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Microenvironmental Effects of Cell Death in Malignant Disease

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Apoptosis in Cancer Pathogenesis and Anti-cancer Therapy

Abstract

Although apoptosis is well recognized as a cell death program with clear anticancer roles, accumulating evidence linking apoptosis with tissue repair and regeneration indicates that its relationship with malignant disease is more complex than previously thought. Here we review how the responses of neighboring cells in the microenvironment of apoptotic tumor cells may contribute to the cell birth/cell death disequilibrium that provides the basis for cancerous tissue emergence and growth. We describe the bioactive properties of apoptotic cells and consider, in particular, how apoptosis of tumor cells can engender a range of responses including pro-oncogenic signals having proliferative, angiogenic, reparatory, and immunosuppressive features. Drawing on the parallels between wound healing, tissue regeneration and cancer, we propose the concept of the “onco-regenerative niche,” a cell death-driven generic network of tissue repair and regenerative mechanisms that are hijacked in cancer. Finally, we consider how the responses to cell death in tumors can be targeted to provide more effective and long-lasting therapies.

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References

  1. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000;100:57–70.

    Article  CAS  PubMed  Google Scholar 

  2. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646–74.

    Article  CAS  PubMed  Google Scholar 

  3. Wyllie AH. The biology of cell death in tumours. Anticancer Res. 1985;5:131–6.

    CAS  PubMed  Google Scholar 

  4. Weinstein GD, Frost P. Cell proliferation in human basal cell carcinoma. Cancer Res. 1970;30:724–8.

    CAS  PubMed  Google Scholar 

  5. Holmgren L, O’Reilly MS, Folkman J. Dormancy of micrometastases: balanced proliferation and apoptosis in the presence of angiogenesis suppression. Nat Med. 1995;1:149–53.

    Article  CAS  PubMed  Google Scholar 

  6. Clifton KH, Yatvin MB. Cell population growth and cell loss in the MTG-B mouse mammary carcinoma. Cancer Res. 1970;30:658–64.

    CAS  PubMed  Google Scholar 

  7. Revesz L, Klein G. Quantitative studies on the multiplication of neoplastic cells in vivo. II. Growth curves of three ascites lymphomas. J Natl Cancer Inst. 1954;15:253–73.

    CAS  PubMed  Google Scholar 

  8. Lala PK. Evaluation of the mode of cell death in Ehrlich ascites tumor. Cancer. 1972;29:261–6.

    Article  CAS  PubMed  Google Scholar 

  9. Leoncini L, Del Vecchio MT, Megha T, Barbini P, Galieni P, Pileri S, Sabattini E, Gherlinzoni F, Tosi P, Kraft R, et al. Correlations between apoptotic and proliferative indices in malignant non-Hodgkin’s lymphomas. Am J Pathol. 1993;142:755–63.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Ohbu M, Saegusa M, Okayasu I. Apoptosis and cellular proliferation in oesophageal squamous cell carcinomas: differences between keratinizing and nonkeratinizing types. Virchows Archiv. 1995;427:271–6.

    Article  CAS  PubMed  Google Scholar 

  11. Naresh KN, Lakshminarayanan K, Pai SA, Borges AM. Apoptosis index is a predictor of metastatic phenotype in patients with early stage squamous carcinoma of the tongue: a hypothesis to support this paradoxical association. Cancer. 2001;91:578–84.

    Article  CAS  PubMed  Google Scholar 

  12. Jalalinadoushan M, Peivareh H, Azizzadeh Delshad A. Correlation between apoptosis and histological grade of transitional cell carcinoma of urinary bladder. Urol J. 2004;1:177–9.

    PubMed  Google Scholar 

  13. Sun BH, Zhang J, Wang BJ, Zhao XP, Wang YK, Yu ZQ, Yang DL, Hao LJ. Analysis of in vivo patterns of caspase 3 gene expression in primary hepatocellular carcinoma and its relationship to p21(WAF1) expression and hepatic apoptosis. World J Gastroenterol. 2000;6:356–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Hu Q, Peng J, Liu W, He X, Cui L, Chen X, Yang M, Liu H, Liu S, Wang H. Elevated cleaved caspase-3 is associated with shortened overall survival in several cancer types. Int J Clin Exp Pathol. 2014;7:5057–70.

