Subscribe to RSS
DOI: 10.1055/s-0034-1370765
NETosis: A New Factor in Tumor Progression and Cancer-Associated Thrombosis
Publication History
Publication Date:
03 March 2014 (online)
Abstract
Neutrophils have long been known as innate immune cells that phagocytose and kill pathogens and mount inflammatory responses protecting the host from infection. In the past decades, new aspects of neutrophils have emerged unmasking their importance not only in inflammation but also in many pathological conditions including thrombosis and cancer. The 2004 discovery that neutrophils, upon strong activation, release decondensed chromatin to form neutrophil extracellular traps (NETs), has unveiled new avenues of research. Here, we review current knowledge regarding NETs in thrombosis, with a special focus on cancer-associated thrombosis as well as their potential role in cancer growth and metastasis. We discuss the prospective use of NET-specific biomarkers, such as citrullinated histone H3 and NET inhibitors, as tools to anticipate and fight cancer-associated thrombosis. We propose that the rapid developments in the field of NETosis may provide new targets to combat the thrombotic consequences of cancer and perhaps even help to contain the disease itself.
-
References
- 1 Amulic B, Cazalet C, Hayes GL, Metzler KD, Zychlinsky A. Neutrophil function: from mechanisms to disease. Annu Rev Immunol 2012; 30: 459-489
- 2 Mócsai A. Diverse novel functions of neutrophils in immunity, inflammation, and beyond. J Exp Med 2013; 210 (7) 1283-1299
- 3 Brinkmann V, Reichard U, Goosmann C , et al. Neutrophil extracellular traps kill bacteria. Science 2004; 303 (5663) 1532-1535
- 4 Fuchs TA, Abed U, Goosmann C , et al. Novel cell death program leads to neutrophil extracellular traps. J Cell Biol 2007; 176 (2) 231-241
- 5 Pilsczek FH, Salina D, Poon KK , et al. A novel mechanism of rapid nuclear neutrophil extracellular trap formation in response to Staphylococcus aureus. J Immunol 2010; 185 (12) 7413-7425
- 6 Yipp BG, Petri B, Salina D , et al. Infection-induced NETosis is a dynamic process involving neutrophil multitasking in vivo. Nat Med 2012; 18 (9) 1386-1393
- 7 Yipp BG, Kubes P. NETosis: how vital is it?. Blood 2013; 122 (16) 2784-2794
- 8 Bianchi M, Hakkim A, Brinkmann V , et al. Restoration of NET formation by gene therapy in CGD controls aspergillosis. Blood 2009; 114 (13) 2619-2622
- 9 Hakkim A, Fuchs TA, Martinez NE , et al. Activation of the Raf-MEK-ERK pathway is required for neutrophil extracellular trap formation. Nat Chem Biol 2011; 7 (2) 75-77
- 10 Keshari RS, Verma A, Barthwal MK, Dikshit M. Reactive oxygen species-induced activation of ERK and p38 MAPK mediates PMA-induced NETs release from human neutrophils. J Cell Biochem 2013; 114 (3) 532-540
- 11 Parker H, Dragunow M, Hampton MB, Kettle AJ, Winterbourn CC. Requirements for NADPH oxidase and myeloperoxidase in neutrophil extracellular trap formation differ depending on the stimulus. J Leukoc Biol 2012; 92 (4) 841-849
- 12 Papayannopoulos V, Metzler KD, Hakkim A, Zychlinsky A. Neutrophil elastase and myeloperoxidase regulate the formation of neutrophil extracellular traps. J Cell Biol 2010; 191 (3) 677-691
- 13 Wang S, Wang Y. Peptidylarginine deiminases in citrullination, gene regulation, health and pathogenesis. Biochim Biophys Acta 2013; 1829 (10) 1126-1135
- 14 Li P, Li M, Lindberg MR, Kennett MJ, Xiong N, Wang Y. PAD4 is essential for antibacterial innate immunity mediated by neutrophil extracellular traps. J Exp Med 2010; 207 (9) 1853-1862
- 15 Martinod K, Demers M, Fuchs TA , et al. Neutrophil histone modification by peptidylarginine deiminase 4 is critical for deep vein thrombosis in mice. Proc Natl Acad Sci U S A 2013; 110 (21) 8674-8679
