Obstetrics, Gynecology and Reproduction

Advanced search

NETs and oncologic process

Full Text:


Neutrophil Extracellular Traps (NETs) represent the networks consisting of DNA, histones, and proteins produced by activated neutrophils. Such structures have been proved to play a crucial role in inducing neutrophil innate immune response in the pathogenesis of such autoimmune conditions as systemic lupus erythematosus, rheumatoid arthritis, psoriasis, as well as in the pathogenesis of other non-infectious processes, e. g., clotting disorders, thrombosis, diabetes, atherosclerosis, vasculitis and oncology diseases. Recent studies on animal models and human pathologies have uncovered a tremendous role for NETs in tumor progression and metastasis. In this regard, NETs should be considered as pro-oncogenic substances, which further investigation will provide an opportunity to develop new therapeutic strategies.

About the Author

E. V. Slukhanchuk
Petrovsky National Research Centre of Surgery
Russian Federation

Ekaterina V. Slukhanchuk - MD, PhD, Head of Department of Gynecology, Petrovsky National Research Centre of Surgery.
2 Abrikosovskiy Lane, Moscow 119991.


1. Zamarron B.F., Chen W. Dual roles of immune cells and their factors in cancer development and progression. Int J Biol Sci. 2011;7(5):651—8.

2. Dunn G.P., Old L.J., Schreiber R.D. The immunobiology of cancer immunosurveillance and immunoediting. Immunity. 2004;21(2):137-48.

3. Smyth M.J., Dunn G.P., Schreiber R.D. Cancer immunosurveillance and immunoediting: the roles of immunity in suppressing tumor development and shaping tumor immunogenicity. Adv Immunol. 2006;90:1-50.

4. Schreiber R.D., Old L.J., Smyth M.J.. Cancer immunoediting: integrating immunity's roles in cancer suppression and promotion. Science. 2011;331(6024):1565-70.

5. Dunn G.P., Old L.J., Schreiber R.D. The three Es of cancer immunoediting. Annu Rev Immunol. 2004;22:329-60.

6. Whiteside T. The tumor microenvironment and its role in promoting tumor growth. Oncogene. 2008;27(45):5904-12.

7. Szala S. Angiogenesis and immune suppression: yin and yang of tumor progression? Postepy Hig Med Dosw (Online). 2009;63:598-612. [Article in Polish].

8. Garley M., Jabtonska E., D^browska D. NETs in cancer. Tumor Biol. 2016;37(11):14355-61.

9. Granot Z., Jablonska J. Distinct functions of neutrophil in cancer and its regulation. Mediators Inflamm. 2015;2015:701067.

10. Fridlender Z.G., Albelda S.M. Tumor-associated neutrophils: friend or foe? Carcinogenesis. 2012;33(5):949-55.

11. Li L., Neaves W.B. Normal stem cells and cancer stem cells: the niche matters. Cancer Res. 2006;66(9):4553-7.

12. Wels J., Kaplan R.N., Rafii S., Lyden D. Migratory neighbors and distant invaders: tumor-associated niche cells. Genes Dev. 2008;22(5):559-74.

13. Kim J., Bae J.-S. Tumor-associated macrophages and neutrophils in tumor microenvironment. Mediators Inflamm. 2016;2016:6058147.

14. Fridlender Z.G., Sun J., Kim S. et al. Polarization of tumor-associated neutrophil phenotype by TGF-e:“II1” versus “II2” TAII. Cancer Cell. 2009;16(3):183-94.

15. Mittendorf ЕА, Alatrash G., Qiao II. et al. Breast cancer cell uptake of the inflammatory mediator neutrophil elastase triggers an anticancer adaptive immune response. Cancer Res. 2012;72(13):3153-62.

16. Brinkmann V., Reichard U., Goosmann C. et al. Ieutrophil extracellular traps kill bacteria. Science. 2004;303(5663):1532-5.

17. Papayannopoulos V. Ieutrophil extracellular traps in immunity and disease. Nat Rev Immunol. 2018;18(2):134-147.

18. Е^ЗИв^™ Е.М., Shoeib S.A., Elghotmy A.H. Jeutrophil extracellular traps in systemic lupus erythematosus. Menoufia Med J. 2020;33(3):729-32.

19. Manneras-Holm L., Baghaei F., Holm G. et al. Coagulation and fibrinolytic disturbances in women with polycystic ovary syndrome. J Clin Endocrinol Metab. 2011;96(4):1068-76.