    PubMed  PubMed Central  Google Scholar 

  15. Gregory CD, Pound JD. Cell death in the neighbourhood: direct microenvironmental effects of apoptosis in normal and neoplastic tissues. J Pathol. 2011;223:177–94.

    Article  CAS  PubMed  Google Scholar 

  16. Refsum SB, Berdal P. Cell loss in malignant tumours in man. Eur J Cancer. 1967;3:235–6.

    Article  CAS  PubMed  Google Scholar 

  17. Langley RR, Fidler IJ. The seed and soil hypothesis revisited—the role of tumor-stroma interactions in metastasis to different organs. Int J Cancer. 2011;128:2527–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Dvorak HF. Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing. N Engl J Med. 1986;315:1650–9.

    Article  CAS  PubMed  Google Scholar 

  19. Flusberg DA, Sorger PK. Surviving apoptosis: life-death signaling in single cells. Trends Cell Biol. 2015;25(8):446–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Bergsmedh A, Ehnfors J, Kawane K, Motoyama N, Nagata S, Holmgren L. DNase II and the Chk2 DNA damage pathway form a genetic barrier blocking replication of horizontally transferred DNA. Mol Cancer Res. 2006;4:187–95.

    Article  CAS  PubMed  Google Scholar 

  21. Bergsmedh A, Szeles A, Henriksson M, Bratt A, Folkman MJ, Spetz AL, Holmgren L. Horizontal transfer of oncogenes by uptake of apoptotic bodies. Proc Natl Acad Sci U S A. 2001;98:6407–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Ehnfors J, Kost-Alimova M, Persson NL, Bergsmedh A, Castro J, Levchenko-Tegnebratt T, Yang L, Panaretakis T, Holmgren L. Horizontal transfer of tumor DNA to endothelial cells in vivo. Cell Death Differ. 2009;16:749–57.

    Article  CAS  PubMed  Google Scholar 

  23. Holmgren L, Szeles A, Rajnavolgyi E, Folkman J, Klein G, Ernberg I, Falk KI. Horizontal transfer of DNA by the uptake of apoptotic bodies. Blood. 1999;93:3956–63.

    CAS  PubMed  Google Scholar 

  24. Han H, Iwanaga T, Uchiyama Y, Fujita T. Aggregation of macrophages in the tips of intestinal villi in guinea pigs: their possible role in the phagocytosis of effete epithelial cells. Cell Tissue Res. 1993;271:407–16.

    Article  CAS  PubMed  Google Scholar 

  25. Huang Q, Li F, Liu X, Li W, Shi W, Liu FF, O’Sullivan B, He Z, Peng Y, Tan AC, Zhou L, Shen J, Han G, Wang XJ, Thorburn J, Thorburn A, Jimeno A, Raben D, Bedford JS, Li CY. Caspase 3-mediated stimulation of tumor cell repopulation during cancer radiotherapy. Nat Med. 2011;17:860–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Lauber K, Munoz LE, Berens C, Jendrossek V, Belka C, Herrmann M. Apoptosis induction and tumor cell repopulation: the yin and yang of radiotherapy. Radiat Oncol. 2011;6:176.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Ford CA, Petrova S, Pound JD, Voss JJ, Melville L, Paterson M, Farnworth SL, Gallimore AM, Cuff S, Wheadon H, Dobbin E, Ogden CA, Dumitriu IE, Dunbar DR, Murray PG, Ruckerl D, Allen JE, Hume DA, van Rooijen N, Goodlad JR, Freeman TC, Gregory CD. Oncogenic properties of apoptotic tumor cells in aggressive B cell lymphoma. Curr Biol. 2015;25:577–88.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Lauber K, Herrmann M. Tumor biology: with a little help from my dying friends. Curr Biol. 2015;25:R198–201.

