The role of neutrophil extracellular traps in cancer metastasis

Clinical and Translational MedicineVolume 10, Issue 6 e126 SHORT COMMUNICATIONOpen Access The role of neutrophil extracellular traps in cancer metastasis William Wang, William Wang Zhongshan Hospital Institute of Clinical Science, Fudan University Shanghai Medical College, Center for Tumor Diagnosis and Therapy, Jinshan Hospital, Fudan University, Shanghai, China Authors are co-first authors of the study.Search for more papers by this authorJiayang Zhang, Jiayang Zhang orcid.org/0000-0002-1367-9644 Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Breast Oncology, Peking University Cancer Hospital & Institute, Beijing, China Authors are co-first authors of the study.Search for more papers by this authorNanan Zheng, Nanan Zheng Zhongshan Hospital Institute of Clinical Science, Fudan University Shanghai Medical College, Center for Tumor Diagnosis and Therapy, Jinshan Hospital, Fudan University, Shanghai, China Authors are co-first authors of the study.Search for more papers by this authorLi Li, Li Li Center for Clinical Single Cell Biomedicine, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Zhengzhou, Henan, ChinaSearch for more papers by this authorXiangdong Wang, Corresponding Author Xiangdong Wang xdwang@fuccb.com Zhongshan Hospital Institute of Clinical Science, Fudan University Shanghai Medical College, Center for Tumor Diagnosis and Therapy, Jinshan Hospital, Fudan University, Shanghai, China Correspondence Prof Xiangdong Wang, MD, PhD Email: xdwang@fuccb.com Prof. Yiming Zeng, MD Email: zeng_yiming@fjmu.edu.cnSearch for more papers by this authorYiming Zeng, Corresponding Author Yiming Zeng zeng_yiming@fjmu.edu.cn orcid.org/0000-0001-5635-3006 Department of Pulmonary and Critical Care Medicine, Clinical Center for Molecular Diagnosis and Therapy, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian Province, China Correspondence Prof Xiangdong Wang, MD, PhD Email: xdwang@fuccb.com Prof. Yiming Zeng, MD Email: zeng_yiming@fjmu.edu.cnSearch for more papers by this author William Wang, William Wang Zhongshan Hospital Institute of Clinical Science, Fudan University Shanghai Medical College, Center for Tumor Diagnosis and Therapy, Jinshan Hospital, Fudan University, Shanghai, China Authors are co-first authors of the study.Search for more papers by this authorJiayang Zhang, Jiayang Zhang orcid.org/0000-0002-1367-9644 Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Breast Oncology, Peking University Cancer Hospital & Institute, Beijing, China Authors are co-first authors of the study.Search for more papers by this authorNanan Zheng, Nanan Zheng Zhongshan Hospital Institute of Clinical Science, Fudan University Shanghai Medical College, Center for Tumor Diagnosis and Therapy, Jinshan Hospital, Fudan University, Shanghai, China Authors are co-first authors of the study.Search for more papers by this authorLi Li, Li Li Center for Clinical Single Cell Biomedicine, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Zhengzhou, Henan, ChinaSearch for more papers by this authorXiangdong Wang, Corresponding Author Xiangdong Wang xdwang@fuccb.com Zhongshan Hospital Institute of Clinical Science, Fudan University Shanghai Medical College, Center for Tumor Diagnosis and Therapy, Jinshan Hospital, Fudan University, Shanghai, China Correspondence Prof Xiangdong Wang, MD, PhD Email: xdwang@fuccb.com Prof. Yiming Zeng, MD Email: zeng_yiming@fjmu.edu.cnSearch for more papers by this authorYiming Zeng, Corresponding Author Yiming Zeng zeng_yiming@fjmu.edu.cn orcid.org/0000-0001-5635-3006 Department of Pulmonary and Critical Care Medicine, Clinical Center for Molecular Diagnosis and Therapy, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian Province, China Correspondence Prof Xiangdong Wang, MD, PhD Email: xdwang@fuccb.com Prof. Yiming Zeng, MD Email: zeng_yiming@fjmu.edu.cnSearch for more papers by this author First published: 22 September 2020 https://doi.org/10.1002/ctm2.126Citations: 10 AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Extracellular traps are web-like structures and consist of chromatin DNA filaments, histones, and granule proteins. These are released together with inflammatory mediators and pathogens after the stimulation of inflammatory cells, for example, neutrophils, monocytes, eosinophils, mast cells, and macrophages. Extracellular trap production and activation are immune defense mechanisms that contribute to the development of inflammation, immune hyperresponsiveness, hemodynamics alterations, endothelial barrier function, and induction of tumor microenvironment heterogeneity. Neutrophil extracellular traps (NETs) are released by neutrophils