Research Progress of Neutrophil Extracellular Traps in Gastric Cancer

doi:10.12114/j.issn.1007-9572.2024.0289

Abstract

Abstract:

In recent years, neutrophil extracellular traps (NETs) have garnered increasing attention in cancer research, particularly regarding their mechanisms and clinical significance in gastric cancer. This paper systematically and comprehensively explores the research progress of NETs in gastric cancer, including the formation mechanisms of NETs, their role in the gastric cancer microenvironment, and their impact on the occurrence, development, and metastasis of gastric cancer. By reviewing relevant literature, the paper summarizes the crucial roles of NETs in gastric cancer immune evasion, inflammatory response, and interactions with other tumor cells. The paper indicates that NETs not only promote the proliferation and metastasis of tumor cells during the occurrence and progression of gastric cancer but are also closely associated with poor prognosis in gastric cancer patients. Additionally, NETs affect the treatment outcomes of gastric cancer by inducing an immunosuppressive environment and enhancing cancer cell drug resistance. This paper provides a reference for the diagnosis and treatment of gastric cancer and offers insights for further research on NETs in gastric cancer.

Key words: Gastric cancer, Neutrophil extracellular traps, Gastric cancer metastasis, Mechanism of action, Review

摘要：

近年来，中性粒细胞外陷阱（NETs）在癌症研究中受到越来越多的关注，特别是在胃癌中的作用机制和临床意义。本文系统、全面地探讨了NETs在胃癌中的研究进展，包括NETs的形成机制、在胃癌微环境中的作用及其对胃癌发生、发展和转移的影响，并通过梳理相关文献，总结了NETs在胃癌免疫逃逸、炎症反应及其与其他肿瘤细胞相互作用中的重要角色。本文表明，在胃癌的发生和进展过程中，NETs不仅促进肿瘤细胞的增殖和转移，还与胃癌患者的不良预后密切相关；此外，NETs通过诱导免疫抑制环境和增强癌细胞的耐药性来影响胃癌的治疗效果。本文能够为胃癌的诊断和治疗提供一定的参考，并为NETs在胃癌中的研究进一步深入开展提供借鉴。

关键词: 胃癌, 中性粒细胞外陷阱, 胃癌转移, 作用机制, 综述

CLC Number:

R 735.2

MA Xiaoyu,MA Xiaomei,WU Guozhi, et al. Research Progress of Neutrophil Extracellular Traps in Gastric Cancer[J]. Chinese General Practice, 2026, 29(17): 2425-2432. DOI: 10.12114/j.issn.1007-9572.2024.0289.
马晓雨,马晓梅,武国智等. 中性粒细胞外陷阱在胃癌中的研究进展[J]. 中国全科医学, 2026, 29(17): 2425-2432. DOI: 10.12114/j.issn.1007-9572.2024.0289.