20. Gray R.D., Hardisty G., Regan K.H. et al. Delayed neutrophil apoptosis enhances I^T formation in cystic fibrosis. Thorax. 2018;73(2):134-44.

21. Fuchs T.A., Brill A., Duerschmied D. et al. Extracellular DIIA traps promote thrombosis. Proc Natl Acad Sci U S A. 2010;107(36):15880-5.

22. Wang L., Zhou X., Yin Y. et al. Hyperglycemia induces neutrophil extracellular traps formation through an IADPH oxidase-dependent pathway in diabetic retinopathy. Front Immunol. 2019;9:3076.

23. Warnatsch A., Ioannou M., Wang Q., Papayannopoulos V. Ieutrophil extracellular traps license macrophages for cytokine production in atherosclerosis. Science. 2015;349(6245):316-20.

24. Grayson P.C., Kaplan M.J. At the bench: neutrophil extracellular traps (I^Ts) highlight novel aspects of innate immune system involvement in autoimmune diseases. J Leukoc Biol. 2016;99(2):253-64.

25. Lin A.M., Rubin C.J., Khandpur R. et al. Mast cells and neutrophils release IL-17 through extracellular trap formation in psoriasis. J Immunol. 2011;187(1):490-500.

26. Demers M., Krause D.S., Schatzberg D. et al. Cancers predispose neutrophils to release extracellular DIA traps that contribute to cancer-associated thrombosis. Proc Natl Acad Sci U S A. 2012;109(32):13076-81.

27. Gupta A.K., Joshi M.B., Philippova M. et al. Activated endothelial cells induce neutrophil extracellular traps and are susceptible to I^Tosis-mediated cell death. FEBS Lett. 2010;584(14):3193-7.

28. Chen K.W., Monteleone M., Boucher D. et al. Ioncanonical inflammasome signaling elicits gasdermin D-dependent neutrophil extracellular traps. Sci Immunol. 2018;3(26):eaar6676.

29. Pertiwi K.R., de Boer O.J., Mackaaij C. et al. Extracellular traps derived from macrophages, mast cells, eosinophils and neutrophils are generated in a time-dependent manner during atherothrombosis. J Pathol. 2019;247(4):505-12.

30. Mantovani A., Allavena P., Sica A., Balkwill F. Cancer-related inflammation. Nature. 2008;454(7203):436-44.

31. Cedervall J., Zhang Y., Huang H. et al. Ieutrophil extracellular traps accumulate in peripheral blood vessels and compromise organ function in tumor-bearing animals. Cancer Res. 2015;75(13):2653-62.

32. Berger-Achituv S., Brinkmann V., Abu-Abed U. et al. A proposed role for neutrophil extracellular traps in cancer immunoediting. Front Immunol. 2013;4:48.

33. Oklu R., Sheth R.A., Wong K.H. et al. Ieutrophil extracellular traps are increased in cancer patients but does not associate with venous thrombosis. Cardiovasc Diagn Ther. 2017;7(Suppl 3):S140-9.

34. Li Y., Yang Y., Gan T. et al. Extracellular RIIAs from lung cancer cells activate epithelial cells and induce neutrophil extracellular traps. Int J Ooncol. 2019;55(1):69-80.

35. Metzler K.D., Fuchs T.A., Iauseef W.M. et al. Myeloperoxidase is required for neutrophil extracellular trap formation: implications for innate immunity. Blood. 2011;117(3):953-9.

36. Al-Benna S., Shai Y., Jacobsen .F, Steinstraesser L. Oncolytic activities of host defense peptides. Int J Mol Sci. 2011;12(11):8027-51.

37. Acuff H.B., Carter K.J., Fingleton B. et al. Matrix metalloproteinase-9 from bone marrow-derived cells contributes to survival but not growth of tumor cells in the lung microenvironment. Cancer Res. 2006;66(1):259-66.

38. Masson V., De La Ballina L.R., Munaut C. et al. Contribution of host MMP-2 and MMP-9 to promote tumor vascularization and invasion of malignant keratinocytes. FASEB J. 2005;19(2):234-6.

39. Pahler J.C., Tazzyman S., Erez II. et al. Plasticity in tumor-promoting inflammation: impairment of macrophage recruitment evokes a compensatory neutrophil response. Neoplasia. 2008;10(4):329-40.

40. Cools-Lartigue J., Spicer J., McDonald B. et al. Ieutrophil extracellular traps sequester circulating tumor cells and promote metastasis. J Clin Invest. 2013;123(8):3446-58.

