Tumor-associated neutrophils (TAN) develop pro-tumorigenic properties during tumor progression
Tóm tắt
The role and characteristics of tumor-associated neutrophils (TAN) in cancer are poorly defined. We have recently shown that TAN can have anti-tumorigenic (N1) or pro-tumorigenic (N2) functions. An interesting unanswered question is how the phenotype of TAN is influenced by the ongoing evolvement of tumor microenvironment. We therefore studied the phenotype and effects of TAN at different time points during tumor progression. We used two models of murine tumor cancer cell lines—Lewis lung carcinoma (LLC) and AB12 (mesothelioma). Neutrophils were studied at early and late stages and compared to each other and to neutrophils from bone marrow/periphery of naïve mice. Although there was no difference in the number of neutrophils entering the tumor, we found that at early stages of tumor development, neutrophils were almost exclusively at the periphery of the tumor. Only at later stages, neutrophils were also found scattered among the tumor cells. We further found that TAN from early tumors are more cytotoxic toward tumor cells and produce higher levels of TNF-α, NO and H2O2. In established tumors, these functions are down-regulated and TAN acquire a more pro-tumorigenic phenotype. In line with this phenotype, only depletion of neutrophils at later stages of tumor development inhibited tumor growth, possibly due to their central location in the tumor. Our work adds another important layer to the understanding of neutrophils in cancer by further characterizing the changes in TAN during time. Additional research on the functional role of TAN and differences between subsets of TAN is currently underway.
Tài liệu tham khảo
Finn OJ (2008) Cancer immunology. N Engl J Med 358(25):2704–2715. doi:10.1056/NEJMra072739
Costello RT, Gastaut JA, Olive D (1999) Tumor escape from immune surveillance. Arch Immunol Ther Exp (Warsz) 47(2):83–88
Whiteside TL (2009) Tricks tumors use to escape from immune control. Oral Oncol 45(10):e119–e123. doi:10.1016/j.oraloncology.2009.03.006
Fridlender ZG, Sun J, Mishalian I, Singhal S, Cheng G, Kapoor V, Horng W, Fridlender G, Bayuh R, Worthen GS, Albelda SM (2012) Transcriptomic analysis comparing tumor-associated neutrophils with granulocytic myeloid-derived suppressor cells and normal neutrophils. PLoS ONE 7(2):e31524. doi:10.1371/journal.pone.0031524
Gabrilovich DI, Ostrand-Rosenberg S, Bronte V (2012) Coordinated regulation of myeloid cells by tumours. Nat Rev Immunol 12(4):253–268. doi:10.1038/nri3175
Solinas G, Germano G, Mantovani A, Allavena P (2009) Tumor-associated macrophages (TAM) as major players of the cancer-related inflammation. J Leukoc Biol 86(5):1065–1073. doi:10.1189/jlb.0609385
Balkwill F, Coussens LM (2004) Cancer: an inflammatory link. Nature 431(7007):405–406. doi:10.1038/431405a431405a
Luo Y, Zhou H, Krueger J, Kaplan C, Lee SH, Dolman C, Markowitz D, Wu W, Liu C, Reisfeld RA, Xiang R (2006) Targeting tumor-associated macrophages as a novel strategy against breast cancer. J Clin Invest 116(8):2132–2141. doi:10.1172/JCI27648
Biswas SK, Sica A, Lewis CE (2008) Plasticity of macrophage function during tumor progression: regulation by distinct molecular mechanisms. J Immunol 180(4):2011–2017
Lewis CE, Pollard JW (2006) Distinct role of macrophages in different tumor microenvironments. Cancer Res 66(2):605–612. doi:10.1158/0008-5472.CAN-05-4005
Martinez FO, Helming L, Gordon S (2009) Alternative activation of macrophages: an immunologic functional perspective. Annu Rev Immunol 27:451–483. doi:10.1146/annurev.immunol.021908.132532
Mantovani A, Sozzani S, Locati M, Allavena P, Sica A (2002) Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol 23(11):549–555
Saccani A, Schioppa T, Porta C, Biswas SK, Nebuloni M, Vago L, Bottazzi B, Colombo MP, Mantovani A, Sica A (2006) p50 nuclear factor-kappaB overexpression in tumor-associated macrophages inhibits M1 inflammatory responses and antitumor resistance. Cancer Res 66(23):11432–11440. doi:10.1158/0008-5472.CAN-06-1867
