Neutrophils and granulocytic MDSC: The Janus god of cancer immunotherapy

Vaccines

Volumn 4, Issue 3, 2016, Pages

  Zilio, Serena ^a   Serafini, Paolo ^a  

^a UNIVERSITY OF MIAMI MILLER SCHOOL OF MEDICINE   (United States)

Author keywords

Cancer; gMDSC; Immunotherapy; Neutrophils; Sex

Indexed keywords

CHEMOKINE; CHEMOKINE RECEPTOR; CHEMOTACTIC FACTOR; CYTOKINE; GROWTH FACTOR; INTERFERON; LEUKOCYTE ELASTASE; METALLOPROTEINASE;

ANGIOGENESIS; ANTIBODY DEPENDENT CELLULAR CYTOTOXICITY; ANTINEOPLASTIC ACTIVITY; CANCER IMMUNOTHERAPY; CANCER PROGNOSIS; CANCER SURVIVAL; EPITHELIAL MESENCHYMAL TRANSITION; HUMAN; IMMUNE RESPONSE; IMMUNOMODULATION; IMMUNOPHENOTYPING; LEUKOCYTE ACTIVATION; METASTASIS; NEUTROPHIL; NEUTROPHIL CHEMOTAXIS; NONHUMAN; OVERALL SURVIVAL; POLYMORPHONUCLEAR CELL; PROTEIN EXPRESSION; REVIEW; SEX DIFFERENCE; SUPPRESSOR CELL; TUMOR ASSOCIATED LEUKOCYTE; TUMOR GROWTH; TUMOR IMMUNITY; TUMOR INVASION; TUMOR MICROENVIRONMENT;

EID: 85016848075     PISSN: None     EISSN: 2076393X     Source Type: Journal    
DOI: 10.3390/vaccines4030031     Document Type: Review

References (156)

1. Ehrlich, P. Ueber Die Specifischen Granulationen des Blutes. Available online: http://www.pei.de/EN/institute/paul-ehrlich/publications/publications-of-paul-ehrlich-node.html (accessed on 2 September 2016). (In German).
2. Lectures on the Comparative Pathology of Inflammation (Kegan Paul, London GB, 1893). Available online: https://archive.org/details/lecturesoncompar00metcuoft (accessed on 2 September 2016).
3. McCracken, J.M.; Allen, L.A. Regulation of human neutrophil apoptosis and lifespan in health and disease. J. Cell Death 2014, 7, 15–23. [PubMed]
4. Coffelt, S.B.; Wellenstein, M.D.; de Visser, K.E. Neutrophils in cancer: Neutral no more. Nat. Rev. Cancer 2016, 16, 431–446. [CrossRef] [PubMed]
5. Koffel, R.; Meshcheryakova, A.; Warszawska, J.; Hennig, A.; Wagner, K.; Jorgl, A.; Gubi, D.; Moser, D.; Hladik, A.; Hoffmann, U.; et al. Monocytic cell differentiation from band-stage neutrophils under inflammatory conditions via MKK6 activation. Blood 2014, 124, 2713–2724. [CrossRef] [PubMed]
6. Youn, J.I.; Kumar, V.; Collazo, M.; Nefedova, Y.; Condamine, T.; Cheng, P.; Villagra, A.; Antonia, S.; McCaffrey, J.C.; Fishman, M.; et al. Epigenetic silencing of retinoblastoma gene regulates pathologic differentiation of myeloid cells in cancer. Nat. Immunol. 2013, 14, 211–220. [CrossRef] [PubMed]
7. Mayer-Scholl, A.; Averhoff, P.; Zychlinsky, A. How do neutrophils and pathogens interact? Curr. Opin. Microbiol. 2004, 7, 62–66. [CrossRef] [PubMed]
8. Beyrau, M.; Bodkin, J.V.; Nourshargh, S. Neutrophil heterogeneity in health and disease: A revitalized avenue in inflammation and immunity. Open Biol. 2012. [CrossRef] [PubMed]
9. Sangaletti, S.; Tripodo, C.; Chiodoni, C.; Guarnotta, C.; Cappetti, B.; Casalini, P.; Piconese, S.; Parenza, M.; Guiducci, C.; Vitali, C.; et al. Neutrophil extracellular traps mediate transfer of cytoplasmic neutrophil antigens to myeloid dendritic cells toward anca induction and associated autoimmunity. Blood 2012, 120, 3007–3018. [CrossRef] [PubMed]
10. Kaplan, M.J. Neutrophils in the pathogenesis and manifestations of sle. Nat. Rev. Rheumatol. 2011, 7, 691–699. [CrossRef] [PubMed]
11. Talukdar, S.; Oh, D.Y.; Bandyopadhyay, G.; Li, D.; Xu, J.; McNelis, J.; Lu, M.; Li, P.; Yan, Q.; Zhu, Y.; et al. Neutrophils mediate insulin resistance in mice fed a high-fat diet through secreted elastase. Nat. Med. 2012, 18, 1407–1412. [CrossRef] [PubMed]
12. Wong, S.L.; Demers, M.; Martinod, K.; Gallant, M.; Wang, Y.; Goldfine, A.B.; Kahn, C.R.; Wagner, D.D. Diabetes primes neutrophils to undergo netosis, which impairs wound healing. Nat. Med. 2015, 21, 815–819. [CrossRef] [PubMed]
13. Chtanova, T.; Schaeffer, M.; Han, S.J.; van Dooren, G.G.; Nollmann, M.; Herzmark, P.; Chan, S.W.; Satija, H.; Camfield, K.; Aaron, H.; et al. Dynamics of neutrophil migration in lymph nodes during infection. Immunity 2008, 29, 487–496. [CrossRef] [PubMed]
14. Singhal, S.; Bhojnagarwala, P.S.; O’Brien, S.; Moon, E.K.; Garfall, A.L.; Rao, A.S.; Quatromoni, J.G.; Stephen, T.L.; Litzky, L.; Deshpande, C.; et al. Origin and role of a subset of tumor-associated neutrophils with antigen-presenting cell features in early-stage human lung cancer. Cancer Cell 2016. [CrossRef] [PubMed]
15. Buckley, C.D.; Ross, E.A.; McGettrick, H.M.; Osborne, C.E.; Haworth, O.; Schmutz, C.; Stone, P.C.; Salmon, M.; Matharu, N.M.; Vohra, R.K.; et al. Identification of a phenotypically and functionally distinct population of long-lived neutrophils in a model of reverse endothelial migration. J. Leukoc. Biol. 2006, 79, 303–311. [CrossRef] [PubMed]
16. Mathias, J.R.; Perrin, B.J.; Liu, T.X.; Kanki, J.; Look, A.T.; Huttenlocher, A. Resolution of inflammation by retrograde chemotaxis of neutrophils in transgenic zebrafish. J. Leukoc. Biol. 2006, 80, 1281–1288. [CrossRef] [PubMed]