    Article  CAS  PubMed  Google Scholar 

  29. Kerr JF, Wyllie AH, Currie AR. Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer. 1972;26:239–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Green DR. Means to an end. Apoptosis and other cell death mechanisms. New York: Cold Spring Harbor Laboratory Press; 2011.

    Google Scholar 

  31. Savill J, Dransfield I, Gregory C, Haslett C. A blast from the past: clearance of apoptotic cells regulates immune responses. Nat Rev Immunol. 2002;2:965–75.

    Article  CAS  PubMed  Google Scholar 

  32. Zitvogel L, Kepp O, Kroemer G. Decoding cell death signals in inflammation and immunity. Cell. 2010;140:798–804.

    Article  CAS  PubMed  Google Scholar 

  33. Obenauf AC, Massague J. Surviving at a distance: organ specific metastasis. Trends Cancer. 2015;1:76–91.

    Article  PubMed  Google Scholar 

  34. Perez-Garijo A, Fuchs Y, Steller H. Apoptotic cells can induce non-autonomous apoptosis through the TNF pathway. eLife. 2013;2, e01004.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Galluzzi L, Bravo-San Pedro JM, Kroemer G. Organelle-specific initiation of cell death. Nat Cell Biol. 2014;16:728–36.

    Article  CAS  PubMed  Google Scholar 

  36. Green DR, Galluzzi L, Kroemer G. Cell biology. Metabolic control of cell death. Science. 2014;345:1250256.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. Galluzzi L, Bravo-San Pedro JM, Vitale I, Aaronson SA, Abrams JM, Adam D, Alnemri ES, Altucci L, Andrews D, Annicchiarico-Petruzzelli M, Baehrecke EH, Bazan NG, Bertrand MJ, Bianchi K, Blagosklonny MV, Blomgren K, Borner C, Bredesen DE, Brenner C, Campanella M, Candi E, Cecconi F, Chan FK, Chandel NS, Cheng EH, Chipuk JE, Cidlowski JA, Ciechanover A, Dawson TM, Dawson VL, De Laurenzi V, De Maria R, Debatin KM, Di Daniele N, Dixit VM, Dynlacht BD, El-Deiry WS, Fimia GM, Flavell RA, Fulda S, Garrido C, Gougeon ML, Green DR, Gronemeyer H, Hajnoczky G, Hardwick JM, Hengartner MO, Ichijo H, Joseph B, Jost PJ, Kaufmann T, Kepp O, Klionsky DJ, Knight RA, Kumar S, Lemasters JJ, Levine B, Linkermann A, Lipton SA, Lockshin RA, Lopez-Otin C, Lugli E, Madeo F, Malorni W, Marine JC, Martin SJ, Martinou JC, Medema JP, Meier P, Melino S, Mizushima N, Moll U, Munoz-Pinedo C, Nunez G, Oberst A, Panaretakis T, Penninger JM, Peter ME, Piacentini M, Pinton P, Prehn JH, Puthalakath H, Rabinovich GA, Ravichandran KS, Rizzuto R, Rodrigues CM, Rubinsztein DC, Rudel T, Shi Y, Simon HU, Stockwell BR, Szabadkai G, Tait SW, Tang HL, Tavernarakis N, Tsujimoto Y, Vanden Berghe T, Vandenabeele P, Villunger A, Wagner EF, Walczak H, White E, Wood WG, Yuan J, Zakeri Z, Zhivotovsky B, Melino G, Kroemer G. Essential versus accessory aspects of cell death: recommendations of the NCCD 2015. Cell Death Differ. 2015;22:58–73.