41. Iajmeh S., Cools-Lartigue J., Rayes R.F. et al. Ieutrophil extracellular traps sequester circulating tumor cells via в 1-integrin mediated interactions. Int J Cancer. 2017;140(10):2321-30.

42. Monti M., De Rosa V., Iommelli F. et al. Ieutrophil extracellular traps as an adhesion substrate for different tumor cells expressing RGD-binding integrins. Int J Mol Sci. 2018;19(8):2350.

43. Yazdani H.O., Roy Е., Comerci A.J. et al. Ieutrophil extracellular traps drive mitochondrial homeostasis in tumors to augment growth. Cancer Res. 2019;79(21):5626-39.

44. Albrengues J., Shields M.A., Ig D. et al. Ieutrophil extracellular traps produced during inflammation awaken dormant cancer cells in mice. Science. 2018;361(6409):eaao4227.

45. Demers M., Wagner D.D. Ieutrophil extracellular traps: A new link to cancer-associated thrombosis and potential implications for tumor progression. Oncoimmunology. 2013;2(2):e22946.

46. Gregory A.D., Houghton A.M. Tumor-associated neutrophils: new targets for cancer therapy. Cancer Res. 2011;71(7):2411-6.

47. Park J., Wysocki R.W., Amoozgar Z. et al. Cancer cells induce metastasissupporting neutrophil extracellular DIA traps. Sci Transl Med. 2016;8(361):361ra138.

48. Thalin C., Lundstrom S., Seignez C. et al. Citrullinated histone H3 as a novel prognostic blood marker in patients with advanced cancer. PLoS One. 2018;13(1):e0191231.

49. Hawes M.C., Wen F., Е^^э Е. Extracellular DIIA: a bridge to cancer. Cancer Res. 2015;75(20):4260-4.

50. Lazarus R.A., Wagener J.S. Recombinant human deoxyribonuclease I. In: Pharmaceutical Biotechnology. Eds. D. Crommelin, R. Sindelar, B. Meibohm. Springer: New York, 2019. 471-88.

51. Lewis H.D., Liddle J., Coote Jf. et al. Inhibition of PAD4 activity is sufficient to disrupt mouse and human I^T formation. Nat Chem Biol. 2015;11(3):189-91.

52. Domingo-Gonzalez R., Martinez-Colon G.J., Smith A.J. et al. Inhibition of neutrophil extracellular trap formation after stem cell transplant by prostaglandin Е2. Am J Respir Crit Care Med. 2016;193(2):186-97.

53. Mohammed B.M., Fisher B.J., Kraskauskas D. et al. Vitamin C: a novel regulator of neutrophil extracellular trap formation. Nutrients. 2013;5(8):3131-51.

54. Shishikura K., Horiuchi T., Sakata I. et al. Prostaglandin Е2 inhibits neutrophil extracellular trap formation through production of cyclic AMP. Br J Pharmacol. 2016;173(2):319-31.

55. Jung H.S., Gu J., Kim J.-Е. et al. Cancer cell-induced neutrophil extracellular traps promote both hypercoagulability and cancer progression. PloS One. 2019;14(4):e0216055.

56. Liu K., Sun E., Lei M. et al. BCG-induced formation of neutrophil extracellular traps play an important role in bladder cancer treatment. Clin Immunol. 2019;201:4-14.

57. Li R.H., Tablin F. A comparative review of neutrophil extracellular traps in sepsis. Front Vet Sci. 2018;5:291.

58. Russell C.D., Millar J.E., Baillie J.K. Clinical evidence does not support corticosteroid treatment for 2019-nCoV lung injury. Lancet. 2020;395(10223):473-5.

59. Traylor Z.P., Aeffner F., Davis I.C. Influenza A H1N1 induces declines in alveolar gas exchange in mice consistent with rapid post-infection progression from acute lung injury to ARDS. Influenza Other Respir Viruses. 2013;7(3):472-9.

60. Huang C., Wang Y., Li X. et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395(10223):497-506.

61. Organization W.H. Clinical management of severe acute respiratory infection when novel coronavirus (2019-nCoV) infection is suspected: interim guidance, 28 January 2020. World Health Organization, 2020. 11 p. Available at:

For citation:

Slukhanchuk E.V. NETs and oncologic process. Obstetrics, Gynecology and Reproduction. 2021;15(1):107-116. (In Russ.)

Views: 49

ISSN 2313-7347 (Print)
ISSN 2500-3194 (Online)