Figures/Tables 3

References 59

[1]	BRAY F, LAVERSANNE M, SUNG H, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J]. CA Cancer J Clin, 2024, 74(3): 229-263. DOI: 10.3322/caac.21834.
[2]	HE F F, WANG S M, ZHENG R S, et al. Trends of gastric cancer burdens attributable to risk factors in China from 2000 to 2050[J]. Lancet Reg Health West Pac, 2024, 44: 101003. DOI: 10.1016/j.lanwpc.2023.101003.
[3]	BURUCOA C, AXON A. Epidemiology of Helicobacter pylori infection[J]. Helicobacter, 2017, 22(Suppl 1). DOI: 10.1111/hel.12403.
[4]	LI C J, ZOU X M, CAI Q X, et al. Comprehensive expression profile analysis of neutrophil extracellular trap-affected genes in gastric cancer cells and the clinical significance of lncRNA NEAT1-related signaling[J]. Front Oncol, 2022, 12: 798531. DOI: 10.3389/fonc.2022.798531.
[5]	YANG C F, SUN W Y, CUI W, et al. Procoagulant role of neutrophil extracellular traps in patients with gastric cancer[J]. Int J Clin Exp Pathol, 2015, 8(11): 14075-14086.
[6]	LI J C, ZOU X M, YANG S F, et al. Neutrophil extracellular traps participate in the development of cancer-associated thrombosis in patients with gastric cancer[J]. World J Gastroenterol, 2022, 28(26): 3132-3149. DOI: 10.3748/wjg.v28.i26.3132.
[7]	YANG S F, SUN B S, LI J C, et al. Neutrophil extracellular traps promote angiogenesis in gastric cancer[J]. Cell Commun Signal, 2023, 21(1): 176. DOI: 10.1186/s12964-023-01196-z.
[8]	ZHANG Y Y, HU Y Y, MA C, et al. Diagnostic, therapeutic predictive, and prognostic value of neutrophil extracellular traps in patients with gastric adenocarcinoma[J]. Front Oncol, 2020, 10: 1036. DOI: 10.3389/fonc.2020.01036.
[9]	TAKEI H, ARAKI A, WATANABE H, et al. Rapid killing of human neutrophils by the potent activator phorbol 12-myristate 13-acetate(PMA)accompanied by changes different from typical apoptosis or necrosis[J]. J Leukoc Biol, 1996, 59(2): 229-240. DOI: 10.1002/jlb.59.2.229.
[10]	JUNG H S, GU J, KIM J E, et al. Cancer cell-induced neutrophil extracellular traps promote both hypercoagulability and cancer progression[J]. PLoS One, 2019, 14(4): e0216055. DOI: 10.1371/journal.pone.0216055.
[11]	MASUCCI M T, MINOPOLI M, DEL VECCHIO S, et al. The emerging role of neutrophil extracellular traps(NETs)in tumor progression and metastasis[J]. Front Immunol, 2020, 11: 1749. DOI: 10.3389/fimmu.2020.01749.
[12]	ZHONG W T, WANG Q Y, SHEN X F, et al. The emerging role of neutrophil extracellular traps in cancer: from lab to ward[J]. Front Oncol, 2023, 13: 1163802. DOI: 10.3389/fonc.2023.1163802.
[13]	SONG Y H, WANG Z J, KANG L, et al. PADs and NETs in digestive system: from physiology to pathology[J]. Front Immunol, 2023, 14: 1077041. DOI: 10.3389/fimmu.2023.1077041.
[14]	YAZDANI H O, ROY E, COMERCI A J, et al. Neutrophil extracellular traps drive mitochondrial homeostasis in tumors to augment growth[J]. Cancer Res, 2019, 79(21): 5626-5639. DOI: 10.1158/0008-5472.CAN-19-0800.
[15]	CHEN Y X, HAN L L, QIU X Y, et al. Neutrophil extracellular traps in digestive cancers: warrior or accomplice[J]. Front Oncol, 2021, 11: 766636. DOI: 10.3389/fonc.2021.766636.
[16]	PAPAYANNOPOULOS V. Neutrophil extracellular traps in immunity and disease[J]. Nat Rev Immunol, 2018, 18(2): 134-147. DOI: 10.1038/nri.2017.105.
