯·克里克研究院（原名英国医学研究创新中心，2011年为纪念DNA双螺旋结构发现者和诺贝尔奖获得者弗朗西斯·克里克而更名）发表同期报道：中性粒细胞“安全网”可引起癌细胞的转移和繁殖。
相关链接
Nature. 2020 Jun 11. Online ahead of print.
DNA of neutrophil extracellular traps promotes cancer metastasis via CCDC25.
Linbin Yang, Qiang Liu, Xiaoqian Zhang, Xinwei Liu, Boxuan Zhou, Jianing Chen, Di Huang, Jiaqian Li, Heliang Li, Fei Chen, Jiang Liu, Yue Xing, Xueman Chen, Shicheng Su, Erwei Song.
Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China; Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China; Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Guangzhou, China.
Neutrophil extracellular traps (NETs), which consist of chromatin DNA filaments coated with granule proteins, are released by neutrophils to trap microorganisms. Recent studies have suggested that the DNA component of NETs (NET-DNA) is associated with cancer metastasis in mouse models. However, the functional role and clinical importance of NET-DNA in metastasis in patients with cancer remain unclear. Here we show that NETs are abundant in the liver metastases of patients with breast and colon cancers, and that serum NETs can predict the occurrence of liver metastases in patients with early-stage breast cancer. NET-DNA acts as a chemotactic factor to attract cancer cells, rather than merely acting as a 'trap' for them; in several mouse models, NETs in the liver or lungs were found to attract cancer cells to form distant metastases. We identify the transmembrane protein CCDC25 as a NET-DNA receptor on cancer cells that senses extracellular DNA and subsequently activates the ILK-β-parvin pathway to enhance cell motility. NET-mediated metastasis is abrogated in CCDC25-knockout cells. Clinically, we show that the expression of CCDC25 on primary cancer cells is closely associated with a poor prognosis for patients. Overall, we describe a transmembrane DNA receptor that mediates NET-dependent metastasis, and suggest that targeting CCDC25 could be an appealing therapeutic strategy for the prevention of cancer metastasis.
DOI: 10.1038/s41586-020-2394-6
Nature. 2020 Jun 11. Online ahead of print.
Neutrophil 'safety net' causes cancer cells to metastasize and proliferate.
Emma Nolan, Ilaria Malanchi.
Francis Crick Institute, London, UK.
Immune cells called neutrophils can support the spread of cancer. How neutrophils aid this process now comes into focus through insights into the function of structures called neutrophil extracellular traps.
DOI: 10.1038/d41586-020-01672-3
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