    Article  CAS  PubMed  Google Scholar 

  38. Wyllie AH, Kerr JFR, Currie AR. Cell death: the significance of apoptosis. Int Rev Cytol. 1980;68:251–305.

    Article  CAS  PubMed  Google Scholar 

  39. Gregory CD, Pound JD. Microenvironmental influences of apoptosis in vivo and in vitro. Apoptosis. 2010;15:1029–49.

    Article  CAS  PubMed  Google Scholar 

  40. Degterev A, Hitomi J, Germscheid M, Ch’en IL, Korkina O, Teng X, Abbott D, Cuny GD, Yuan C, Wagner G, Hedrick SM, Gerber SA, Lugovskoy A, Yuan J. Identification of RIP1 kinase as a specific cellular target of necrostatins. Nat Chem Biol. 2008;4:313–21.

    Article  CAS  PubMed  Google Scholar 

  41. Medzhitov R, Janeway Jr CA. Decoding the patterns of self and nonself by the innate immune system. Science. 2002;296:298–300.

    Article  CAS  PubMed  Google Scholar 

  42. Vakkila J, Lotze MT. Inflammation and necrosis promote tumour growth. Nat Rev Immunol. 2004;4:641–8.

    Article  CAS  PubMed  Google Scholar 

  43. Gamrekelashvili J, Kruger C, von Wasielewski R, Hoffmann M, Huster KM, Busch DH, Manns MP, Korangy F, Greten TF. Necrotic tumor cell death in vivo impairs tumor-specific immune responses. J Immunol. 2007;178:1573–80.

    Article  CAS  PubMed  Google Scholar 

  44. Moreira S, Stramer B, Evans I, Wood W, Martin P. Prioritization of competing damage and developmental signals by migrating macrophages in the Drosophila embryo. Curr Biol. 2010;20:464–70.

    Article  CAS  PubMed  Google Scholar 

  45. Marino G, Niso-Santano M, Baehrecke EH, Kroemer G. Self-consumption: the interplay of autophagy and apoptosis. Nat Rev Mol Cell Biol. 2014;15(2):81–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. White E. Deconvoluting the context-dependent role for autophagy in cancer. Nat Rev Cancer. 2012;12:401–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Changou CA, Chen YR, Xing L, Yen Y, Chuang FY, Cheng RH, Bold RJ, Ann DK, Kung HJ. Arginine starvation-associated atypical cellular death involves mitochondrial dysfunction, nuclear DNA leakage, and chromatin autophagy. Proc Natl Acad Sci U S A. 2014;111:14147–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Degenhardt K, Mathew R, Beaudoin B, Bray K, Anderson D, Chen G, Mukherjee C, Shi Y, Gelinas C, Fan Y, Nelson DA, Jin S, White E. Autophagy promotes tumor cell survival and restricts necrosis, inflammation, and tumorigenesis. Cancer Cell. 2006;10:51–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Wen Z, Fan L, Li Y, Zou Z, Scott MJ, Xiao G, Li S, Billiar TR, Wilson MA, Shi X, Fan J. Neutrophils counteract autophagy-mediated anti-inflammatory mechanisms in alveolar macrophage: role in posthemorrhagic shock acute lung inflammation. J Immunol. 2014;193:4623–33.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  50. Dou Z, Xu C, Donahue G, Shimi T, Pan JA, Zhu J, Ivanov A, Capell BC, Drake AM, Shah PP, Catanzaro JM, Daniel Ricketts M, Lamark T, Adam SA, Marmorstein R, Zong WX, Johansen T, Goldman RD, Adams PD, Berger SL. Autophagy mediates degradation of nuclear lamina. Nature. 2015;527:105–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Revesz L. Effect of tumour cells killed by x-rays upon the growth of admixed viable cells. Nature. 1956;178:1391–2.

    Article  CAS  PubMed  Google Scholar 

  52. Revesz L. Effect of lethally damaged tumor cells upon the development of admixed viable cells. J Natl Cancer Inst. 1958;20:1157–86.

    CAS  PubMed  Google Scholar 

  53. Ringertz N, Klein E, Revesz L. Growth of small compatible tumor implants in presence of admixed radiation-killed or incompatible tumor cells. Cancer. 1959;12:697–707.