[17]	LI P X, LI M, LINDBERG M R, et al. PAD4 is essential for antibacterial innate immunity mediated by neutrophil extracellular traps[J]. J Exp Med, 2010, 207(9): 1853-1862. DOI: 10.1084/jem.20100239.
[18]	CASTANHEIRA F V S, KUBES P. Neutrophils and NETs in modulating acute and chronic inflammation[J]. Blood, 2019, 133(20): 2178-2185. DOI: 10.1182/blood-2018-11-844530.
[19]	ZHANG Y J, SONG J J, ZHANG Y W, et al. Emerging role of neutrophil extracellular traps in gastrointestinal tumors: a narrative review[J]. Int J Mol Sci, 2022, 24(1): 334. DOI: 10.3390/ijms24010334.
[20]	BERGER-ACHITUV S, BRINKMANN V, ABED U A, et al. A proposed role for neutrophil extracellular traps in cancer immunoediting[J]. Front Immunol, 2013, 4: 48. DOI: 10.3389/fimmu.2013.00048.
[21]	TOHME S, YAZDANI H O, AL-KHAFAJI A B, et al. Neutrophil extracellular traps promote the development and progression of liver metastases after surgical stress[J]. Cancer Res, 2016, 76(6): 1367-1380. DOI: 10.1158/0008-5472.CAN-15-1591.
[22]	DEMERS M, KRAUSE D S, SCHATZBERG D, et al. Cancers predispose neutrophils to release extracellular DNA traps that contribute to cancer-associated thrombosis[J]. Proc Natl Acad Sci U S A, 2012, 109(32): 13076-13081. DOI: 10.1073/pnas.1200419109.
[23]	MILLRUD C R, KÅGEDAL Å, KUMLIEN GEORÉN S, et al. NET-producing CD16high CD62Ldim neutrophils migrate to tumor sites and predict improved survival in patients with HNSCC[J]. Int J Cancer, 2017, 140(11): 2557-2567. DOI: 10.1002/ijc.30671.
[24]	LEE W, KO S Y, MOHAMED M S, et al. Neutrophils facilitate ovarian cancer premetastatic niche formation in the omentum[J]. J Exp Med, 2019, 216(1): 176-194. DOI: 10.1084/jem.20181170.
[25]	ZHU T, ZOU X M, YANG C F, et al. Neutrophil extracellular traps promote gastric cancermetastasis by inducing epithelial-mesenchymal transition[J]. Int J Mol Med, 2021, 48(1): 127. DOI: 10.3892/ijmm.2021.4960.
[26]	YOO D G, FLOYD M, WINN M, et al. NET formation induced by Pseudomonas aeruginosa cystic fibrosis isolates measured as release of myeloperoxidase-DNA and neutrophil elastase-DNA complexes[J]. Immunol Lett, 2014, 160(2): 186-194. DOI: 10.1016/j.imlet.2014.03.003.
[27]	YU C, ZHOU G Q, SHI Z L, et al. TREM1 facilitates the development of gastric cancer through regulating neutrophil extracellular traps-mediated macrophage polarization[J]. Dig Liver Dis, 2024, 56(7): 1237-1247. DOI: 10.1016/j.dld.2023.12.002.
[28]	WANG Q L, ZHANG Y Y, DING W X, et al. Neutrophil extracellular traps induced by interleukin 8 via CXCR1/2 promote the progression of gastric carcinoma through transcription factor IIB-related factor 1 and cyclin[J]. Genes Dis, 2024, 11(2): 575-578. DOI: 10.1016/j.gendis.2023.03.025.
[29]	LI J C, XIA Y, SUN B Y, et al. Neutrophil extracellular traps induced by the hypoxic microenvironment in gastric cancer augment tumour growth[J]. Cell Commun Signal, 2023, 21(1): 86. DOI: 10.1186/s12964-023-01112-5.
[30]	KANAMARU R, OHZAWA H, MIYATO H, et al. Neutrophil extracellular traps generated by low density neutrophils obtained from peritoneal lavage fluid mediate tumor cell growth and attachment[J]. J Vis Exp, 2018(138): 58201. DOI: 10.3791/58201.