- 16 Wang Y, Li M, Stadler S , et al. Histone hypercitrullination mediates chromatin decondensation and neutrophil extracellular trap formation. J Cell Biol 2009; 184 (2) 205-213
- 17 Leshner M, Wang S, Lewis C , et al. PAD4 mediated histone hypercitrullination induces heterochromatin decondensation and chromatin unfolding to form neutrophil extracellular trap-like structures. Front Immunol 2012; 3: 307
- 18 Fuchs TA, Brill A, Duerschmied D , et al. Extracellular DNA traps promote thrombosis. Proc Natl Acad Sci U S A 2010; 107 (36) 15880-15885
- 19 Massberg S, Grahl L, von Bruehl ML , et al. Reciprocal coupling of coagulation and innate immunity via neutrophil serine proteases. Nat Med 2010; 16 (8) 887-896
- 20 Brill A, Fuchs TA, Savchenko AS , et al. Neutrophil extracellular traps promote deep vein thrombosis in mice. J Thromb Haemost 2012; 10 (1) 136-144
- 21 Nakazawa D, Tomaru U, Yamamoto C, Jodo S, Ishizu A. Abundant neutrophil extracellular traps in thrombus of patient with microscopic polyangiitis. Front Immunol 2012; 3: 333
- 22 Diaz JA, Fuchs TA, Jackson TO , et al. Plasma DNA is elevated in patients with deep vein thrombosis. J Vasc Surg Venous Lymphat Disord 2013; 1 (4) 341-348
- 23 van Montfoort ML, Stephan F, Lauw MN , et al. Circulating nucleosomes and neutrophil activation as risk factors for deep vein thrombosis. Arterioscler Thromb Vasc Biol 2013; 33 (1) 147-151
- 24 von Brühl ML, Stark K, Steinhart A , et al. Monocytes, neutrophils, and platelets cooperate to initiate and propagate venous thrombosis in mice in vivo. J Exp Med 2012; 209 (4) 819-835
- 25 Fuchs TA, Kremer Hovinga JA, Schatzberg D, Wagner DD, Lämmle B. Circulating DNA and myeloperoxidase indicate disease activity in patients with thrombotic microangiopathies. Blood 2012; 120 (6) 1157-1164
- 26 Borissoff JI, Joosen IA, Versteylen MO , et al. Elevated levels of circulating DNA and chromatin are independently associated with severe coronary atherosclerosis and a prothrombotic state. Arterioscler Thromb Vasc Biol 2013; 33 (8) 2032-2040
- 27 Kannemeier C, Shibamiya A, Nakazawa F , et al. Extracellular RNA constitutes a natural procoagulant cofactor in blood coagulation. Proc Natl Acad Sci U S A 2007; 104 (15) 6388-6393
- 28 Swystun LL, Mukherjee S, Liaw PC. Breast cancer chemotherapy induces the release of cell-free DNA, a novel procoagulant stimulus. J Thromb Haemost 2011; 9 (11) 2313-2321
- 29 Xu J, Zhang X, Pelayo R , et al. Extracellular histones are major mediators of death in sepsis. Nat Med 2009; 15 (11) 1318-1321
- 30 Ammollo CT, Semeraro F, Xu J, Esmon NL, Esmon CT. Extracellular histones increase plasma thrombin generation by impairing thrombomodulin-dependent protein C activation. J Thromb Haemost 2011; 9 (9) 1795-1803
- 31 Semeraro F, Ammollo CT, Morrissey JH , et al. Extracellular histones promote thrombin generation through platelet-dependent mechanisms: involvement of platelet TLR2 and TLR4. Blood 2011; 118 (7) 1952-1961
- 32 Fuchs TA, Bhandari AA, Wagner DD. Histones induce rapid and profound thrombocytopenia in mice. Blood 2011; 118 (13) 3708-3714
- 33 Kambas K, Chrysanthopoulou A, Vassilopoulos D , et al. Tissue factor expression in neutrophil extracellular traps and neutrophil derived microparticles in antineutrophil cytoplasmic antibody associated vasculitis may promote thromboinflammation and the thrombophilic state associated with the disease. Ann Rheum Dis 2013; . doi:10.1136/annrheumdis-2013-203430 [e-pub ahead of print]
- 34 Kambas K, Mitroulis I, Apostolidou E , et al. Autophagy mediates the delivery of thrombogenic tissue factor to neutrophil extracellular traps in human sepsis. PLoS ONE 2012; 7 (9) e45427
- 35 Brandau S, Dumitru CA, Lang S. Protumor and antitumor functions of neutrophil granulocytes. Semin Immunopathol 2013; 35 (2) 163-176