Sica A, Schioppa T, Mantovani A, Allavena P (2006) Tumour-associated macrophages are a distinct M2 polarized population promoting tumour progression: potential targets of anti-cancer therapy. Eur J Cancer 42(6):717–727. doi:10.1016/j.ejca.2006.01.003
Mantovani A, Sica A (2010) Macrophages, innate immunity and cancer: balance, tolerance, and diversity. Curr Opin Immunol 22(2):231–237. doi:10.1016/j.coi.2010.01.009
Pekarek LA, Starr BA, Toledano AY, Schreiber H (1995) Inhibition of tumor growth by elimination of granulocytes. J Exp Med 181(1):435–440
Shojaei F, Singh M, Thompson JD, Ferrara N (2008) Role of Bv8 in neutrophil-dependent angiogenesis in a transgenic model of cancer progression. Proc Natl Acad Sci USA 105(7):2640–2645. doi:10.1073/pnas.0712185105
Tazawa H, Okada F, Kobayashi T, Tada M, Mori Y, Une Y, Sendo F, Kobayashi M, Hosokawa M (2003) Infiltration of neutrophils is required for acquisition of metastatic phenotype of benign murine fibrosarcoma cells: implication of inflammation-associated carcinogenesis and tumor progression. Am J Pathol 163(6):2221–2232. doi:10.1016/S0002-9440(10)63580-8
Colombo MP, Lombardi L, Stoppacciaro A, Melani C, Parenza M, Bottazzi B, Parmiani G (1992) Granulocyte colony-stimulating factor (G-CSF) gene transduction in murine adenocarcinoma drives neutrophil-mediated tumor inhibition in vivo. Neutrophils discriminate between G-CSF-producing and G-CSF-nonproducing tumor cells. J Immunol 149(1):113–119
Hicks AM, Riedlinger G, Willingham MC, Alexander-Miller MA, Von Kap-Herr C, Pettenati MJ, Sanders AM, Weir HM, Du W, Kim J, Simpson AJ, Old LJ, Cui Z (2006) Transferable anticancer innate immunity in spontaneous regression/complete resistance mice. Proc Natl Acad Sci USA 103(20):7753–7758. doi:10.1073/pnas.0602382103
Di Carlo E, Forni G, Lollini P, Colombo MP, Modesti A, Musiani P (2001) The intriguing role of polymorphonuclear neutrophils in antitumor reactions. Blood 97(2):339–345
Fridlender ZG, Sun J, Kim S, Kapoor V, Cheng G, Ling L, Worthen GS, Albelda SM (2009) Polarization of tumor-associated neutrophil phenotype by TGF-beta: “N1” versus “N2” TAN. Cancer Cell 16(3):183–194. doi:10.1016/j.ccr.2009.06.017
Jablonska J, Leschner S, Westphal K, Lienenklaus S, Weiss S (2010) Neutrophils responsive to endogenous IFN-beta regulate tumor angiogenesis and growth in a mouse tumor model. J Clin Invest 120(4):1151–1164. doi:10.1172/JCI37223
Granot Z, Henke E, Comen EA, King TA, Norton L, Benezra R (2011) Tumor entrained neutrophils inhibit seeding in the premetastatic lung. Cancer Cell 20(3):300–314. doi:10.1016/j.ccr.2011.08.012
Kim R, Emi M, Tanabe K, Arihiro K (2006) Tumor-driven evolution of immunosuppressive networks during malignant progression. Cancer Res 66(11):5527–5536. doi:10.1158/0008-5472.CAN-05-4128
Kim S, Buchlis G, Fridlender ZG, Sun J, Kapoor V, Cheng G, Haas A, Cheung HK, Zhang X, Corbley M, Kaiser LR, Ling L, Albelda SM (2008) Systemic blockade of transforming growth factor-beta signaling augments the efficacy of immunogene therapy. Cancer Res 68(24):10247–10256. doi:10.1158/0008-5472.CAN-08-1494
Basit A, Reutershan J, Morris MA, Solga M, Rose CE Jr, Ley K (2006) ICAM-1 and LFA-1 play critical roles in LPS-induced neutrophil recruitment into the alveolar space. Am J Physiol Lung Cell Mol Physiol 291(2):L200–L207. doi:10.1152/ajplung.0.0346.2005
Piccard H, Muschel RJ, Opdenakker G (2012) On the dual roles and polarized phenotypes of neutrophils in tumor development and progression. Crit Rev Oncol Hematol 82(3):296–309. doi:10.1016/j.critrevonc.2011.06.004
Scapini P, Lapinet-Vera JA, Gasperini S, Calzetti F, Bazzoni F, Cassatella MA (2000) The neutrophil as a cellular source of chemokines. Immunol Rev 177:195–203
