Neutrophil Extracellular Traps in Cancer

Overview

Journal MedComm (2020)

Specialty Health Services

Date 2024 Jul 17

PMID 39015554

Authors

Yuxi Ma

Jielin Wei

Wenshan He

Jinghua Ren

Affiliations

Soon will be listed here.

Abstract

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.

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References

Czeiger D, Shaked G, Eini H, Vered I, Belochitski O, Avriel A . Measurement of circulating cell-free DNA levels by a new simple fluorescent test in patients with primary colorectal cancer. Am J Clin Pathol. 2011; 135(2):264-70. DOI: 10.1309/AJCP4RK2IHVKTTZV. View

Xie M, Hao Y, Feng L, Wang T, Yao M, Li H . Neutrophil Heterogeneity and its Roles in the Inflammatory Network after Ischemic Stroke. Curr Neuropharmacol. 2022; 21(3):621-650. PMC: 10207908. DOI: 10.2174/1570159X20666220706115957. View

Giancotti F . Mechanisms governing metastatic dormancy and reactivation. Cell. 2013; 155(4):750-64. PMC: 4354734. DOI: 10.1016/j.cell.2013.10.029. View

Albrengues J, Shields M, Ng D, Park C, Ambrico A, Poindexter M . Neutrophil extracellular traps produced during inflammation awaken dormant cancer cells in mice. Science. 2018; 361(6409). PMC: 6777850. DOI: 10.1126/science.aao4227. View

Zhang Y, Hu Y, Ma C, Sun H, Wei X, Li M . Diagnostic, Therapeutic Predictive, and Prognostic Value of Neutrophil Extracellular Traps in Patients With Gastric Adenocarcinoma. Front Oncol. 2020; 10:1036. PMC: 7344202. DOI: 10.3389/fonc.2020.01036. View

Heinrich B, Brown Z, Diggs L, Vormehr M, Ma C, Subramanyam V . Steatohepatitis Impairs T-cell-Directed Immunotherapies Against Liver Tumors in Mice. Gastroenterology. 2020; 160(1):331-345.e6. PMC: 7755834. DOI: 10.1053/j.gastro.2020.09.031. View

Boone B, Orlichenko L, Schapiro N, Loughran P, Gianfrate G, Ellis J . The receptor for advanced glycation end products (RAGE) enhances autophagy and neutrophil extracellular traps in pancreatic cancer. Cancer Gene Ther. 2015; 22(6):326-34. PMC: 4470814. DOI: 10.1038/cgt.2015.21. View

Rayes R, Mouhanna J, Nicolau I, Bourdeau F, Giannias B, Rousseau S . Primary tumors induce neutrophil extracellular traps with targetable metastasis promoting effects. JCI Insight. 2019; 5. PMC: 6777835. DOI: 10.1172/jci.insight.128008. View

Zhaolin Z, Guohua L, Shiyuan W, Zuo W . Role of pyroptosis in cardiovascular disease. Cell Prolif. 2018; 52(2):e12563. PMC: 6496801. DOI: 10.1111/cpr.12563. View

10.

Romao S, Tejera E, Nytko K, Siler U, Munz C, Reichenbach J . Defective nuclear entry of hydrolases prevents neutrophil extracellular trap formation in patients with chronic granulomatous disease. J Allergy Clin Immunol. 2015; 136(6):1703-1706.e5. DOI: 10.1016/j.jaci.2015.09.007. View

11.

Li P, Li M, Lindberg M, Kennett M, Xiong N, Wang Y . PAD4 is essential for antibacterial innate immunity mediated by neutrophil extracellular traps. J Exp Med. 2010; 207(9):1853-62. PMC: 2931169. DOI: 10.1084/jem.20100239. View

12.

Zhou W, Cao X, Xu Q, Qu J, Sun Y . The double-edged role of neutrophil heterogeneity in inflammatory diseases and cancers. MedComm (2020). 2023; 4(4):e325. PMC: 10363828. DOI: 10.1002/mco2.325. View

13.

Muto M, Nakata H, Ishigaki K, Tachibana S, Yoshida M, Muto M . Successful Treatment of Advanced Gastric Cancer with Brain Metastases through an Abscopal Effect by Radiation and Immune Checkpoint Inhibitor Therapy. J Gastric Cancer. 2021; 21(3):319-324. PMC: 8505119. DOI: 10.5230/jgc.2021.21.e24. View

14.

Arelaki S, Arampatzioglou A, Kambas K, Sivridis E, Giatromanolaki A, Ritis K . Mast cells co-expressing CD68 and inorganic polyphosphate are linked with colorectal cancer. PLoS One. 2018; 13(3):e0193089. PMC: 5854234. DOI: 10.1371/journal.pone.0193089. View

15.

Alfaro C, Teijeira A, Onate C, Perez G, Sanmamed M, Andueza M . Tumor-Produced Interleukin-8 Attracts Human Myeloid-Derived Suppressor Cells and Elicits Extrusion of Neutrophil Extracellular Traps (NETs). Clin Cancer Res. 2016; 22(15):3924-36. DOI: 10.1158/1078-0432.CCR-15-2463. View

16.

Yang L, Luo Q, Lu L, Zhu W, Sun H, Wei R . Increased neutrophil extracellular traps promote metastasis potential of hepatocellular carcinoma via provoking tumorous inflammatory response. J Hematol Oncol. 2020; 13(1):3. PMC: 6945602. DOI: 10.1186/s13045-019-0836-0. View

17.

Schoeps B, Eckfeld C, Prokopchuk O, Bottcher J, Haussler D, Steiger K . TIMP1 Triggers Neutrophil Extracellular Trap Formation in Pancreatic Cancer. Cancer Res. 2021; 81(13):3568-3579. DOI: 10.1158/0008-5472.CAN-20-4125. View

18.

Tatsiy O, McDonald P . Physiological Stimuli Induce PAD4-Dependent, ROS-Independent NETosis, With Early and Late Events Controlled by Discrete Signaling Pathways. Front Immunol. 2018; 9:2036. PMC: 6153332. DOI: 10.3389/fimmu.2018.02036. View

19.

Ramachandran I, Condamine T, Lin C, Herlihy S, Garfall A, Vogl D . Bone marrow PMN-MDSCs and neutrophils are functionally similar in protection of multiple myeloma from chemotherapy. Cancer Lett. 2015; 371(1):117-24. PMC: 4919899. DOI: 10.1016/j.canlet.2015.10.040. View

20.

Massberg S, Grahl L, von Bruehl M, Manukyan D, Pfeiler S, Goosmann C . Reciprocal coupling of coagulation and innate immunity via neutrophil serine proteases. Nat Med. 2010; 16(8):887-96. DOI: 10.1038/nm.2184. View