Neutrophil extracellular traps in cancer

• Published in: MedComm (2020) Vol. 5; no. 8; pp. e647 - n/a
• Main Authors: Ma, Yuxi, Wei, Jielin, He, Wenshan, Ren, Jinghua
• Format: Journal Article
• Language: English
• Published: China John Wiley & Sons, Inc 01-08-2024; John Wiley and Sons Inc; Wiley
• Subjects: Cancer; Metastasis; NETosis; NETs formation; neutrophil; neutrophil extracellular traps; Neutrophils; Review; Tumors; cancer; NETosis; neutrophil extracellular traps; NETs formation; neutrophil
• ISSN: 2688-2663; 2688-2663
• DOI: 10.1002/mco2.647

Neutrophil extracellular traps (NETs), which consist of chromatin DNA studded with granule proteins, are released by neutrophils in response to both infectious and sterile inflammation. Beyond the canonical role in defense against pathogens, the extrusion of NETs also contributes to the initiation, metastasis, and therapeutic response of malignant diseases. Recently, NETs have been implicated in the development and therapeutic responses of various types of tumors. Although extensive work regarding inflammation in tumors has been reported, a comprehensive summary of how these web‐like extracellular structures initiate and propagate tumor progression under the specific microenvironment is lacking. In this review, we demonstrate the initiators and related signaling pathways that trigger NETs formation in cancers. Additionally, this review will outline the current molecular mechanisms and regulatory networks of NETs during dormant cancer cells awakening, circulating tumor cells (CTCs) extravasation, and metastatic recurrence of cancer. This is followed by a perspective on the current and potential clinical potential of NETs as therapeutic targets in the treatment of both local and metastatic disease, including the improvement of the efficacy of existing therapies.
To support primary tumor growth, the formation of NETs triggered by tumor‐derived CXCL chemokines (CXCL‐1, ‐2, ‐5, ‐6, and ‐8) shield around tumor cells from T cell‐ and NK‐mediated immune attacks. It is possible that these web‐like extracellular structures contribute to the robustness of the tumor, leading to the emergence of resistance to immune checkpoint inhibitors. Once in circulation, NETs capture both CTC and CTC/platelet aggregations directly or indirectly by the CCDC25 receptor–ligand interaction, thus facilitating CTC colonization in distant organs. Along with MPO‐HOCl, ROS that produced during NETosis impairs lung endothelial barrier integrity and facilitates tumor extravasation by reprogramming the expression of the tight junction protein JAM 1 in the endothelium. More intriguingly, MMP9 and NE located on the NETs can awaken dormant cancer cells by degradation of laminin‐111 within ECM.