阿斯利康旧爱可抑制乳腺癌肺转移

中国科学家发现乳腺癌肺转移新对策

　　肺转移是乳腺癌相关死亡的主要原因。既往研究发现，中性粒细胞相关炎症微环境有助于肿瘤细胞转移并定植于肺，不过其具体机制尚不明确。

　　2021年1月14日，美国《细胞》旗下《癌细胞》在线发表中国科学院上海营养与健康研究所、上海交通大学附属第六人民医院、复旦大学附属中山医院、上海交通大学医学院附属第一人民医院、山东大学齐鲁医院的研究报告，发现肿瘤分泌的组织蛋白酶通过调节中性粒细胞浸润、形成中性粒细胞外诱捕网，可促进乳腺癌肺转移。

　　该研究证实肿瘤分泌的组织蛋白酶C（CTSC，又称二肽基肽酶DPP1）通过调节中性粒细胞聚集、形成中性粒细胞外诱捕网NET，可促进乳腺癌转移至肺。CTSC通过激活中性粒细胞膜结合蛋白酶PR3可促进白细胞介素IL-1β加工成熟和细胞核因子NFκB活化，从而提高白细胞介素IL-6和趋化因子配体CCL3水平，促进中性粒细胞募集。

　　此外，CTSC→PR3→IL-1β信号传导可诱发中性粒细胞产生氧自由基ROS并形成NET，继而降解血小板应答蛋白TSP-1并帮助癌细胞转移至肺并生长。而且，CTSC表达和分泌水平越高，人类乳腺肿瘤NET形成和肺转移比例越高。

　　重要的是，利用阿斯利康当初打算治疗慢性阻塞性肺病或哮喘的口服小分子CTSC抑制剂布伦卡替（AZD7986）可有效抑制小鼠模型乳腺癌肺转移。

　　因此，该研究结果表明，肿瘤细胞可分泌CTSC调节转移微环境中性粒细胞并帮助乳腺癌肺转移，CTSC抑制剂布伦卡替（AZD7986）有望成为防治乳腺癌肺转移的新对策。可惜的是，阿斯利康已于2016年将布伦卡替（AZD7986）卖给美国INSMED制药，被改名为INS1007并于2020年登上《新英格兰医学杂志》还被美国食品药品监督管理局授予支气管扩张突破性治疗药物资格。

Cancer Cell. 2021 Jan 14. Online ahead of print.

Cathepsin C promotes breast cancer lung metastasis by modulating neutrophil infiltration and neutrophil extracellular trap formation.

Yansen Xiao, Min Cong, Jiatao Li, Dasa He, Qiuyao Wu, Pu Tian, Yuan Wang, Shuaixi Yang, Chenxi Liang, Yajun Liang, Jili Wen, Yingjie Liu, Wenqian Luo, Xianzhe Lv, Yunfei He, Dong-dong Cheng, Tianhao Zhou, Wenjing Zhao, Peiyuan Zhang, Xue Zhang, Yichuan Xiao, Youcun Qian, Hongxia Wang, Qiang Gao, Qing-cheng Yang, Qifeng Yang, Guohong Hu.

Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China; Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China; Zhongshan Hospital, Fudan University, Shanghai, China; Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Qilu Hospital of Shandong University, Ji'nan, China.

HIGHLIGHTS

  • Tumor-secreted CTSC promotes breast-to-lung metastasis by regulating neutrophils

  • CTSC activates membrane-bound PR3 of neutrophils to upregulate IL-1β secretion

  • CTSC enhances neutrophil recruitment into metastatic niches and induces NETosis

  • Targeting CTSC with AZD7986 effectively inhibits lung metastasis in mice

Lung metastasis is the major cause of breast cancer-related mortality. The neutrophil-associated inflammatory microenvironment aids tumor cells in metastatic colonization in lungs. Here, we show that tumor-secreted protease cathepsin C (CTSC) promotes breast-to-lung metastasis by regulating recruitment of neutrophils and formation of neutrophil extracellular traps (NETs). CTSC enzymatically activates neutrophil membrane-bound proteinase 3 (PR3) to facilitate interleukin-1β (IL-1β) processing and nuclear factor κB activation, thus upregulating IL-6 and CCL3 for neutrophil recruitment. In addition, the CTSC-PR3-IL-1β axis induces neutrophil reactive oxygen species production and formation of NETs, which degrade thrombospondin-1 and support metastatic growth of cancer cells in the lungs. CTSC expression and secretion are associated with NET formation and lung metastasis in human breast tumors. Importantly, targeting CTSC with compound AZD7986 effectively suppresses lung metastasis of breast cancer in a mouse model. Overall, our findings reveal a mechanism of how tumor cells regulate neutrophils in metastatic niches and support CTSC-targeting approaches for cancer treatment.

KEYWORDS: breast cancer; lung metastasis; neutrophil; neutrophil extracellular trap; Cathespin C; metastatic niche

DOI: 10.1016/j.ccell.2020.12.012

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