- 36 Gregory AD, Houghton AM. Tumor-associated neutrophils: new targets for cancer therapy. Cancer Res 2011; 71 (7) 2411-2416
- 37 Demers M, Wagner DD. Neutrophil extracellular traps: A new link to cancer-associated thrombosis and potential implications for tumor progression. OncoImmunology 2013; 2 (2) e22946
- 38 Ho-Tin-Noé B, Carbo C, Demers M, Cifuni SM, Goerge T, Wagner DD. Innate immune cells induce hemorrhage in tumors during thrombocytopenia. Am J Pathol 2009; 175 (4) 1699-1708
- 39 Berger-Achituv S, Brinkmann V, Abed UA , et al. A proposed role for neutrophil extracellular traps in cancer immunoediting. Front Immunol 2013; 4: 48
- 40 McInturff AM, Cody MJ, Elliott EA , et al. Mammalian target of rapamycin regulates neutrophil extracellular trap formation via induction of hypoxia-inducible factor 1 α. Blood 2012; 120 (15) 3118-3125
- 41 Mishalian I, Bayuh R, Levy L, Zolotarov L, Michaeli J, Fridlender ZG. Tumor-associated neutrophils (TAN) develop pro-tumorigenic properties during tumor progression. Cancer Immunol Immunother 2013; 62 (11) 1745-1756
- 42 Cools-Lartigue J, Spicer J, McDonald B , et al. Neutrophil extracellular traps sequester circulating tumor cells and promote metastasis. J Clin Invest 2013;
- 43 Clark SR, Ma AC, Tavener SA , et al. Platelet TLR4 activates neutrophil extracellular traps to ensnare bacteria in septic blood. Nat Med 2007; 13 (4) 463-469
- 44 McDonald B, Urrutia R, Yipp BG, Jenne CN, Kubes P. Intravascular neutrophil extracellular traps capture bacteria from the bloodstream during sepsis. Cell Host Microbe 2012; 12 (3) 324-333
- 45 Green D, Karpatkin S. Role of thrombin as a tumor growth factor. Cell Cycle 2010; 9 (4) 656-661
- 46 Hu L, Ibrahim S, Liu C, Skaar J, Pagano M, Karpatkin S. Thrombin induces tumor cell cycle activation and spontaneous growth by down-regulation of p27Kip1, in association with the up-regulation of Skp2 and MiR-222. Cancer Res 2009; 69 (8) 3374-3381
- 47 Hu L, Lee M, Campbell W, Perez-Soler R, Karpatkin S. Role of endogenous thrombin in tumor implantation, seeding, and spontaneous metastasis. Blood 2004; 104 (9) 2746-2751
- 48 Hu L, Roth JM, Brooks P, Ibrahim S, Karpatkin S. Twist is required for thrombin-induced tumor angiogenesis and growth. Cancer Res 2008; 68 (11) 4296-4302
- 49 Hu L, Roth JM, Brooks P, Luty J, Karpatkin S. Thrombin up-regulates cathepsin D which enhances angiogenesis, growth, and metastasis. Cancer Res 2008; 68 (12) 4666-4673
- 50 Varki A. Trousseau's syndrome: multiple definitions and multiple mechanisms. Blood 2007; 110 (6) 1723-1729
- 51 Connolly GC, Khorana AA. Emerging risk stratification approaches to cancer-associated thrombosis: risk factors, biomarkers and a risk score. Thromb Res 2010; 125 (Suppl. 02) S1-S7
- 52 Connolly GC, Khorana AA, Kuderer NM, Culakova E, Francis CW, Lyman GH. Leukocytosis, thrombosis and early mortality in cancer patients initiating chemotherapy. Thromb Res 2010; 126 (2) 113-118
- 53 Shao B, Wahrenbrock MG, Yao L , et al. Carcinoma mucins trigger reciprocal activation of platelets and neutrophils in a murine model of Trousseau syndrome. Blood 2011; 118 (15) 4015-4023
- 54 Shoenfeld Y, Tal A, Berliner S, Pinkhas J. Leukocytosis in non hematological malignancies—a possible tumor-associated marker. J Cancer Res Clin Oncol 1986; 111 (1) 54-58
- 55 Donskov F. Immunomonitoring and prognostic relevance of neutrophils in clinical trials. Semin Cancer Biol 2013; 23 (3) 200-207
- 56 Paneesha S, McManus A, Arya R , et al; VERITY Investigators. Frequency, demographics and risk (according to tumour type or site) of cancer-associated thrombosis among patients seen at outpatient DVT clinics. Thromb Haemost 2010; 103 (2) 338-343