17. Woodfin, A.; Voisin, M.B.; Beyrau, M.; Colom, B.; Caille, D.; Diapouli, F.M.; Nash, G.B.; Chavakis, T.; Albelda, S.M.; Rainger, G.E.; et al. The junctional adhesion molecule JAM-c regulates polarized transendothelial migration of neutrophils in vivo. Nat. Immunol. 2011, 12, 761–769. [CrossRef] [PubMed]
18. Sweet, R.D. An acute febrile neutrophilic dermatosis. Br. J. Dermatol. 1964, 76, 349–356. [CrossRef] [PubMed]
19. Shapiro, L.; Baraf, C.S.; Richheimer, L.L. Sweet’s syndrome (acute febrile neutrophilic dermatosis). Report of a case. Arch. Dermatol. 1971, 103, 81–84. [CrossRef] [PubMed]
20. Costello, M.J.; Canizares, O.; Montague, M.; Buncke, C.M. Cutaneous manifestations of myelogenous leukemia. AMA Arch. Dermatol. 1955, 71, 605–614. [CrossRef]
21. 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, 54–58. [CrossRef] [PubMed]
22. Jensen, H.K.; Donskov, F.; Marcussen, N.; Nordsmark, M.; Lundbeck, F.; von der Maase, H. Presence of intratumoral neutrophils is an independent prognostic factor in localized renal cell carcinoma. J. Clin. Oncol. 2009, 27, 4709–4717. [CrossRef] [PubMed]
23. Donskov, F.; Hokland, M.; Marcussen, N.; Torp Madsen, H.H.; von der Maase, H. Monocytes and neutrophils as “bad guys” for the outcome of interleukin-2 with and without histamine in metastatic renal cell carcinoma—Results from a randomised phase ii trial. Br. J. Cancer 2006, 94, 218–226. [CrossRef] [PubMed]
24. Trellakis, S.; Farjah, H.; Bruderek, K.; Dumitru, C.A.; Hoffmann, T.K.; Lang, S.; Brandau, S. Peripheral blood neutrophil granulocytes from patients with head and neck squamous cell carcinoma functionally differ from their counterparts in healthy donors. Int. J. Immunopathol. Pharmacol. 2011, 24, 683–693. [PubMed]
25. Kuang, D.M.; Zhao, Q.; Wu, Y.; Peng, C.; Wang, J.; Xu, Z.; Yin, X.Y.; Zheng, L. Peritumoral neutrophils link inflammatory response to disease progression by fostering angiogenesis in hepatocellular carcinoma. J. Hepatol. 2011, 54, 948–955. [CrossRef] [PubMed]
26. Jensen, T.O.; Schmidt, H.; Moller, H.J.; Donskov, F.; Hoyer, M.; Sjoegren, P.; Christensen, I.J.; Steiniche, T. Intratumoral neutrophils and plasmacytoid dendritic cells indicate poor prognosis and are associated with pstat3 expression in AJCC stage I/II melanoma. Cancer 2012, 118, 2476–2485. [CrossRef] [PubMed]
27. Zhao, J.J.; Pan, K.; Wang, W.; Chen, J.G.; Wu, Y.H.; Lv, L.; Li, J.J.; Chen, Y.B.; Wang, D.D.; Pan, Q.Z.; et al. The prognostic value of tumor-infiltrating neutrophils in gastric adenocarcinoma after resection. PLoS ONE 2012, 7, e33655. [CrossRef] [PubMed]
28. Rao, H.L.; Chen, J.W.; Li, M.; Xiao, Y.B.; Fu, J.; Zeng, Y.X.; Cai, M.Y.; Xie, D. Increased intratumoral neutrophil in colorectal carcinomas correlates closely with malignant phenotype and predicts patients' adverse prognosis. PLoS ONE 2012, 7, e30806. [CrossRef] [PubMed]
29. Reid, M.D.; Basturk, O.; Thirabanjasak, D.; Hruban, R.H.; Klimstra, D.S.; Bagci, P.; Altinel, D.; Adsay, V. Tumor-infiltrating neutrophils in pancreatic neoplasia. Mod. Pathol. 2011, 24, 1612–1619. [CrossRef] [PubMed]
30. Carus, A.; Ladekarl, M.; Hager, H.; Pilegaard, H.; Nielsen, P.S.; Donskov, F. Tumor-associated neutrophils and macrophages in non-small cell lung cancer: No immediate impact on patient outcome. Lung Cancer 2013, 81, 130–137. [CrossRef] [PubMed]
31. Ilie, M.; Hofman, V.; Ortholan, C.; Bonnetaud, C.; Coelle, C.; Mouroux, J.; Hofman, P. Predictive clinical outcome of the intratumoral CD66B-positive neutrophil-to-CD8-positive t-cell ratio in patients with resectable nonsmall cell lung cancer. Cancer 2012, 118, 1726–1737. [CrossRef] [PubMed]
32. Eruslanov, E.B.; Bhojnagarwala, P.S.; Quatromoni, J.G.; Stephen, T.L.; Ranganathan, A.; Deshpande, C.; Akimova, T.; Vachani, A.; Litzky, L.; Hancock, W.W.; et al. Tumor-associated neutrophils stimulate t cell responses in early-stage human lung cancer. J. Clin. Investig. 2014, 124, 5466–5480. [CrossRef] [PubMed]
33. Liu, C.Y.; Wang, Y.M.; Wang, C.L.; Feng, P.H.; Ko, H.W.; Liu, Y.H.; Wu, Y.C.; Chu, Y.; Chung, F.T.; Kuo, C.H.; et al. Population alterations of L-arginase- and inducible nitric oxide synthase-expressed CD11B+/CD14(-)/CD15+/CD33+ myeloid-derived suppressor cells and CD8+ T lymphocytes in patients with advanced-stage non-small cell lung cancer. J. Cancer Res. Clin. Oncol. 2010, 136, 35–45. [CrossRef] [PubMed]
34. Halazun, K.J.; Hardy, M.A.; Rana, A.A.; Woodland, D.C.T.; Luyten, E.J.; Mahadev, S.; Witkowski, P.; Siegel, A.B.; Brown, R.S., Jr.; Emond, J.C. Negative impact of neutrophil-lymphocyte ratio on outcome after liver transplantation for hepatocellular carcinoma. Ann. Surg. 2009, 250, 141–151. [CrossRef] [PubMed]
35. Li, Y.W.; Qiu, S.J.; Fan, J.; Zhou, J.; Gao, Q.; Xiao, Y.S.; Xu, Y.F. Intratumoral neutrophils: A poor prognostic factor for hepatocellular carcinoma following resection. J. Hepatol. 2011, 54, 497–505. [CrossRef] [PubMed]
36. Ohno, Y.; Nakashima, J.; Ohori, M.; Hatano, T.; Tachibana, M. Pretreatment neutrophil-to-lymphocyte ratio as an independent predictor of recurrence in patients with nonmetastatic renal cell carcinoma. J. Urol. 2010, 184, 873–878. [CrossRef] [PubMed]
