Targeting NETosis: nature’s alarm system in cancer progression

Abstract

Neutrophils are recognized active participants in inflammatory responses and are intricately linked to cancer progression. In response to inflammatory stimuli, neutrophils become activated, releasing neutrophils extracellular traps (NETs) for the capture and eradication of pathogens, a phenomenon termed NETosis. With a deeper understanding of NETs, there is growing evidence supporting their role in cancer progression and their involvement in conferring resistance to various cancer therapies, especially concerning tumor reactions to chemotherapy, radiation therapy (RT), and immunotherapy. This review summarizes the roles of NETs in the tumor microenvironment (TME) and their mechanisms of neutrophil involvement in the host defense. Additionally, it elucidates the mechanisms through which NETs promote tumor progression and their role in cancer treatment resistance, highlighting their potential as promising therapeutic targets in cancer treatment and their clinical applicability.

Keywords

Neutrophils / neutrophils extracellular traps (NETs) / NETosis / cancer progression / cancer therapeutics

References

[1] Denk D.Inflammation: the incubator of the tumor microenvironment.Trends Cancer2022;8:901-14

[2] Libby P.Inflammation: a common contributor to cancer, aging, and cardiovascular diseases-expanding the concept of cardio-oncology.Cardiovasc Res2019;115:824-9 PMCID:PMC6452304

[3] Rossi JF,Massart C.Dynamic immune/inflammation precision medicine: the good and the bad inflammation in infection and cancer.Front Immunol2021;12:595722 PMCID:PMC7940508

[4] Hinshaw DC.The tumor microenvironment innately modulates cancer progression.Cancer Res2019;79:4557-66 PMCID:PMC6744958

[5] Pramanik A.Myeloid derived suppressor cells and innate immune system interaction in tumor microenvironment.Life Sci2022;305:120755

[6] Wang S,Li Y.Metabolic reprogramming induces macrophage polarization in the tumor microenvironment.Front Immunol2022;13:840029 PMCID:PMC9302576

[7] Lu C,Ali NM,Cui X.The role of innate immune cells in the tumor microenvironment and research progress in anti-tumor therapy.Front Immunol2022;13:1039260 PMCID:PMC9893925

[8] Rosales C.Neutrophils at the crossroads of innate and adaptive immunity.J Leukoc Biol2020;108:377-96

[9] Delgado-Rizo V,Iñiguez-Gutierrez L,Alvarado-Navarro A.Neutrophil extracellular traps and its implications in inflammation: an overview.Front Immunol2017;8:81 PMCID:PMC5292617

[10] Coffelt SB,de Visser KE.Neutrophils in cancer: neutral no more.Nat Rev Cancer2016;16:431-46

[11] Colotta F,Polentarutti N,Mantovani A.Modulation of granulocyte survival and programmed cell death by cytokines and bacterial products.Blood1992;80:2012-20

[12] van Raam BJ, Drewniak A, Groenewold V, van den Berg TK, Kuijpers TW. Granulocyte colony-stimulating factor delays neutrophil apoptosis by inhibition of calpains upstream of caspase-3.Blood2008;112:2046-54 PMCID:PMC2518906

[13] Farraye FA,Eaden J.AGA technical review on the diagnosis and management of colorectal neoplasia in inflammatory bowel disease.Gastroenterology2010;138:746-74.e4

[14] Itzkowitz SH.Inflammation and cancer IV. Colorectal cancer in inflammatory bowel disease: the role of inflammation.Am J Physiol Gastrointest Liver Physiol2004;287:G7-17

[15] Sun B.Obesity, inflammation, and liver cancer.J Hepatol2012;56:704-13 PMCID:PMC3889660

[16] Dancey JT,Harker LA.Neutrophil kinetics in man.J Clin Invest1976;58:705-15 PMCID:PMC333229

[17] Martin C,Bridger G,Williams TJ.Chemokines acting via CXCR2 and CXCR4 control the release of neutrophils from the bone marrow and their return following senescence.Immunity2003;19:583-93

[18] Templeton AJ,Šeruga B.Prognostic role of neutrophil-to-lymphocyte ratio in solid tumors: a systematic review and meta-analysis.J Natl Cancer Inst2014;106:dju124

[19] Gentles AJ,Liu CL.The prognostic landscape of genes and infiltrating immune cells across human cancers.Nat Med2015;21:938-45 PMCID:PMC4852857

[20] Cupp MA,Tzoulaki I,Evangelou E.Neutrophil to lymphocyte ratio and cancer prognosis: an umbrella review of systematic reviews and meta-analyses of observational studies.BMC Med2020;18:360 PMCID:PMC7678319