    Article  CAS  PubMed  Google Scholar 

  54. Seelig KJ, Revesz L. Effect of lethally damaged tumour cells upon the growth of admixed viable cells in diffusion chambers. Br J Cancer. 1960;14:126–38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Puck TT, Marcus PI, Cieciura SJ. Clonal growth of mammalian cells in vitro; growth characteristics of colonies from single HeLa cells with and without a feeder layer. J Exp Med. 1956;103:273–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Gregory CD, Pound JD, Devitt A, Wilson-Jones M, Ray P, Murray RJ. Inhibitory effects of persistent apoptotic cells on monoclonal antibody production in vitro: simple removal of non-viable cells improves antibody productivity by hybridoma cells in culture. MAbs. 2009;1:370–6.

    Article  PubMed  PubMed Central  Google Scholar 

  57. Fadok VA, Voelker DR, Campbell PA, Cohen JJ, Bratton DL, Henson PM. Exposure of phosphatidylserine on the surface of apoptotic lymphocytes triggers specific recognition and removal by macrophages. J Immunol. 1992;148:2207–16.

    CAS  PubMed  Google Scholar 

  58. Fadok VA, Bratton DL, Konowal A, Freed PW, Westcott JY, Henson PM. Macrophages that have ingested apoptotic cells in vitro inhibit proinflammatory cytokine production through autocrine/paracrine mechanisms involving TGF-β, PGE2, and PAF. J Clin Invest. 1998;101:890–8.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  59. Fond AM, Lee CS, Schulman IG, Kiss RS, Ravichandran KS. Apoptotic cells trigger a membrane-initiated pathway to increase ABCA1. J Clin Invest. 2015;125:2748–58.

    Article  PubMed  PubMed Central  Google Scholar 

  60. Emoto K, Toyama-Sorimachi N, Karasuyama H, Inoue K, Umeda M. Exposure of phosphatidylethanolamine on the surface of apoptotic cells. Exp Cell Res. 1997;232:430–4.

    Article  CAS  PubMed  Google Scholar 

  61. Gude DR, Alvarez SE, Paugh SW, Mitra P, Yu J, Griffiths R, Barbour SE, Milstien S, Spiegel S. Apoptosis induces expression of sphingosine kinase 1 to release sphingosine-1-phosphate as a “come-and-get-me” signal. FASEB J. 2008;22:2629–38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Lauber K, Bohn E, Krober SM, Xiao YJ, Blumenthal SG, Lindemann RK, Marini P, Wiedig C, Zobywalski A, Baksh S, Xu Y, Autenrieth IB, Schulze-Osthoff K, Belka C, Stuhler G, Wesselborg S. Apoptotic cells induce migration of phagocytes via caspase-3- mediated release of a lipid attraction signal. Cell. 2003;113:717–30.

    Article  CAS  PubMed  Google Scholar 

  63. Brown S, Heinisch I, Ross E, Shaw K, Buckley CD, Savill J. Apoptosis disables CD31-mediated cell detachment from phagocytes promoting binding and engulfment. Nature. 2002;418:200–3.

    Article  CAS  PubMed  Google Scholar 

  64. Gardai SJ, McPhillips KA, Frasch SC, Janssen WJ, Starefeldt A, Murphy-Ullrich JE, Bratton DL, Oldenborg PA, Michalak M, Henson PM. Cell-surface calreticulin initiates clearance of viable or apoptotic cells through trans-activation of LRP on the phagocyte. Cell. 2005;123:321–34.

    Article  CAS  PubMed  Google Scholar 

  65. Truman LA, Ford CA, Pasikowska M, Pound JD, Wilkinson SJ, Dumitriu IE, Melville L, Melrose LA, Ogden CA, Nibbs R, Graham G, Combadiere C, Gregory CD. CX3CL1/fractalkine is released from apoptotic lymphocytes to stimulate macrophage chemotaxis. Blood. 2008;112:5026–36.