37. Cho, H.; Hur, H.W.; Kim, S.W.; Kim, S.H.; Kim, J.H.; Kim, Y.T.; Lee, K. Pre-treatment neutrophil to lymphocyte ratio is elevated in epithelial ovarian cancer and predicts survival after treatment. Cancer Immunol. Immunother. 2009, 58, 15–23. [CrossRef] [PubMed]
38. Halazun, K.J.; Aldoori, A.; Malik, H.Z.; Al-Mukhtar, A.; Prasad, K.R.; Toogood, G.J.; Lodge, J.P. Elevated preoperative neutrophil to lymphocyte ratio predicts survival following hepatic resection for colorectal liver metastases. Eur. J. Surg. Oncol. 2008, 34, 55–60. [CrossRef] [PubMed]
39. Jung, M.R.; Park, Y.K.; Jeong, O.; Seon, J.W.; Ryu, S.Y.; Kim, D.Y.; Kim, Y.J. Elevated preoperative neutrophil to lymphocyte ratio predicts poor survival following resection in late stage gastric cancer. J. Surg. Oncol. 2011, 104, 504–510. [CrossRef] [PubMed]
40. Shimada, H.; Takiguchi, N.; Kainuma, O.; Soda, H.; Ikeda, A.; Cho, A.; Miyazaki, A.; Gunji, H.; Yamamoto, H.; Nagata, M. High preoperative neutrophil-lymphocyte ratio predicts poor survival in patients with gastric cancer. Gastric Cancer 2010, 13, 170–176. [CrossRef] [PubMed]
41. Khaled, Y.S.; Ammori, B.J.; Elkord, E. Increased levels of granulocytic myeloid-derived suppressor cells in peripheral blood and tumour tissue of pancreatic cancer patients. J. Immunol. Res. 2014. [CrossRef] [PubMed]
42. An, X.; Ding, P.R.; Wang, F.H.; Jiang, W.Q.; Li, Y.H. Elevated neutrophil to lymphocyte ratio predicts poor prognosis in nasopharyngeal carcinoma. Tumour Biol. 2011, 32, 317–324. [CrossRef] [PubMed]
43. Azab, B.; Bhatt, V.R.; Phookan, J.; Murukutla, S.; Kohn, N.; Terjanian, T.; Widmann, W.D. Usefulness of the neutrophil-to-lymphocyte ratio in predicting short- and long-term mortality in breast cancer patients. Ann. Surg. Oncol. 2012, 19, 217–224. [CrossRef] [PubMed]
44. Noh, H.; Eomm, M.; Han, A. Usefulness of pretreatment neutrophil to lymphocyte ratio in predicting disease-specific survival in breast cancer patients. J. Breast Cancer 2013, 16, 55–59. [CrossRef] [PubMed]
45. Chen, J.; Deng, Q.; Pan, Y.; He, B.; Ying, H.; Sun, H.; Liu, X.; Wang, S. Prognostic value of neutrophil-to-lymphocyte ratio in breast cancer. FEBS Open Bio 2015, 5, 502–507. [CrossRef] [PubMed]
46. Caruso, R.A.; Bellocco, R.; Pagano, M.; Bertoli, G.; Rigoli, L.; Inferrera, C. Prognostic value of intratumoral neutrophils in advanced gastric carcinoma in a high-risk area in northern italy. Mod. Pathol. 2002, 15, 831–837. [CrossRef] [PubMed]
47. Sconocchia, G.; Zlobec, I.; Lugli, A.; Calabrese, D.; Iezzi, G.; Karamitopoulou, E.; Patsouris, E.S.; Peros, G.; Horcic, M.; Tornillo, L.; et al. Tumor infiltration by fcgammariii (CD16)+ myeloid cells is associated with improved survival in patients with colorectal carcinoma. Int. J. Cancer 2011, 128, 2663–2672. [CrossRef] [PubMed]
48. Droeser, R.A.; Hirt, C.; Eppenberger-Castori, S.; Zlobec, I.; Viehl, C.T.; Frey, D.M.; Nebiker, C.A.; Rosso, R.; Zuber, M.; Amicarella, F.; et al. High myeloperoxidase positive cell infiltration in colorectal cancer is an independent favorable prognostic factor. PLoS ONE 2013, 8, e64814. [CrossRef] [PubMed]
49. Stockmeyer, B.; Beyer, T.; Neuhuber, W.; Repp, R.; Kalden, J.R.; Valerius, T.; Herrmann, M. Polymorphonuclear granulocytes induce antibody-dependent apoptosis in human breast cancer cells. J. Immunol. 2003, 171, 5124–5129. [CrossRef] [PubMed]
50. Albanesi, M.; Mancardi, D.A.; Jonsson, F.; Iannascoli, B.; Fiette, L.; Di Santo, J.P.; Lowell, C.A.; Bruhns, P. Neutrophils mediate antibody-induced antitumor effects in mice. Blood 2013, 122, 3160–3164. [CrossRef] [PubMed]
51. Niitsu, N.; Khori, M.; Hayama, M.; Kajiwara, K.; Higashihara, M.; Tamaru, J. Phase i/ii study of the rituximab-epoct regimen in combination with granulocyte colony-stimulating factor in patients with relapsed or refractory follicular lymphoma including evaluation of its cardiotoxicity using b-type natriuretic peptide and troponin t levels. Clin. Cancer Res. 2005, 11, 697–702. [PubMed]
52. Hernandez-Ilizaliturri, F.J.; Jupudy, V.; Ostberg, J.; Oflazoglu, E.; Huberman, A.; Repasky, E.; Czuczman, M.S. Neutrophils contribute to the biological antitumor activity of rituximab in a non-hodgkin’s lymphoma severe combined immunodeficiency mouse model. Clin. Cancer Res. 2003, 9, 5866–5873. [PubMed]
53. Demers, M.; Krause, D.S.; Schatzberg, D.; Martinod, K.; Voorhees, J.R.; Fuchs, T.A.; Scadden, D.T.; Wagner, D.D. Cancers predispose neutrophils to release extracellular DNA traps that contribute to cancer-associated thrombosis. Proc. Natl. Acad. Sci. USA 2012, 109, 13076–13081. [CrossRef] [PubMed]
54. Martinod, K.; Wagner, D.D. Thrombosis: Tangled up in nets. Blood 2014, 123, 2768–2776. [CrossRef] [PubMed]
55. Cools-Lartigue, J.; Spicer, J.; McDonald, B.; Gowing, S.; Chow, S.; Giannias, B.; Bourdeau, F.; Kubes, P.; Ferri, L. Neutrophil extracellular traps sequester circulating tumor cells and promote metastasis. J. Clin. Investig. 2013. [CrossRef] [PubMed]