- 57 DuPre' SA, Hunter Jr KW. Murine mammary carcinoma 4T1 induces a leukemoid reaction with splenomegaly: association with tumor-derived growth factors. Exp Mol Pathol 2007; 82 (1) 12-24
- 58 Demers M, Krause DS, Schatzberg D , et al. Cancers predispose neutrophils to release extracellular DNA traps that contribute to cancer-associated thrombosis. Proc Natl Acad Sci U S A 2012; 109 (32) 13076-13081
- 59 Joshita S, Nakazawa K, Sugiyama Y , et al. Granulocyte-colony stimulating factor-producing pancreatic adenosquamous carcinoma showing aggressive clinical course. Intern Med 2009; 48 (9) 687-691
- 60 Kaira K, Ishizuka T, Tanaka H , et al. Lung cancer producing granulocyte colony-stimulating factor and rapid spreading to peritoneal cavity. J Thorac Oncol 2008; 3 (9) 1054-1055
- 61 Kawaguchi M, Asada Y, Terada T , et al. Aggressive recurrence of gastric cancer as a granulocyte-colony-stimulating factor-producing tumor. Int J Clin Oncol 2010; 15 (2) 191-195
- 62 Leon SA, Shapiro B, Sklaroff DM, Yaros MJ. Free DNA in the serum of cancer patients and the effect of therapy. Cancer Res 1977; 37 (3) 646-650
- 63 Fleischhacker M, Schmidt B. Circulating nucleic acids (CNAs) and cancer—a survey. Biochim Biophys Acta 2007; 1775 (1) 181-232
- 64 Jahr S, Hentze H, Englisch S , et al. DNA fragments in the blood plasma of cancer patients: quantitations and evidence for their origin from apoptotic and necrotic cells. Cancer Res 2001; 61 (4) 1659-1665
- 65 García-Olmo DC, Picazo MG, Toboso I, Asensio AI, García-Olmo D. Quantitation of cell-free DNA and RNA in plasma during tumor progression in rats. Mol Cancer 2013; 12: 8
- 66 García-Olmo DC, Samos J, Picazo MG, Asensio AI, Toboso I, García-Olmo D. Release of cell-free DNA into the bloodstream leads to high levels of non-tumor plasma DNA during tumor progression in rats. Cancer Lett 2008; 272 (1) 133-140
- 67 McMahon BJ, Kwaan HC. Thrombotic and bleeding complications associated with chemotherapy. Semin Thromb Hemost 2012; 38 (8) 808-817
- 68 Kwee S, Song MA, Cheng I, Loo L, Tiirikainen M. Measurement of circulating cell-free DNA in relation to 18F-fluorocholine PET/CT imaging in chemotherapy-treated advanced prostate cancer. Clin Transl Sci 2012; 5 (1) 65-70
- 69 Deligezer U, Eralp Y, Akisik EE , et al. Size distribution of circulating cell-free DNA in sera of breast cancer patients in the course of adjuvant chemotherapy. Clin Chem Lab Med 2008; 46 (3) 311-317
- 70 Van Den Berg YW, Reitsma PH. Not exclusively tissue factor: neutrophil extracellular traps provide another link between chemotherapy and thrombosis. J Thromb Haemost 2011; 9 (11) 2311-2312
- 71 Chang X, Han J. Expression of peptidylarginine deiminase type 4 (PAD4) in various tumors. Mol Carcinog 2006; 45 (3) 183-196
- 72 Chang X, Han J, Pang L, Zhao Y, Yang Y, Shen Z. Increased PADI4 expression in blood and tissues of patients with malignant tumors. BMC Cancer 2009; 9: 40
- 73 Li P, Yao H, Zhang Z , et al. Regulation of p53 target gene expression by peptidylarginine deiminase 4. Mol Cell Biol 2008; 28 (15) 4745-4758
- 74 Luo Y, Knuckley B, Lee YH, Stallcup MR, Thompson PR. A fluoroacetamidine-based inactivator of protein arginine deiminase 4: design, synthesis, and in vitro and in vivo evaluation. J Am Chem Soc 2006; 128 (4) 1092-1093
- 75 Jones JE, Slack JL, Fang P , et al. Synthesis and screening of a haloacetamidine containing library to identify PAD4 selective inhibitors. ACS Chem Biol 2012; 7 (1) 160-165
- 76 Li P, Wang D, Yao H , et al. Coordination of PAD4 and HDAC2 in the regulation of p53-target gene expression. Oncogene 2010; 29 (21) 3153-3162
- 77 Wang Y, Li P, Wang S , et al. Anticancer peptidylarginine deiminase (PAD) inhibitors regulate the autophagy flux and the mammalian target of rapamycin complex 1 activity. J Biol Chem 2012; 287 (31) 25941-25953