    Article  CAS  PubMed  Google Scholar 

  66. Leonardi-Essmann F, Emig M, Kitamura Y, Spanagel R, Gebicke-Haerter PJ. Fractalkine-upregulated milk-fat globule EGF factor-8 protein in cultured rat microglia. J Neuroimmunol. 2005;160:92–101.

    Article  CAS  PubMed  Google Scholar 

  67. Miksa M, Amin D, Wu R, Ravikumar TS, Wang P. Fractalkine-induced MFG-E8 leads to enhanced apoptotic cell clearance by macrophages. Mol Med. 2007;13:553–60.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  68. Sapozhnikov AM, Ponomarev ED, Tarasenko TN, Telford WG. Spontaneous apoptosis and expression of cell surface heat-shock proteins in cultured EL-4 lymphoma cells. Cell Prolif. 1999;32:363–78.

    Article  CAS  PubMed  Google Scholar 

  69. Basu S, Binder RJ, Suto R, Anderson KM, Srivastava PK. Necrotic but not apoptotic cell death releases heat shock proteins, which deliver a partial maturation signal to dendritic cells and activate the NF-kappa B pathway. Int Immunol. 2000;12:1539–46.

    Article  CAS  PubMed  Google Scholar 

  70. Feng H, Zeng Y, Whitesell L, Katsanis E. Stressed apoptotic tumor cells express heat shock proteins and elicit tumor-specific immunity. Blood. 2001;97:3505–12.

    Article  CAS  PubMed  Google Scholar 

  71. Goh YC, Yap CT, Huang BH, Cronshaw AD, Leung BP, Lai PB, Hart SP, Dransfield I, Ross JA. Heat-shock protein 60 translocates to the surface of apoptotic cells and differentiated megakaryocytes and stimulates phagocytosis. Cell Mol Life Sci. 2011;68:1581–92.

    Article  CAS  PubMed  Google Scholar 

  72. Gao Y, Herndon JM, Zhang H, Griffith TS, Ferguson TA. Antiinflammatory effects of CD95 ligand (FasL)-induced apoptosis. J Exp Med. 1998;188:887–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Chen W, Frank ME, Jin W, Wahl SM. TGF-beta released by apoptotic T cells contributes to an immunosuppressive milieu. Immunity. 2001;14:715–25.

    Article  CAS  PubMed  Google Scholar 

  74. Bournazou I, Pound JD, Duffin R, Bournazos S, Melville LA, Brown SB, Rossi AG, Gregory CD. Apoptotic human cells inhibit migration of granulocytes via release of lactoferrin. J Clin Invest. 2009;119:20–32.

    CAS  PubMed  Google Scholar 

  75. Bournazou I, Mackenzie KJ, Duffin R, Rossi AG, Gregory CD. Inhibition of eosinophil migration by lactoferrin. Immunol Cell Biol. 2010;88:220–3.

    Article  CAS  PubMed  Google Scholar 

  76. Miles K, Clarke DJ, Lu W, Sibinska Z, Beaumont PE, Davidson DJ, Barr TA, Campopiano DJ, Gray M. Dying and necrotic neutrophils are anti-inflammatory secondary to the release of alpha-defensins. J Immunol. 2009;183:2122–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Elliott MR, Chekeni FB, Trampont PC, Lazarowski ER, Kadl A, Walk SF, Park D, Woodson RI, Ostankovich M, Sharma P, Lysiak JJ, Harden TK, Leitinger N, Ravichandran KS. Nucleotides released by apoptotic cells act as a find-me signal to promote phagocytic clearance. Nature. 2009;461:282–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Horino K, Nishiura H, Ohsako T, Shibuya Y, Hiraoka T, Kitamura N, Yamamoto T. A monocyte chemotactic factor, S19 ribosomal protein dimer, in phagocytic clearance of apoptotic cells. Lab Invest. 1998;78:603–17.