[21] Kao SCH,Harvie R.High blood neutrophil-to-lymphocyte ratio is an indicator of poor prognosis in malignant mesothelioma patients undergoing systemic therapy.Clin Cancer Res2010;16:5805-13

[22] Azab B,Phookan J.Usefulness of the neutrophil-to-lymphocyte ratio in predicting short- and long-term mortality in breast cancer patients.Ann Surg Oncol2012;19:217-24

[23] Fridlender ZG,Kim S.Polarization of tumor-associated neutrophil phenotype by TGF-beta: “N1” versus “N2” TAN.Cancer Cell2009;16:183-94 PMCID:PMC2754404

[24] Zhu Q,Zhang L.The IL-6-STAT3 axis mediates a reciprocal crosstalk between cancer-derived mesenchymal stem cells and neutrophils to synergistically prompt gastric cancer progression.Cell Death Dis2014;5:e1295 PMCID:PMC4611735

[25] Zilionis R,Pfirschke C.Single-cell transcriptomics of human and mouse lung cancers reveals conserved myeloid populations across individuals and species.Immunity2019;50:1317-34.e10 PMCID:PMC6620049

[26] Adrover JM,He XY,Egeblad M.NETworking with cancer: the bidirectional interplay between cancer and neutrophil extracellular traps.Cancer Cell2023;41:505-26 PMCID:PMC10280682

[27] Lee WL,Grinstein S.Phagocytosis by neutrophils.Microbes Infect2003;5:1299-306

[28] Ulfig A.The effects of neutrophil-generated hypochlorous acid and other hypohalous acids on host and pathogens.Cell Mol Life Sci2021;78:385-414 PMCID:PMC7873122

[29] Davies MJ.Myeloperoxidase: mechanisms, reactions and inhibition as a therapeutic strategy in inflammatory diseases.Pharmacol Ther2021;218:107685

[30] Burn GL,Marsman G,Zychlinsky A.The neutrophil.Immunity2021;54:1377-91

[31] Mollinedo F.Neutrophil degranulation, plasticity, and cancer metastasis.Trends Immunol2019;40:228-42

[32] Kolaczkowska E.Neutrophil recruitment and function in health and inflammation.Nat Rev Immunol2013;13:159-75

[33] Cowland JB.Granulopoiesis and granules of human neutrophils.Immunol Rev2016;273:11-28

[34] Takei H,Watanabe H,Sendo F.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 Leukoc Biol1996;59:229-40

[35] Brinkmann V,Goosmann C.Neutrophil extracellular traps kill bacteria.Science2004;303:1532-5

[36] Barnes BJ,Baxter-Stoltzfus A.Targeting potential drivers of COVID-19: neutrophil extracellular traps.J Exp Med2020;217:e20200652 PMCID:PMC7161085

[37] Fuchs TA,Goosmann C.Novel cell death program leads to neutrophil extracellular traps.J Cell Biol2007;176:231-41 PMCID:PMC2063942

[38] Herre M,Mackman N.Neutrophil extracellular traps in the pathology of cancer and other inflammatory diseases.Physiol Rev2023;103:277-312 PMCID:PMC9576172

[39] Pilsczek FH,Poon KKH.A novel mechanism of rapid nuclear neutrophil extracellular trap formation in response to Staphylococcus aureus.J Immunol2010;185:7413-25

[40] Yousefi S,Kozlowski E,Simon HU.Viable neutrophils release mitochondrial DNA to form neutrophil extracellular traps.Cell Death Differ2009;16:1438-44

[41] Tan C,Wang P.The vitals of NETs.J Leukoc Biol2021;110:797-808 PMCID:PMC9059135

[42] Hakkim A,Martinez NE.Activation of the Raf-MEK-ERK pathway is required for neutrophil extracellular trap formation.Nat Chem Biol2011;7:75-7

[43] Karacs J,Kitzmüller C.Adjuvants and vaccines used in allergen-specific immunotherapy induce neutrophil extracellular traps.Vaccines2021;9:321 PMCID:PMC8066953

[44] Li P,Lindberg MR,Xiong N.PAD4 is essential for antibacterial innate immunity mediated by neutrophil extracellular traps.J Exp Med2010;207:1853-62 PMCID:PMC2931169

[45] Douda DN,Grasemann H.SK3 channel and mitochondrial ROS mediate NADPH oxidase-independent NETosis induced by calcium influx.Proc Natl Acad Sci U S A2015;112:2817-22 PMCID:PMC4352781

[46] Shaul ME.The dual role of neutrophils in cancer.Semin Immunol2021;57:101582

[47] Cristinziano L,Antonelli A.Neutrophil extracellular traps in cancer.Semin Cancer Biol2022;79:91-104