[31]	KUMAGAI Y, OHZAWA H, MIYATO H, et al. Surgical stress increases circulating low-density neutrophils which may promote tumor recurrence[J]. J Surg Res, 2020, 246: 52-61. DOI: 10.1016/j.jss.2019.08.022.
[32]	LI M Z, ZHAO Z D, MAK T K, et al. Neutrophil extracellular traps-related signature predicts the prognosis and immune infiltration in gastric cancer[J]. Front Med, 2023, 10: 1174764. DOI: 10.3389/fmed.2023.1174764.
[33]	ZHAO J, LI X Y, LI L M, et al. Identification of neutrophil extracellular trap-driven gastric cancer heterogeneity and C5AR1 as a therapeutic target[J]. Acta Biochim Biophys Sin, 2024, 56(4): 538-550. DOI: 10.3724/abbs.2023290.
[34]	XIA X, ZHANG Z Z, ZHU C C, et al. Neutrophil extracellular traps promote metastasis in gastric cancer patients with postoperative abdominal infectious complications[J]. Nat Commun, 2022, 13(1): 1017. DOI: 10.1038/s41467-022-28492-5.
[35]	NATALWALA A, SPYCHAL R, TSELEPIS C. Epithelial-mesenchymal transition mediated tumourigenesis in the gastrointestinal tract[J]. World J Gastroenterol, 2008, 14(24): 3792-3797. DOI: 10.3748/wjg.14.3792.
[36]	YANG S F, ZOU X M, LI J C, et al. Immunoregulation and clinical significance of neutrophils/NETs-ANGPT2 in tumor microenvironment of gastric cancer[J]. Front Immunol, 2022, 13: 1010434. DOI: 10.3389/fimmu.2022.1010434.
[37]	YANG L B, LIU Q, ZHANG X Q, et al. DNA of neutrophil extracellular traps promotes cancer metastasis via CCDC25[J]. Nature, 2020, 583(7814): 133-138. DOI: 10.1038/s41586-020-2394-6.
[38]	ZHANG F B, YAN Y, CAO X G, et al. TGF-β-driven LIF expression influences neutrophil extracellular traps(NETs)and contributes to peritoneal metastasis in gastric cancer[J]. Cell Death Dis, 2024, 15(3): 218. DOI: 10.1038/s41419-024-06594-w.
[39]	LIU D H, YANG X Y, WANG X Y. Neutrophil extracellular traps promote gastric cancer cell metastasis via the NAT10-mediated N4-acetylcytidine modification of SMYD2[J]. Cell Signal, 2024, 116: 111014. DOI: 10.1016/j.cellsig.2023.111014.
[40]	XING L, WU S L, XUE S Y, et al. A novel neutrophil extracellular trap signature predicts patient chemotherapy resistance and prognosis in lung adenocarcinoma[J]. Mol Biotechnol, 2024. DOI: 10.1007/s12033-024-01170-1.
[41]	FU Y F, TAO J X, GU Y N, et al. Multiomics integration reveals NETosis heterogeneity and TLR2 as a prognostic biomarker in pancreatic cancer[J]. NPJ Precis Oncol, 2024, 8(1): 109. DOI: 10.1038/s41698-024-00586-x.
[42]	WANG Q, HUANG Y X, ZHU Y, et al. The m6A methyltransferase METTL5 promotes neutrophil extracellular trap network release to regulate hepatocellular carcinoma progression[J]. Cancer Med, 2024, 13(7): e7165. DOI: 10.1002/cam4.7165.
[43]	REN J H, HE J Y, ZHANG H J, et al. Platelet TLR4-ERK5 axis facilitates NET-mediated capturing of circulating tumor cells and distant metastasis after surgical stress[J]. Cancer Res, 2021, 81(9): 2373-2385. DOI: 10.1158/0008-5472.CAN-20-3222.
[44]	MOUSSET A, LECORGNE E, BOURGET I, et al. Neutrophil extracellular traps formed during chemotherapy confer treatment resistance via TGF-β activation[J]. Cancer Cell, 2023, 41(4): 757-775.e10. DOI: 10.1016/j.ccell.2023.03.008.
[45]	RAYES R F, MOUHANNA J G, NICOLAU I, et al. Primary tumors induce neutrophil extracellular traps with targetable metastasis promoting effects[J]. JCI Insight, 2019, 5(16): e128008. DOI: 10.1172/jci.insight.128008.