Biswas SK, Gangi L, Paul S, Schioppa T, Saccani A, Sironi M, Bottazzi B, Doni A, Vincenzo B, Pasqualini F, Vago L, Nebuloni M, Mantovani A, Sica A (2006) A distinct and unique transcriptional program expressed by tumor-associated macrophages (defective NF-kappaB and enhanced IRF-3/STAT1 activation). Blood 107(5):2112–2122. doi:10.1182/blood-2005-01-0428
Sugai H, Kono K, Takahashi A, Ichihara F, Kawaida H, Fujii H, Matsumoto Y (2004) Characteristic alteration of monocytes with increased intracellular IL-10 and IL-12 in patients with advanced-stage gastric cancer. J Surg Res 116(2):277–287. doi:10.1016/j.jss.2003.10.008
Tsai CS, Chen FH, Wang CC, Huang HL, Jung SM, Wu CJ, Lee CC, McBride WH, Chiang CS, Hong JH (2007) Macrophages from irradiated tumors express higher levels of iNOS, arginase-I and COX-2, and promote tumor growth. Int J Radiat Oncol Biol Phys 68(2):499–507. doi:10.1016/j.ijrobp.2007.01.041
Mantovani A, Cassatella MA, Costantini C, Jaillon S (2011) Neutrophils in the activation and regulation of innate and adaptive immunity. Nat Rev Immunol 11(8):519–531. doi:10.1038/nri3024
Fridlender ZG, Albelda SM (2012) Tumor-associated neutrophils: friend or foe? Carcinogenesis 33(5):949–955. doi:10.1093/carcin/bgs123
Beutler BA (1999) The role of tumor necrosis factor in health and disease. J Rheumatol Suppl 57:16–21
Balkwill F (2002) Tumor necrosis factor or tumor promoting factor? Cytokine Growth Factor Rev 13(2):135–141
Karin M, Greten FR (2005) NF-kappaB: linking inflammation and immunity to cancer development and progression. Nat Rev Immunol 5(10):749–759. doi:10.1038/nri1703
Karin M, Lawrence T, Nizet V (2006) Innate immunity gone awry: linking microbial infections to chronic inflammation and cancer. Cell 124(4):823–835. doi:10.1016/j.cell.2006.02.016
van Gisbergen KP, Geijtenbeek TB, van Kooyk Y (2005) Close encounters of neutrophils and DCs. Trends Immunol 26(12):626–631. doi:10.1016/j.it.2005.09.007
Dallegri F, Patrone F, Frumento G, Sacchetti C (1984) Antibody-dependent killing of tumor cells by polymorphonuclear leukocytes. Involvement of oxidative and nonoxidative mechanisms. J Natl Cancer Inst 73(2):331–339
Gerrard TL, Cohen DJ, Kaplan AM (1981) Human neutrophil-mediated cytotoxicity to tumor cells. J Natl Cancer Inst 66(3):483–488
Katano M, Torisu M (1982) Neutrophil-mediated tumor cell destruction in cancer ascites. Cancer 50(1):62–68
Dallegri F, Ottonello L, Ballestrero A, Dapino P, Ferrando F, Patrone F, Sacchetti C (1991) Tumor cell lysis by activated human neutrophils: analysis of neutrophil-delivered oxidative attack and role of leukocyte function-associated antigen 1. Inflammation 15(1):15–30
Lichtenstein A, Seelig M, Berek J, Zighelboim J (1989) Human neutrophil-mediated lysis of ovarian cancer cells. Blood 74(2):805–809
Zivkovic M, Poljak-Blazi M, Egger G, Sunjic SB, Schaur RJ, Zarkovic N (2005) Oxidative burst and anticancer activities of rat neutrophils. BioFactors 24(1–4):305–312
Balbin M, Fueyo A, Tester AM, Pendas AM, Pitiot AS, Astudillo A, Overall CM, Shapiro SD, Lopez-Otin C (2003) Loss of collagenase-2 confers increased skin tumor susceptibility to male mice. Nat Genet 35(3):252–257. doi:10.1038/ng1249
Kousis PC, Henderson BW, Maier PG, Gollnick SO (2007) Photodynamic therapy enhancement of antitumor immunity is regulated by neutrophils. Cancer Res 67(21):10501–10510. doi:10.1158/0008-5472.CAN-07-1778
Stoppacciaro A, Melani C, Parenza M, Mastracchio A, Bassi C, Baroni C, Parmiani G, Colombo MP (1993) Regression of an established tumor genetically modified to release granulocyte colony-stimulating factor requires granulocyte-T cell cooperation and T cell-produced interferon gamma. J Exp Med 178(1):151–161
Nozawa H, Chiu C, Hanahan D (2006) Infiltrating neutrophils mediate the initial angiogenic switch in a mouse model of multistage carcinogenesis. Proc Natl Acad Sci USA 103(33):12493–12498. doi:10.1073/pnas.0601807103
Daley JM, Thomay AA, Connolly MD, Reichner JS, Albina JE (2008) Use of Ly6G-specific monoclonal antibody to deplete neutrophils in mice. J Leukoc Biol 83(1):64–70. doi:10.1189/jlb.0407247