[48] Poto R,Modestino L.Neutrophil extracellular traps, angiogenesis and cancer.Biomedicines2022;10:431 PMCID:PMC8962440

[49] Schedel F,Pappelbaum KI.Evidence and impact of neutrophil extracellular traps in malignant melanoma.Pigment Cell Melanoma Res2020;33:63-73

[50] Chan YT,Lu Y.Pancreatic melatonin enhances anti-tumor immunity in pancreatic adenocarcinoma through regulating tumor-associated neutrophils infiltration and NETosis.Acta Pharm Sin B2023;13:1554-67 PMCID:PMC10150138

[51] Zhang R,Han Y.Neutrophil autophagy and NETosis in COVID-19: perspectives.Autophagy2023;19:758-67 PMCID:PMC9980466

[52] Njeim R,Fares AH,Kfoury Kassouf H.NETosis contributes to the pathogenesis of diabetes and its complications.J Mol Endocrinol2020;65:R65-76

[53] Xiong S,Cheng L.Neutrophils in cancer carcinogenesis and metastasis.J Hematol Oncol2021;14:173 PMCID:PMC8529570

[54] Zhou Y,Shen F,Xu Z.The emerging role of neutrophil extracellular traps in arterial, venous and cancer-associated thrombosis.Front Cardiovasc Med2021;8:786387 PMCID:PMC8674622

[55] Mitsis M,Tatsis V.Neutrophil extracellular traps and pancreatic cancer development: a vicious cycle.Cancers2022;14:3339 PMCID:PMC9318070

[56] Guglietta S,Zagato E.Coagulation induced by C3aR-dependent NETosis drives protumorigenic neutrophils during small intestinal tumorigenesis.Nat Commun2016;7:11037 PMCID:PMC4802169

[57] Deryugina EI,Juncker-Jensen A,Welter L.Tissue-infiltrating neutrophils constitute the major in vivo source of angiogenesis-inducing MMP-9 in the tumor microenvironment.Neoplasia2014;16:771-88 PMCID:PMC4212255

[58] Li J,Sun B.Neutrophil extracellular traps induced by the hypoxic microenvironment in gastric cancer augment tumour growth.Cell Commun Signal2023;21:86 PMCID:PMC10152773

[59] Tan DS,Kaye SB.Mechanisms of transcoelomic metastasis in ovarian cancer.Lancet Oncol2006;7:925-34

[60] Lengyel E.Ovarian cancer development and metastasis.Am J Pathol2010;177:1053-64 PMCID:PMC2928939

[61] Lee W,Mohamed MS,Lengyel E.Neutrophils facilitate ovarian cancer premetastatic niche formation in the omentum.J Exp Med2019;216:176-94 PMCID:PMC6314534

[62] Yang LY,Lu L.Increased neutrophil extracellular traps promote metastasis potential of hepatocellular carcinoma via provoking tumorous inflammatory response.J Hematol Oncol2020;13:3 PMCID:PMC6945602

[63] Yang L,Zhang X.DNA of neutrophil extracellular traps promotes cancer metastasis via CCDC25.Nature2020;583:133-8

[64] Xiao Y,Li J.Cathepsin C promotes breast cancer lung metastasis by modulating neutrophil infiltration and neutrophil extracellular trap formation.Cancer Cell2021;39:423-37.e7

[65] Rayes RF,Bou Rjeily M.Neutrophil extracellular trap-associated CEACAM1 as a putative therapeutic target to prevent metastatic progression of colon carcinoma.J Immunol2020;204:2285-94 PMCID:PMC7534954

[66] Ducker TP.Subcellular localization of CD66, CD67, and NCA in human neutrophils.J Leukoc Biol1992;52:11-6

[67] Hirao H,Dery KJ.Neutrophil CEACAM1 determines susceptibility to NETosis by regulating the S1PR2/S1PR3 axis in liver transplantation.J Clin Invest2023;133:e162940 PMCID:PMC9888387

[68] Babaei G,Jaghi NZZ.EMT, cancer stem cells and autophagy; the three main axes of metastasis.Biomed Pharmacother2021;133:110909

[69] Pastushenko I.EMT transition states during tumor progression and metastasis.Trends Cell Biol2019;29:212-26

[70] Morimoto-Kamata R.Insulin-like growth factor-1 signaling is responsible for cathepsin G-induced aggregation of breast cancer MCF-7 cells.Cancer Sci2017;108:1574-83 PMCID:PMC5543509

[71] Padmanaban V,Suhail Y.E-cadherin is required for metastasis in multiple models of breast cancer.Nature2019;573:439-44 PMCID:PMC7365572