    CAS  PubMed  Google Scholar 

  79. Knies UE, Behrensdorf HA, Mitchell CA, Deutsch U, Risau W, Drexler HC, Clauss M. Regulation of endothelial monocyte-activating polypeptide II release by apoptosis. Proc Natl Acad Sci U S A. 1998;95:12322–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Thery C, Boussac M, Veron P, Ricciardi-Castagnoli P, Raposo G, Garin J, Amigorena S. Proteomic analysis of dendritic cell-derived exosomes: a secreted subcellular compartment distinct from apoptotic vesicles. J Immunol. 2001;166:7309–18.

    Article  CAS  PubMed  Google Scholar 

  81. Zirngibl M, Furnrohr BG, Janko C, Munoz LE, Voll RE, Gregory CD, Schett G, Herrmann M. Loading of nuclear autoantigens prototypically recognized by systemic lupus erythematosus sera into late apoptotic vesicles requires intact microtubules and myosin light chain kinase activity. Clin Exp Immunol. 2015;179:39–49.

    Article  CAS  PubMed  Google Scholar 

  82. Blume KE, Soeroes S, Waibel M, Keppeler H, Wesselborg S, Herrmann M, Schulze-Osthoff K, Lauber K. Cell surface externalization of annexin A1 as a failsafe mechanism preventing inflammatory responses during secondary necrosis. J Immunol. 2009;183:8138–47.

    Article  CAS  PubMed  Google Scholar 

  83. Krispin A, Bledi Y, Atallah M, Trahtemberg U, Verbovetski I, Nahari E, Zelig O, Linial M, Mevorach D. Apoptotic cell thrombospondin-1 and heparin-binding domain lead to dendritic-cell phagocytic and tolerizing states. Blood. 2006;108:3580–9.

    Article  CAS  PubMed  Google Scholar 

  84. Soulez M, Sirois I, Brassard N, Raymond MA, Nicodeme F, Noiseux N, Durocher Y, Pshezhetsky AV, Hebert MJ. Epidermal growth factor and perlecan fragments produced by apoptotic endothelial cells co-ordinately activate ERK1/2-dependent antiapoptotic pathways in mesenchymal stem cells. Stem Cells. 2010;28:810–20.

    Article  CAS  PubMed  Google Scholar 

  85. Soulez M, Pilon EA, Dieude M, Cardinal H, Brassard N, Qi S, Wu SJ, Durocher Y, Madore F, Perreault C, Hebert MJ. The perlecan fragment LG3 is a novel regulator of obliterative remodeling associated with allograft vascular rejection. Circ Res. 2012;110:94–104.

    Article  CAS  PubMed  Google Scholar 

  86. Moffatt OD, Devitt A, Bell ED, Simmons DL, Gregory CD. Macrophage recognition of ICAM-3 on apoptotic leukocytes. J Immunol. 1999;162:6800–10.

    CAS  PubMed  Google Scholar 

  87. Torr EE, Gardner DH, Thomas L, Goodall DM, Bielemeier A, Willetts R, Griffiths HR, Marshall LJ, Devitt A. Apoptotic cell-derived ICAM-3 promotes both macrophage chemoattraction to and tethering of apoptotic cells. Cell Death Differ. 2012;19:671–9.

    Article  CAS  PubMed  Google Scholar 

  88. Kobara M, Sunagawa N, Abe M, Tanaka N, Toba H, Hayashi H, Keira N, Tatsumi T, Matsubara H, Nakata T. Apoptotic myocytes generate monocyte chemoattractant protein-1 and mediate macrophage recruitment. J Appl Physiol. 2008;104:601–9.

    Article  CAS  PubMed  Google Scholar 

  89. Renz A, Berdel WE, Kreuter M, Belka C, Schulze-Osthoff K, Los M. Rapid extracellular release of cytochrome c is specific for apoptosis and marks cell death in vivo. Blood. 2001;98:1542–8.

    Article  CAS  PubMed  Google Scholar 

  90. Codina R, Vanasse A, Kelekar A, Vezys V, Jemmerson R. Cytochrome c-induced lymphocyte death from the outside in: inhibition by serum leucine-rich alpha-2-glycoprotein-1. Apoptosis. 2010;15:139–52.