56. Rymaszewski, A.L.; Tate, E.; Yimbesalu, J.P.; Gelman, A.E.; Jarzembowski, J.A.; Zhang, H.; Pritchard, K.A., Jr.; Vikis, H.G. The role of neutrophil myeloperoxidase in models of lung tumor development. Cancers 2014, 6, 1111–1127. [CrossRef] [PubMed]
57. Serafini, P.; Borrello, I.; Bronte, V. Myeloid suppressor cells in cancer: Recruitment, phenotype, properties, and mechanisms of immune suppression. Semin. Cancer Biol. 2006, 16, 53–65. [CrossRef] [PubMed]
58. Marigo, I.; Dolcetti, L.; Serafini, P.; Zanovello, P.; Bronte, V. Tumor-induced tolerance and immune suppression by myeloid derived suppressor cells. Immunol. Rev. 2008, 222, 162–179. [CrossRef] [PubMed]
59. Gabrilovich, D.I.; Bronte, V.; Chen, S.H.; Colombo, M.P.; Ochoa, A.; Ostrand-Rosenberg, S.; Schreiber, H. The terminology issue for myeloid-derived suppressor cells. Cancer Res. 2007. [CrossRef] [PubMed]
60. Arina, A.; Bronte, V. Myeloid-derived suppressor cell impact on endogenous and adoptively transferred t cells. Curr. Opin. Immunol. 2015, 33, 120–125. [CrossRef] [PubMed]
61. Hoechst, B.; Voigtlaender, T.; Ormandy, L.; Gamrekelashvili, J.; Zhao, F.; Wedemeyer, H.; Lehner, F.; Manns, M.P.; Greten, T.F.; Korangy, F. Myeloid derived suppressor cells inhibit natural killer cells in patients with hepatocellular carcinoma via the NKP30 receptor. Hepatology 2009, 50, 799–807. [CrossRef] [PubMed]
62. Li, H.; Han, Y.; Guo, Q.; Zhang, M.; Cao, X. Cancer-expanded myeloid-derived suppressor cells induce anergy of NK cells through membrane-bound tgf-beta1. J. Immunol. 2009, 182, 240–249. [CrossRef] [PubMed]
63. Murdoch, C.; Muthana, M.; Coffelt, S.B.; Lewis, C.E. The role of myeloid cells in the promotion of tumour angiogenesis. Nat. Rev. Cancer 2008, 8, 618–631. [CrossRef] [PubMed]
64. Condamine, T.; Ramachandran, I.; Youn, J.I.; Gabrilovich, D.I. Regulation of tumor metastasis by myeloid-derived suppressor cells. Annu. Rev. Med. 2015, 66, 97–110. [CrossRef] [PubMed]
65. Connolly, M.K.; Mallen-St Clair, J.; Bedrosian, A.S.; Malhotra, A.; Vera, V.; Ibrahim, J.; Henning, J.; Pachter, H.L.; Bar-Sagi, D.; Frey, A.B.; et al. Distinct populations of metastases-enabling myeloid cells expand in the liver of mice harboring invasive and preinvasive intra-abdominal tumor. J. Leukoc. Biol. 2010, 87, 713–725. [CrossRef] [PubMed]
66. Acharyya, S.; Oskarsson, T.; Vanharanta, S.; Malladi, S.; Kim, J.; Morris, P.G.; Manova-Todorova, K.; Leversha, M.; Hogg, N.; Seshan, V.E.; et al. A CXCL1 paracrine network links cancer chemoresistance and metastasis. Cell 2012, 150, 165–178. [CrossRef] [PubMed]
67. Panni, R.Z.; Sanford, D.E.; Belt, B.A.; Mitchem, J.B.; Worley, L.A.; Goetz, B.D.; Mukherjee, P.; Wang-Gillam, A.; Link, D.C.; Denardo, D.G.; et al. Tumor-induced stat3 activation in monocytic myeloid-derived suppressor cells enhances stemness and mesenchymal properties in human pancreatic cancer. Cancer Immunol. Immunother. 2014, 63, 513–528. [CrossRef] [PubMed]
68. Jablonska, J.; Leschner, S.; Westphal, K.; Lienenklaus, S.; Weiss, S. Neutrophils responsive to endogenous IFN-beta regulate tumor angiogenesis and growth in a mouse tumor model. J. Clin. Investig. 2010, 120, 1151–1164. [CrossRef] [PubMed]
69. Liang, W.; Ferrara, N. The complex role of neutrophils in tumor angiogenesis andmetastasis. Cancer Immunol. Res. 2016, 4, 83–91. [CrossRef] [PubMed]
70. Delano, M.J.; Scumpia, P.O.; Weinstein, J.S.; Coco, D.; Nagaraj, S.; Kelly-Scumpia, K.M.; O’Malley, K.A.; Wynn, J.L.; Antonenko, S.; Al-Quran, S.Z.; et al. MYD88-dependent expansion of an immature gr-1(+)cd11b(+) population induces T cell suppression and TH2 polarization in sepsis. J. Exp. Med. 2007, 204, 1463–1474. [CrossRef] [PubMed]
71. Zhang, J.; Qiao, X.; Shi, H.; Han, X.; Liu, W.; Tian, X.; Zeng, X. Circulating tumor-associated neutrophils (CTAN) contribute to circulating tumor cell survival by suppressing peripheral leukocyte activation. Tumour Biol. 2015. [CrossRef] [PubMed]
72. Bekes, E.M.; Schweighofer, B.; Kupriyanova, T.A.; Zajac, E.; Ardi, V.C.; Quigley, J.P.; Deryugina, E.I. Tumor-recruited neutrophils and neutrophil timp-free MMP-9 regulate coordinately the levels of tumor angiogenesis and efficiency of malignant cell intravasation. Am. J. Pathol. 2011, 179, 1455–1470. [CrossRef] [PubMed]
73. Toh, B.; Wang, X.; Keeble, J.; Sim, W.J.; Khoo, K.; Wong, W.C.; Kato, M.; Prevost-Blondel, A.; Thiery, J.P.; Abastado, J.P. Mesenchymal transition and dissemination of cancer cells is driven by myeloid-derived suppressor cells infiltrating the primary tumor. PLoS Biol. 2011, 9, e1001162. [CrossRef] [PubMed]
74. Kalluri, R.; Weinberg, R.A. The basics of epithelial-mesenchymal transition. J. Clin. Investig. 2009, 119, 1420–1428. [CrossRef] [PubMed]
75. Hu, P.; Shen, M.; Zhang, P.; Zheng, C.; Pang, Z.; Zhu, L.; Du, J. Intratumoral neutrophil granulocytes contribute to epithelial-mesenchymal transition in lung adenocarcinoma cells. Tumour Biol. 2015, 36, 7789–7796. [CrossRef] [PubMed]