to capture and eliminate pathogens during DNA expulsion (NETosis), a regulated form of neutrophil cell death. The production of NETs and NETosis formations are considered as an evolutionary process, of which disorder and dysregulation can cause a large number of diseases. Preclinical studies demonstrated that NETs and NETosis could play critical roles in the pathogenesis of inflammation, infection, thrombosis, tissue injury, organ dysfunction, and cancer metastasis. NETs mainly contain neutrophil elastase, myeloperoxidase, cathepsin G, proteinase 3, lactoferrin, gelatinase, lysozyme C, calprotectin, neutrophil defensins, and cathelicidins. The aim of this editorial is to provide an update on the latest investigations regarding the interaction between NETs and cancer cells, the potential of NETs and NETs-associated elements in the identification and development of cancer-specific biomarkers and targets, and the value of clinical translation from NETs biology. NETs regulate cancer cell activities and metabolisms, while cancer-associated extracellular vesicles modulate neutrophil behavior and NET extrusion. The complexity of molecular mechanism by which NETs and NETosis contribute to cancer cell biology have exceeded our expectations. For example, cancer-associated inflammation can generate intra- and extracellular environments for neutrophil activation and can produce reactive oxygen species via NETs/NETosis release resulting in systemic oxidative stress. Cancer cells can act as the primary receptor, interacting directly with cytokines/chemokines from other cells, and simultaneously as the secondary producer of those factors to chemoattract the recruitment of inflammatory cells into the microenvironment. Cancer cells are decisive factors in cancer microenvironment formation and composition, inflammatory cell recruitment and activation, and NETs/NETosis production. The number of enzymes (eg, DNAse, peptidylarginine deaminase, neutrophil elastase, and myeloperoxidase), receptors (eg, Toll-like receptor 4, 9; receptor for advanced glycation end products; integrins; lectins), intracellular mediators (eg, high mobility group box 1), and hypoxia are critical factors in the production of NETs and are responsible for cancer cell adhesion, proliferation, migration, and invasion.1 The production of NETs and NETosis formations seems to be regulated by either radical-dependent or independent pathways. Brinkmann systemically overviewed the understanding of NETs and summarized the inducers for NETs/NETosis (eg, bacteria or bacterial components, fungi, protozoa, viruses, activated platelets, complement-derived peptides, autoantibodies, IL-8, hydrogen peroxide, urate crystals, cigarette smoke, and ionophores).2 Histone citrullination is a characteristic of NETosis that can be generated by peptidylarginine deaminase-catalyzed hypercitrullination in the histones H3, H2A, and H4These enzymes are involved in altering chromatin structure and decondensation by binding with DNA, participating in the oxidative reaction, relocating between cytoplasm and the nucleus, and decorating the DNA backbone of NET fibers. NETs production and release is orchestrated by altered chromatin, disordered cell morphology, the ruptured nuclear envelope, and plasma membrane and is driven by the major physical force known as entropic chromatin swelling that is detected in real-time on the single-cell level using fluorescence and atomic force microscopy.3 Neubert et al defined the NETosis process as "a clear point of no return" with three distinct phases, that is, cell activation and initiation of chromatin expansion with intact lobular structures of the nucleus, maximum chromatin expansion near the cellular membrane, rupturing of the cell membrane, and the release of NETs into extracellular space.3 The process of NETosis could be altered if inflammation is induced by lipopolysaccharides or if there are alterations within ion channels. Cancer cells can interact directly and indirectly with neutrophils to induce the production of NETs through the production of extracellular vesicles and proinflammatory mediators (eg, cytokines, chemokines, and tissue factors). Such interactions provoke platelets and endothelia to initiate the inflammatory cascade and to promote the release of NETosis and NETs via surface antigens (eg, P-selectin/P-selectin glycoprotein ligand 1). Intra- and intercellular molecular communications during multicellular interactions create new distant microenvironments that act as a pre-metastatic niche to attract the recruitment of primary cancer cells and to form multiple metastases. It is proposed that NETs play

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