[72] Micalizzi DS,Nicholson BT.Targeting breast and pancreatic cancer metastasis using a dual-cadherin antibody.Proc Natl Acad Sci U S A2022;119:e2209563119 PMCID:PMC9618049

[73] Deryugina E,Ardi V.Neutrophil elastase facilitates tumor cell intravasation and early metastatic events.iScience2020;23:101799 PMCID:PMC7702017

[74] Ramachandran IR,Lin C.Bone marrow PMN-MDSCs and neutrophils are functionally similar in protection of multiple myeloma from chemotherapy.Cancer Lett2016;371:117-24 PMCID:PMC4919899

[75] Hosseini M,Aroua N.Targeting myeloperoxidase disrupts mitochondrial redox balance and overcomes cytarabine resistance in human acute myeloid leukemia.Cancer Res2019;79:5191-203

[76] Mousset A,Bourget I.Neutrophil extracellular traps formed during chemotherapy confer treatment resistance via TGF-β activation.Cancer Cell2023;41:757-75.e10 PMCID:PMC10228050

[77] Morimoto-Kamata R,Ohkura N.Cathepsin G-induced cell aggregation of breast cancer MCF-7 decreases doxorubicin sensitivity in a hypoxia-inducible factor-independent mechanism.Biol Pharm Bull2022;45:1772-83

[78] Kaltenmeier C,Morder K,Simmons RL.Neutrophil extracellular traps promote T cell exhaustion in the tumor microenvironment.Front Immunol2021;12:785222 PMCID:PMC8652262

[79] Ortenberg R,Zippel D.Serum CEACAM1 elevation correlates with melanoma progression and failure to respond to adoptive cell transfer immunotherapy.J Immunol Res2015;2015:902137 PMCID:PMC4673329

[80] Huang YH,Kondo Y.CEACAM1 regulates TIM-3-mediated tolerance and exhaustion.Nature2015;517:386-90 PMCID:PMC4297519

[81] Iwakura Y,Saijo S.Functional specialization of interleukin-17 family members.Immunity2011;34:149-62

[82] Akbay EA,Liu Y.Interleukin-17A promotes lung tumor progression through neutrophil attraction to tumor sites and mediating resistance to PD-1 blockade.J Thorac Oncol2017;12:1268-79 PMCID:PMC5532066

[83] Zhang Y,Riquelme Sanchez E.Interleukin-17-induced neutrophil extracellular traps mediate resistance to checkpoint blockade in pancreatic cancer.J Exp Med2020;217:e20190354 PMCID:PMC7953739

[84] Teijeira Á,Gato M.CXCR1 and CXCR2 chemokine receptor agonists produced by tumors induce neutrophil extracellular traps that interfere with immune cytotoxicity.Immunity2020;52:856-71.e8

[85] Shinde-Jadhav S,Rayes RF.Role of neutrophil extracellular traps in radiation resistance of invasive bladder cancer.Nat Commun2021;12:2776 PMCID:PMC8119713

[86] Wisdom AJ,Lin AJ.Neutrophils promote tumor resistance to radiation therapy.Proc Natl Acad Sci U S A2019;116:18584-9 PMCID:PMC6744874

[87] Thålin C,Seignez C.Citrullinated histone H3 as a novel prognostic blood marker in patients with advanced cancer.PLoS One2018;13:e0191231 PMCID:PMC5764486

[88] Rayes RF,Nicolau I.Primary tumors induce neutrophil extracellular traps with targetable metastasis promoting effects.JCI Insight2019;5:e128008 PMCID:PMC6777835

[89] Grilz E,Posch F.Citrullinated histone H3, a biomarker for neutrophil extracellular trap formation, predicts the risk of mortality in patients with cancer.Br J Haematol2019;186:311-20 PMCID:PMC6618331

[90] Miller-Ocuin JL,Boone BA.DNA released from neutrophil extracellular traps (NETs) activates pancreatic stellate cells and enhances pancreatic tumor growth.Oncoimmunology2019;8:e1605822 PMCID:PMC6685506

[91] Yazdani HO,Comerci AJ.Neutrophil extracellular traps drive mitochondrial homeostasis in tumors to augment growth.Cancer Res2019;79:5626-39 PMCID:PMC6825588

[92] Qu Z,Zhu Q.A novel neutrophil extracellular traps signature for overall survival prediction and tumor microenvironment identification in gastric cancer.J Inflamm Res2023;16:3419-36 PMCID:PMC10438473

[93] Hosseinnejad A,Wienkamp AK.DNase I functional microgels for neutrophil extracellular trap disruption.Biomater Sci2021;10:85-99