76. Grosse-Steffen, T.; Giese, T.; Giese, N.; Longerich, T.; Schirmacher, P.; Hansch, G.M.; Gaida, M.M. Epithelial-to-mesenchymal transition in pancreatic ductal adenocarcinoma and pancreatic tumor cell lines: The role of neutrophils and neutrophil-derived elastase. Clin. Dev. Immunol. 2012. [CrossRef] [PubMed]
77. Seubert, B.; Grunwald, B.; Kobuch, J.; Cui, H.; Schelter, F.; Schaten, S.; Siveke, J.T.; Lim, N.H.; Nagase, H.; Simonavicius, N.; et al. Tissue inhibitor of metalloproteinases (timp)-1 creates a premetastatic niche in the liver through SDF-1/CXCR4-dependent neutrophil recruitment in mice. Hepatology 2015, 61, 238–248. [CrossRef] [PubMed]
78. Youn, J.I.; Collazo, M.; Shalova, I.N.; Biswas, S.K.; Gabrilovich, D.I. Characterization of the nature of granulocytic myeloid-derived suppressor cells in tumor-bearing mice. J. Leukoc. Biol. 2012, 91, 167–181. [CrossRef] [PubMed]
79. Sagiv, J.Y.; Michaeli, J.; Assi, S.; Mishalian, I.; Kisos, H.; Levy, L.; Damti, P.; Lumbroso, D.; Polyansky, L.; Sionov, R.V.; et al. Phenotypic diversity and plasticity in circulating neutrophil subpopulations in cancer. Cell Rep. 2015, 10, 562–573. [CrossRef] [PubMed]
80. Davidson, W.M.; Smith, D.R. A morphological sex difference in the polymorphonuclear neutrophil leucocytes. Br. Med. J. 1954, 2, 6–7. [CrossRef] [PubMed]
81. McKusick, V.A. On the x chromosome of man. Q. Rev. Biol. 1962, 37, 69–175. [CrossRef] [PubMed]
82. Deitch, E.A.; Ananthakrishnan, P.; Cohen, D.B.; Xu, D.Z.; Feketeova, E.; Hauser, C.J. Neutrophil activation is modulated by sex hormones after trauma-hemorrhagic shock and burn injuries. Am. J. Physiol. Heart Circ. Physiol. 2006, 291, H1456–H1465. [CrossRef] [PubMed]
83. Molero, L.; Garcia-Duran, M.; Diaz-Recasens, J.; Rico, L.; Casado, S.; Lopez-Farre, A. Expression of estrogen receptor subtypes and neuronal nitric oxide synthase in neutrophils from women and men: Regulation by estrogen. Cardiovasc. Res. 2002, 56, 43–51. [CrossRef]
84. Robinson, D.P.; Hall, O.J.; Nilles, T.L.; Bream, J.H.; Klein, S.L. 17beta-estradiol protects females against influenza by recruiting neutrophils and increasing virus-specific CD8 T cell responses in the lungs. J. Virol. 2014, 88, 4711–4720. [CrossRef] [PubMed]
85. Su, N.; Yue, Y.; Xiong, S. Monocytic myeloid-derived suppressor cells from females, but not males, alleviate CVB3-induced myocarditis by increasing regulatory and CD4(+)IL-10(+) T cells. Sci. Rep. 2016. [CrossRef] [PubMed]
86. Dong, G.; You, M.; Fan, H.; Ji, J.; Ding, L.; Li, P.; Hou, Y. 17beta-estradiol contributes to the accumulation of myeloid-derived suppressor cells in blood by promoting tnf-alpha secretion. Acta Biochim. Biophys. Sin. 2015, 47, 620–629. [CrossRef] [PubMed]
87. Karakhanova, S.; Yang, Y.; Link, J.; Soltek, S.; von Ahn, K.; Umansky, V.; Werner, J.; Bazhin, A.V. Gender-specific immunological effects of the phosphodiesterase 5 inhibitor sildenafil in healthy mice. Mol. Immunol. 2013, 56, 649–659. [CrossRef] [PubMed]
88. Califano, J.A.; Khan, Z.; Noonan, K.A.; Rudraraju, L.; Zhang, Z.; Wang, H.; Goodman, S.; Gourin, C.G.; Ha, P.K.; Fakhry, C.; et al. Tadalafil augments tumor specific immunity in patients with head and neck squamous cell carcinoma. Clin. Cancer Res. 2015, 21, 30–38. [CrossRef] [PubMed]
89. Weed, D.T.; Vella, J.L.; Reis, I.M.; De la Fuente, A.C.; Gomez, C.; Sargi, Z.; Nazarian, R.; Califano, J.; Borrello, I.; Serafini, P. Tadalafil reduces myeloid-derived suppressor cells and regulatory T cells and promotes tumor immunity in patients with head and neck squamous cell carcinoma. Clin. Cancer Res. 2015, 21, 39–48. [CrossRef] [PubMed]
90. Serafini, P.; Meckel, K.; Kelso, M.; Noonan, K.; Califano, J.; Koch, W.; Dolcetti, L.; Bronte, V.; Borrello, I. Phosphodiesterase-5 inhibition augments endogenous antitumor immunity by reducing myeloid-derived suppressor cell function. J. Exp. Med. 2006, 203, 2691–2702. [CrossRef] [PubMed]
91. Roth, J.A.; Kaeberle, M.L.; Hsu, W.H. Effect of estradiol and progesterone on lymphocyte and neutrophil functions in steers. Infect. Immun. 1982, 35, 997–1002. [PubMed]
92. De Coupade, C.; Gear, R.W.; Dazin, P.F.; Sroussi, H.Y.; Green, P.G.; Levine, J.D. Beta 2-adrenergic receptor regulation of human neutrophil function is sexually dimorphic. Br. J. Pharmacol. 2004, 143, 1033–1041. [CrossRef] [PubMed]
93. Marin, D.P.; Bolin, A.P.; dos Santos Rde, C.; Curi, R.; Otton, R. Testosterone suppresses oxidative stress in human neutrophils. Cell Biochem. Funct. 2010, 28, 394–402. [CrossRef] [PubMed]
94. Molloy, E.J.; O'Neill, A.J.; Grantham, J.J.; Sheridan-Pereira, M.; Fitzpatrick, J.M.; Webb, D.W.; Watson, R.W. Sex-specific alterations in neutrophil apoptosis: The role of estradiol and progesterone. Blood 2003, 102, 2653–2659. [CrossRef] [PubMed]
95. Seino, K.; Kayagaki, N.; Okumura, K.; Yagita, H. Antitumor effect of locally produced CD95 ligand. Nat. Med. 1997, 3, 165–170. [CrossRef] [PubMed]
96. Arai, H.; Gordon, D.; Nabel, E.G.; Nabel, G.J. Gene transfer of fas ligand induces tumor regression in vivo. Proc. Natl. Acad. Sci. USA 1997, 94, 13862–13867. [CrossRef] [PubMed]