[46]	YANG C F, MA R S, JIANG T, et al. Contributions of phosphatidylserine-positive platelets and leukocytes and microparticles to hypercoagulable state in gastric cancer patients[J]. Tumour Biol, 2016, 37(6): 7881-7891. DOI: 10.1007/s13277-015-4667-5.
[47]	ROSELL A, AGUILERA K, HISADA Y, et al. Prognostic value of circulating markers of neutrophil activation, neutrophil extracellular traps, coagulation and fibrinolysis in patients with terminal cancer[J]. Sci Rep, 2021, 11(1): 5074. DOI: 10.1038/s41598-021-84476-3.
[48]	HEERINGA P, RUTGERS A, KALLENBERG C G M. The net effect of ANCA on neutrophil extracellular trap formation[J]. Kidney Int, 2018, 94(1): 14-16. DOI: 10.1016/j.kint.2018.03.010.
[49]	CLARK S R, MA A C, TAVENER S A, et al. Platelet TLR4 activates neutrophil extracellular traps to ensnare bacteria in septic blood[J]. Nat Med, 2007, 13(4): 463-469. DOI: 10.1038/nm1565.
[50]	FOLCO E J, MAWSON T L, VROMMAN A, et al. Neutrophil extracellular traps induce endothelial cell activation and tissue factor production through interleukin-1α and cathepsin G[J]. Arterioscler Thromb Vasc Biol, 2018, 38(8): 1901-1912. DOI: 10.1161/ATVBAHA.118.311150.
[51]	LIU C, ZHANG H, LI T P, et al. Fusobacterium nucleatum promotes megakaryocyte maturation in patients with gastric cancer via inducing the production of extracellular vesicles containing 14-3-3ε[J]. Infect Immun, 2023, 91(8): e0010223. DOI: 10.1128/iai.00102-23.
[52]	JIMÉNEZ-ALCÁZAR M, RANGASWAMY C, PANDA R, et al. Host DNases prevent vascular occlusion by neutrophil extracellular traps[J]. Science, 2017, 358(6367): 1202-1206. DOI: 10.1126/science.aam8897.
[53]	KANAMARU R, OHZAWA H, MIYATO H, et al. Low density neutrophils(LDN)in postoperative abdominal cavity assist the peritoneal recurrence through the production of neutrophil extracellular traps(NETs)[J]. Sci Rep, 2018, 8(1): 632. DOI: 10.1038/s41598-017-19091-2.
[54]	YU J R, LIU Y Y, GAO Y Y, et al. Diterpenoid tanshinones inhibit gastric cancer angiogenesis through the PI3K/Akt/mTOR signaling pathway[J]. J Ethnopharmacol, 2024, 324: 117791. DOI: 10.1016/j.jep.2024.117791.
[55]	TAO L, XU M, DAI X J, et al. Polypharmacological profiles underlying the antitumor property of Salvia miltiorrhiza root(Danshen)interfering with NOX-dependent neutrophil extracellular traps[J]. Oxid Med Cell Longev, 2018, 2018: 4908328. DOI: 10.1155/2018/4908328.
[56]	LI R, ZOU X M, ZHU T, et al. Destruction of neutrophil extracellular traps promotes the apoptosis and inhibits the invasion of gastric cancer cells by regulating the expression of Bcl-2, Bax and NF-κB[J]. Onco Targets Ther, 2020, 13: 5271-5281. DOI: 10.2147/OTT.S227331.
[57]	MANGROLIA U, OSBORNE J W. Probiotics in counteracting the role of neutrophils in cancer metastasis[J]. Vaccines, 2021, 9(11): 1306. DOI: 10.3390/vaccines9111306.
[58]	VILLARROEL-ESPINDOLA F, EJSMENTEWICZ T, GONZALEZ-STEGMAIER R, et al. Intersections between innate immune response and gastric cancer development[J]. World J Gastroenterol, 2023, 29(15): 2222-2240. DOI: 10.3748/wjg.v29.i15.2222.
[59]	NAGARAJU G P, SRIVANI G, DARIYA B, et al. Nanoparticles guided drug delivery and imaging in gastric cancer[J]. Semin Cancer Biol, 2021, 69: 69-76. DOI: 10.1016/j.semcancer.2020.01.006.