[94] Law SM.Neutrophil extracellular traps and the dysfunctional innate immune response of cystic fibrosis lung disease: a review.J Inflamm2017;14:29 PMCID:PMC5745605

[95] Xia Y,Zhang H.AAV-mediated gene transfer of DNase I in the liver of mice with colorectal cancer reduces liver metastasis and restores local innate and adaptive immune response.Mol Oncol2020;14:2920-35 PMCID:PMC7607180

[96] Lewis HD,Coote JE.Inhibition of PAD4 activity is sufficient to disrupt mouse and human NET formation.Nat Chem Biol2015;11:189-91 PMCID:PMC4397581

[97] Jiang ZZ,Liu XC.Neutrophil extracellular traps induce tumor metastasis through dual effects on cancer and endothelial cells.Oncoimmunology2022;11:2052418 PMCID:PMC8928819

[98] Munir H,Janowitz T.Stromal-driven and amyloid β-dependent induction of neutrophil extracellular traps modulates tumor growth.Nat Commun2021;12:683 PMCID:PMC7846803

[99] Li M,Deng H.A novel peptidylarginine deiminase 4 (PAD4) inhibitor BMS-P5 blocks formation of neutrophil extracellular traps and delays progression of multiple myeloma.Mol Cancer Ther2020;19:1530-8 PMCID:PMC7335350

[100] Deng H,Garcia-Gerique L.A novel selective inhibitor JBI-589 targets PAD4-mediated neutrophil migration to suppress tumor progression.Cancer Res2022;82:3561-72 PMCID:PMC9532374

[101] Nie M,Bi X.Neutrophil extracellular traps induced by IL8 promote diffuse large B-cell lymphoma progression via the TLR9 signaling.Clin Cancer Res2019;25:1867-79

[102] Yang Y,Xu Y.Enalapril overcomes chemoresistance and potentiates antitumor efficacy of 5-FU in colorectal cancer by suppressing proliferation, angiogenesis, and NF-κB/STAT3-regulated proteins.Cell Death Dis2020;11:477 PMCID:PMC7314775

[103] Korkmaz B,Domain R.Cathepsin C inhibition as a potential treatment strategy in cancer.Biochem Pharmacol2021;194:114803

[104] Doyle K,Käck H.Discovery of second generation reversible covalent DPP1 inhibitors leading to an oxazepane amidoacetonitrile based clinical candidate (AZD7986).J Med Chem2016;59:9457-72

[105] Palmér R,Jauhiainen A.Dipeptidyl peptidase 1 inhibitor AZD7986 induces a sustained, exposure-dependent reduction in neutrophil elastase activity in healthy subjects.Clin Pharmacol Ther2018;104:1155-64 PMCID:PMC6282495

[106] Schott AF,Cristofanilli M.Phase Ib pilot study to evaluate reparixin in combination with weekly paclitaxel in patients with HER-2-negative metastatic breast cancer.Clin Cancer Res2017;23:5358-65 PMCID:PMC5600824

[107] Greene S,Mydlarz WK.Inhibition of MDSC trafficking with SX-682, a CXCR1/2 inhibitor, enhances NK-cell immunotherapy in head and neck cancer models.Clin Cancer Res2020;26:1420-31 PMCID:PMC7073293

[108] Sun L,Robbins Y.Inhibiting myeloid-derived suppressor cell trafficking enhances T cell immunotherapy.JCI Insight2019;4:126853 PMCID:PMC6483637

[109] Stevens T,Gränse M.AZD9668: pharmacological characterization of a novel oral inhibitor of neutrophil elastase.J Pharmacol Exp Ther2011;339:313-20

[110] Chen J,Liang Q.Localized degradation of neutrophil extracellular traps by photoregulated enzyme delivery for cancer immunotherapy and metastasis suppression.ACS Nano2022;16:2585-97

[111] Yin H,Xiong Y.Tumor-associated neutrophil extracellular traps regulating nanocarrier-enhanced inhibition of malignant tumor growth and distant metastasis.ACS Appl Mater Interfaces2021;13:59683-94

[112] Liang H,Zhu C.Nanoparticulate cationic poly(amino acid)s block cancer metastases by destructing neutrophil extracellular traps.ACS Nano2023;17:2868-80

[113] Wang Z,Shi C.Cell membrane derived liposomes loaded with DNase I target neutrophil extracellular traps which inhibits colorectal cancer liver metastases.J Control Release2023;357:620-9

[114] Ju C,Zhang L.Neoadjuvant chemotherapy based on abraxane/human neutrophils cytopharmaceuticals with radiotherapy for gastric cancer.Small2019;15:e1804191