97. Simon, A.K.; Gallimore, A.; Jones, E.; Sawitzki, B.; Cerundolo, V.; Screaton, G.R. Fas ligand breaks tolerance to self-antigens and induces tumor immunity mediated by antibodies. Cancer Cell 2002, 2, 315–322. [CrossRef]
98. Challacombe, J.M.; Suhrbier, A.; Parsons, P.G.; Jones, B.; Hampson, P.; Kavanagh, D.; Rainger, G.E.; Morris, M.; Lord, J.M.; Le, T.T.; et al. Neutrophils are a key component of the antitumor efficacy of topical chemotherapy with ingenol-3-angelate. J. Immunol. 2006, 177, 8123–8132. [CrossRef] [PubMed]
99. Cataisson, C.; Pearson, A.J.; Torgerson, S.; Nedospasov, S.A.; Yuspa, S.H. Protein kinase c alpha-mediated chemotaxis of neutrophils requires NF-kappa B activity but is independent of TNF alpha signaling in mouse skin in vivo. J. Immunol. 2005, 174, 1686–1692. [CrossRef] [PubMed]
100. Di Carlo, E.; Forni, G.; Musiani, P. Neutrophils in the antitumoral immune response. Chem. Immunol. Allergy 2003, 83, 182–203. [PubMed]
101. Hatjiharissi, E.; Xu, L.; Santos, D.D.; Hunter, Z.R.; Ciccarelli, B.T.; Verselis, S.; Modica, M.; Cao, Y.; Manning, R.J.; Leleu, X.; et al. Increased natural killer cell expression of cd16, augmented binding and adcc activity to rituximab among individuals expressing the FCRIIIA-158 v/v and v/f polymorphism. Blood 2007, 110, 2561–2564. [CrossRef] [PubMed]
102. Van Egmond, M.; Bakema, J.E. Neutrophils as effector cells for antibody-based immunotherapy of cancer. Semin. Cancer Biol. 2013, 23, 190–199. [CrossRef] [PubMed]
103. Nimmerjahn, F.; Ravetch, J.V. Antibodies, FC receptors and cancer. Curr. Opin. Immunol. 2007, 19, 239–245. [CrossRef] [PubMed]
104. Kushner, B.H.; Cheung, N.K. Absolute requirement of CD11/CD18 adhesion molecules, fcrii and the phosphatidylinositol-linked FCRIII for monoclonal antibody-mediated neutrophil antihuman tumor cytotoxicity. Blood 1992, 79, 1484–1490. [PubMed]
105. Dechant, M.; Beyer, T.; Schneider-Merck, T.; Weisner, W.; Peipp, M.; van de Winkel, J.G.; Valerius, T. Effector mechanisms of recombinant iga antibodies against epidermal growth factor receptor. J. Immunol. 2007, 179, 2936–2943. [CrossRef] [PubMed]
106. Guettinger, Y.; Barbin, K.; Peipp, M.; Bruenke, J.; Dechant, M.; Horner, H.; Thierschmidt, D.; Valerius, T.; Repp, R.; Fey, G.H.; et al. A recombinant bispecific single-chain fragment variable specific for hla class ii and FC alpha ri (CD89) recruits polymorphonuclear neutrophils for efficient lysis of malignant B lymphoid cells. J. Immunol. 2010, 184, 1210–1217. [CrossRef] [PubMed]
107. Stockmeyer, B.; Dechant, M.; van Egmond, M.; Tutt, A.L.; Sundarapandiyan, K.; Graziano, R.F.; Repp, R.; Kalden, J.R.; Gramatzki, M.; Glennie, M.J.; et al. Triggering fc alpha-receptor I (CD89) recruits neutrophils as effector cells for CD20-directed antibody therapy. J. Immunol. 2000, 165, 5954–5961. [CrossRef] [PubMed]
108. Zhao, J.; Kuroki, M.; Shibaguchi, H.; Wang, L.; Huo, Q.; Takami, N.; Tanaka, T.; Kinugasa, T.; Kuroki, M. Recombinant human monoclonal IGA antibody against cea to recruit neutrophils to cea-expressing cells. Oncol. Res. 2008, 17, 217–222. [CrossRef] [PubMed]
109. Ottonello, L.; Epstein, A.L.; Mancini, M.; Dapino, P.; Dallegri, F. Monoclonal lym-1 antibody-dependent cytolysis by human neutrophils exposed to GM-CSF: Auto-regulation of target cell attack by cathepsin G. J. Leukoc. Biol. 2004, 75, 99–105. [CrossRef] [PubMed]
110. Li, M.; Wirthmueller, U.; Ravetch, J.V. Reconstitution of human fc gamma RIII cell type specificity in transgenic mice. J. Exp. Med. 1996, 183, 1259–1263. [CrossRef] [PubMed]
111. Meknache, N.; Jonsson, F.; Laurent, J.; Guinnepain, M.T.; Daeron, M. Human basophils express the glycosylphosphatidylinositol-anchored low-affinity igg receptor fcgammariiib (CD16B). J. Immunol. 2009, 182, 2542–2550. [CrossRef] [PubMed]
112. Nakagawa, T.; Natsume, A.; Satoh, M.; Niwa, R. Nonfucosylated anti-CD20 antibody potentially induces apoptosis in lymphoma cells through enhanced interaction with FCIIIB on neutrophils. Leuk. Res. 2010, 34, 666–671. [CrossRef] [PubMed]
113. Masuda, K.; Kubota, T.; Kaneko, E.; Iida, S.; Wakitani, M.; Kobayashi-Natsume, Y.; Kubota, A.; Shitara, K.; Nakamura, K. Enhanced binding affinity for fcgammariiia of fucose-negative antibody is sufficient to induce maximal antibody-dependent cellular cytotoxicity. Mol. Immunol. 2007, 44, 3122–3131. [CrossRef] [PubMed]
114. Pickup, M.; Novitskiy, S.; Moses, H.L. The roles of tgfbeta in the tumour microenvironment. Nat. Rev. Cancer 2013, 13, 788–799. [CrossRef] [PubMed]
115. Fridlender, Z.G.; Sun, J.; Kim, S.; Kapoor, V.; Cheng, G.; Ling, L.; Worthen, G.S.; Albelda, S.M. Polarization of tumor-associated neutrophil phenotype by tgf-beta: “N1” versus “N2” tan. Cancer Cell 2009, 16, 183–194. [CrossRef] [PubMed]
116. Andzinski, L.; Kasnitz, N.; Stahnke, S.; Wu, C.F.; Gereke, M.; von Kockritz-Blickwede, M.; Schilling, B.; Brandau, S.; Weiss, S.; Jablonska, J. Type I ifns induce anti-tumor polarization of tumor associated neutrophils in mice and human. Int. J. Cancer 2016, 138, 1982–1993. [CrossRef] [PubMed]
117. Zhou, S.L.; Zhou, Z.J.; Hu, Z.Q.; Li, X.; Huang, X.W.; Wang, Z.; Fan, J.; Dai, Z.; Zhou, J. CXCR2/CXCL5 axis contributes to epithelial-mesenchymal transition of hcc cells through activating PI3K/AKT/GSK-3beta/snail signaling. Cancer Lett. 2015, 358, 124–135. [CrossRef] [PubMed]
118. Mian, B.M.; Dinney, C.P.; Bermejo, C.E.; Sweeney, P.; Tellez, C.; Yang, X.D.; Gudas, J.M.; McConkey, D.J.; Bar-Eli, M. Fully human anti-interleukin 8 antibody inhibits tumor growth in orthotopic bladder cancer xenografts via down-regulation of matrix metalloproteases and nuclear factor-kappab. Clin. Cancer Res. 2003, 9, 3167–3175. [PubMed]
119. Huang, S.; Mills, L.; Mian, B.; Tellez, C.; McCarty, M.; Yang, X.D.; Gudas, J.M.; Bar-Eli, M. Fully humanized neutralizing antibodies to interleukin-8 (ABX-IL8) inhibit angiogenesis, tumor growth, and metastasis of human melanoma. Am. J. Pathol. 2002, 161, 125–134. [CrossRefs]
120. Merritt, W.M.; Lin, Y.G.; Spannuth, W.A.; Fletcher, M.S.; Kamat, A.A.; Han, L.Y.; Landen, C.N.; Jennings, N.; De Geest, K.; Langley, R.R.; et al. Effect of interleukin-8 gene silencing with liposome-encapsulated small interfering rna on ovarian cancer cell growth. J. Natl. Cancer Inst. 2008, 100, 359–372. [CrossRef] [PubMed]
121. Lev, D.C.; Onn, A.; Melinkova, V.O.; Miller, C.; Stone, V.; Ruiz, M.; McGary, E.C.; Ananthaswamy, H.N.; Price, J.E.; Bar-Eli, M. Exposure of melanoma cells to dacarbazine results in enhanced tumor growth and metastasis in vivo. J. Clin. Oncol. 2004, 22, 2092–2100. [CrossRef] [PubMed]
122. De Larco, J.E.; Wuertz, B.R.; Manivel, J.C.; Furcht, L.T. Progression and enhancement of metastatic potential after exposure of tumor cells to chemotherapeutic agents. Cancer Res. 2001, 61, 2857–2861. [PubMed]
123. Collins, T.S.; Lee, L.F.; Ting, J.P. Paclitaxel up-regulates interleukin-8 synthesis in human lung carcinoma through an NF-kappab- and AP-1-dependent mechanism. Cancer Immunol. Immunother. 2000, 49, 78–84. [CrossRef] [PubMed]
124. Raccosta, L.; Fontana, R.; Maggioni, D.; Lanterna, C.; Villablanca, E.J.; Paniccia, A.; Musumeci, A.; Chiricozzi, E.; Trincavelli, M.L.; Daniele, S.; et al. The oxysterol-CXCR2 axis plays a key role in the recruitment of tumor-promoting neutrophils. J. Exp. Med. 2013, 210, 1711–1728. [CrossRef] [PubMed]
125. Dumitru, C.A.; Gholaman, H.; Trellakis, S.; Bruderek, K.; Dominas, N.; Gu, X.; Bankfalvi, A.; Whiteside, T.L.; Lang, S.; Brandau, S. Tumor-derived macrophage migration inhibitory factor modulates the biology of head and neck cancer cells via neutrophil activation. Int. J. Cancer 2011, 129, 859–869. [CrossRef] [PubMed]
126. Waugh, D.J.; Wilson, C. The interleukin-8 pathway in cancer. Clin. Cancer Res. 2008, 14, 6735–6741. [CrossRef] [PubMed]
127. Stadtmann, A.; Zarbock, A. Cxcr2: From bench to bedside. Front. Immunol. 2012. [CrossRef] [PubMed]
128. Gong, L.; Cumpian, A.M.; Caetano, M.S.; Ochoa, C.E.; de la Garza, M.M.; Lapid, D.J.; Mirabolfathinejad, S.G.; Dickey, B.F.; Zhou, Q.; Moghaddam, S.J. Promoting effect of neutrophils on lung tumorigenesis is mediated by CXCR2 and neutrophil elastase. Mol. Cancer 2013. [CrossRef] [PubMed]
129. Jamieson, T.; Clarke, M.; Steele, C.W.; Samuel, M.S.; Neumann, J.; Jung, A.; Huels, D.; Olson, M.F.; Das, S.; Nibbs, R.J.; et al. Inhibition of CXCR2 profoundly suppresses inflammation-driven and spontaneous tumorigenesis. J. Clin. Investig. 2012, 122, 3127–3144. [CrossRef] [PubMed]
130. Ijichi, H.; Chytil, A.; Gorska, A.E.; Aakre, M.E.; Bierie, B.; Tada, M.; Mohri, D.; Miyabayashi, K.; Asaoka, Y.; Maeda, S.; et al. Inhibiting CXCR2 disrupts tumor-stromal interactions and improves survival in a mouse model of pancreatic ductal adenocarcinoma. J. Clin. Investig. 2011, 121, 4106–4117. [CrossRef] [PubMed]
131. Gaida, M.M.; Gunther, F.; Wagner, C.; Friess, H.; Giese, N.A.; Schmidt, J.; Hansch, G.M.; Wente, M.N. Expression of the CXCR6 on polymorphonuclear neutrophils in pancreatic carcinoma and in acute, localized bacterial infections. Clin. Exp. Immunol. 2008, 154, 216–223. [CrossRef] [PubMed]
132. Lu, Y.; Wang, J.; Xu, Y.; Koch, A.E.; Cai, Z.; Chen, X.; Galson, D.L.; Taichman, R.S.; Zhang, J. Cxcl16 functions as a novel chemotactic factor for prostate cancer cells in vitro. Mol. Cancer Res. 2008, 6, 546–554. [CrossRef] [PubMed]
133. Wente, M.N.; Gaida, M.M.; Mayer, C.; Michalski, C.W.; Haag, N.; Giese, T.; Felix, K.; Bergmann, F.; Giese, N.A.; Friess, H. Expression and potential function of the cxc chemokine cxcl16 in pancreatic ductal adenocarcinoma. Int. J. Oncol. 2008, 33, 297–308. [CrossRef] [PubMed]
134. Jung, Y.; Kim, J.K.; Shiozawa, Y.; Wang, J.; Mishra, A.; Joseph, J.; Berry, J.E.; McGee, S.; Lee, E.; Sun, H.; et al. Recruitment of mesenchymal stem cells into prostate tumours promotes metastasis. Nat. Commun. 2013. [CrossRef] [PubMed]
135. Deng, L.; Chen, N.; Li, Y.; Zheng, H.; Lei, Q. CXCR6/CXCL16 functions as a regulator in metastasis and progression of cancer. Biochim. Biophys. Acta 2010, 1806, 42–49. [CrossRef] [PubMed]
136. Gladue, R.P.; Brown, M.F.; Zwillich, S.H. CCR1 antagonists: What have we learned from clinical trials. Curr. Top. Med. Chem. 2010, 10, 1268–1277. [CrossRef] [PubMed]
137. Vergunst, C.E.; Gerlag, D.M.; Lopatinskaya, L.; Klareskog, L.; Smith, M.D.; van den Bosch, F.; Dinant, H.J.; Lee, Y.; Wyant, T.; Jacobson, E.W.; et al. Modulation of CCR2 in rheumatoid arthritis: A double-blind, randomized, placebo-controlled clinical trial. Arthritis Rheum. 2008, 58, 1931–1939. [CrossRef] [PubMed]
138. Gerlag, D.M.; Hollis, S.; Layton, M.; Vencovsky, J.; Szekanecz, Z.; Braddock, M.; Tak, P.P. Preclinical and clinical investigation of a CCR5 antagonist, AZD5672, in patients with rheumatoid arthritis receiving methotrexate. Arthritis Rheum. 2010, 62, 3154–3160. [CrossRef] [PubMed]
139. Lee, W.L.; Downey, G.P. Leukocyte elastase: Physiological functions and role in acute lung injury. Am. J. Respir. Crit. Care Med. 2001, 164, 896–904. [CrossRef] [PubMed]
140. Gaida, M.M.; Steffen, T.G.; Gunther, F.; Tschaharganeh, D.F.; Felix, K.; Bergmann, F.; Schirmacher, P.; Hansch, G.M. Polymorphonuclear neutrophils promote dyshesion of tumor cells and elastase-mediated degradation of e-cadherin in pancreatic tumors. Eur. J. Immunol. 2012, 42, 3369–3380. [CrossRef] [PubMed]
141. Houghton, A.M.; Rzymkiewicz, D.M.; Ji, H.; Gregory, A.D.; Egea, E.E.; Metz, H.E.; Stolz, D.B.; Land, S.R.; Marconcini, L.A.; Kliment, C.R.; et al. Neutrophil elastase-mediated degradation of IRS-1 accelerates lung tumor growth. Nat. Med. 2010, 16, 219–223. [CrossRef] [PubMed]
142. Kamohara, H.; Sakamoto, K.; Mita, S.; An, X.Y.; Ogawa, M. Neutrophil elastase inhibitor (ONO-5046.Na) suppresses the proliferation, motility and chemotaxis of a pancreatic carcinoma cell line, capan-1. Res. Commun. Mol. Pathol. Pharmacol. 1997, 98, 103–108. [PubMed]
143. Hunt, K.K.; Wingate, H.; Yokota, T.; Liu, Y.N.; Mills, G.B.; Zhang, F.; Fang, B.L.; Su, C.H.; Zhang, M.; Yi, M.; et al. Elafin, an inhibitor of elastase, is a prognostic indicator in breast cancer. Breast Cancer Res. 2013. [CrossRef] [PubMed]
144. Henriksen, P.A.; Devitt, A.; Kotelevtsev, Y.; Sallenave, J.M. Gene delivery of the elastase inhibitor elafin protects macrophages from neutrophil elastase-mediated impairment of apoptotic cell recognition. FEBS Lett. 2004, 574, 80–84. [CrossRef] [PubMed]
145. Xu, Y.; Zhang, J.; Han, J.; Pan, X.; Cao, Y.; Guo, H.; Pan, Y.; An, Y.; Li, X. Curcumin inhibits tumor proliferation induced by neutrophil elastase through the upregulation of alpha1-antitrypsin in lung cancer. Mol. Oncol. 2012, 6, 405–417. [CrossRef] [PubMed]
146. Von Nussbaum, F.; Li, V.M. Neutrophil elastase inhibitors for the treatment of (cardio)pulmonary diseases: Into clinical testing with pre-adaptive pharmacophores. Bioorg. Med. Chem. Lett. 2015, 25, 4370–4381. [CrossRef] [PubMed]
147. Vandenbroucke, R.E.; Libert, C. Is there new hope for therapeutic matrix metalloproteinase inhibition? Nat. Rev. Drug Discov. 2014, 13, 904–927. [CrossRef] [PubMed]
148. Deryugina, E.I.; Zajac, E.; Juncker-Jensen, A.; Kupriyanova, T.A.; Welter, L.; Quigley, J.P. Tissue-infiltrating neutrophils constitute the major in vivo source of angiogenesis-inducing mmp-9 in the tumor microenvironment. Neoplasia 2014, 16, 771–788. [CrossRef] [PubMed]
149. Hashimoto, G.; Inoki, I.; Fujii, Y.; Aoki, T.; Ikeda, E.; Okada, Y. Matrix metalloproteinases cleave connective tissue growth factor and reactivate angiogenic activity of vascular endothelial growth factor 165. J. Biol. Chem. 2002, 277, 36288–36295. [CrossRef] [PubMed]
150. Bergers, G.; Brekken, R.; McMahon, G.; Vu, T.H.; Itoh, T.; Tamaki, K.; Tanzawa, K.; Thorpe, P.; Itohara, S.; Werb, Z.; et al. Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis. Nat. Cell Biol. 2000, 2, 737–744. [PubMed]
151. Akahane, T.; Akahane, M.; Shah, A.; Connor, C.M.; Thorgeirsson, U.P. Timp-1 inhibits microvascular endothelial cell migration by mmp-dependent and mmp-independent mechanisms. Exp. Cell Res. 2004, 301, 158–167. [CrossRef] [PubMed]
152. Ardi, V.C.; Kupriyanova, T.A.; Deryugina, E.I.; Quigley, J.P. Human neutrophils uniquely release timp-free mmp-9 to provide a potent catalytic stimulator of angiogenesis. Proc. Natl. Acad. Sci. USA 2007, 104, 20262–20267. [CrossRef] [PubMed]
153. Wang, D.; Dubois, R.N. Eicosanoids and cancer. Nat. Rev. Cancer 2010, 10, 181–193. [CrossRef] [PubMed]
154. Wculek, S.K.; Malanchi, I. Neutrophils support lung colonization of metastasis-initiating breast cancer cells. Nature 2015, 528, 413–417. [CrossRef] [PubMed]
155. Rioux, N.; Castonguay, A. Inhibitors of lipoxygenase: A new class of cancer chemopreventive agents. Carcinogenesis 1998, 19, 1393–1400. [CrossRef] [PubMed]
156. El Rayes, T.; Catena, R.; Lee, S.; Stawowczyk, M.; Joshi, N.; Fischbach, C.; Powell, C.A.; Dannenberg, A.J.; Altorki, N.K.; Gao, D.; et al. Lung inflammation promotes metastasis through neutrophil protease-mediated degradation of TSP-1. Proc. Natl. Acad. Sci. USA 2015, 112, 16000–16005. [CrossRef] [PubMed]