    Article  CAS  PubMed  Google Scholar 

  91. Casciola-Rosen LA, Anhalt G, Rosen A. Autoantigens targeted in systemic lupus erythematosus are clustered in two populations of surface structures on apoptotic keratinocytes. J Exp Med. 1994;179:1317–30.

    Article  CAS  PubMed  Google Scholar 

  92. Radic M, Marion T, Monestier M. Nucleosomes are exposed at the cell surface in apoptosis. J Immunol. 2004;172:6692–700.

    Article  CAS  PubMed  Google Scholar 

  93. Bilyy RO, Shkandina T, Tomin A, Munoz LE, Franz S, Antonyuk V, Kit YY, Zirngibl M, Furnrohr BG, Janko C, Lauber K, Schiller M, Schett G, Stoika RS, Herrmann M. Macrophages discriminate glycosylation patterns of apoptotic cell-derived microparticles. J Biol Chem. 2012;287:496–503.

    Article  CAS  PubMed  Google Scholar 

  94. Weihua Z, Tsan R, Schroit AJ, Fidler IJ. Apoptotic cells initiate endothelial cell sprouting via electrostatic signaling. Cancer Res. 2005;65:11529–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Sirois I, Raymond MA, Brassard N, Cailhier JF, Fedjaev M, Hamelin K, Londono I, Bendayan M, Pshezhetsky AV, Hebert MJ. Caspase-3-dependent export of TCTP: a novel pathway for antiapoptotic intercellular communication. Cell Death Differ. 2011;18:549–62.

    Article  CAS  PubMed  Google Scholar 

  96. Tennant I, Pound JD, Marr LA, Willems JJ, Petrova S, Ford CA, Paterson M, Devitt A, Gregory CD. Innate recognition of apoptotic cells: novel apoptotic cell-associated molecular patterns revealed by crossreactivity of anti-LPS antibodies. Cell Death Differ. 2013;20:698–708.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Wickman GR, Julian L, Mardilovich K, Schumacher S, Munro J, Rath N, Zander SA, Mleczak A, Sumpton D, Morrice N, Bienvenut WV, Olson MF. Blebs produced by actin-myosin contraction during apoptosis release damage-associated molecular pattern proteins before secondary necrosis occurs. Cell Death Differ. 2013;20:1293–305.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Crescitelli R, Lasser C, Szabo TG, Kittel A, Eldh M, Dianzani I, Buzas EI, Lotvall J. Distinct RNA profiles in subpopulations of extracellular vesicles: apoptotic bodies, microvesicles and exosomes. J extracellular vesicles. 2013;2.

    Google Scholar 

  99. Atkin-Smith GK, Tixeira R, Paone S, Mathivanan S, Collins C, Liem M, Goodall KJ, Ravichandran KS, Hulett MD, Poon IK. A novel mechanism of generating extracellular vesicles during apoptosis via a beads-on-a-string membrane structure. Nat Commun. 2015;6:7439.

    Article  PubMed  PubMed Central  Google Scholar 

  100. Dieude M, Bell C, Turgeon J, Beillevaire D, Pomerleau L, Yang B, Hamelin K, Qi S, Pallet N, Beland C, Dhahri W, Cailhier JF, Rousseau M, Duchez AC, Levesque T, Lau A, Rondeau C, Gingras D, Muruve D, Rivard A, Cardinal H, Perreault C, Desjardins M, Boilard E, Thibault P, Hebert MJ. The 20S proteasome core, active within apoptotic exosome-like vesicles, induces autoantibody production and accelerates rejection. Sci Trans Med. 2015;7:318ra200.

    Article  CAS  Google Scholar 

  101. Chao MP, Alizadeh AA, Tang C, Myklebust JH, Varghese B, Gill S, Jan M, Cha AC, Chan CK, Tan BT, Park CY, Zhao F, Kohrt HE, Malumbres R, Briones J, Gascoyne RD, Lossos IS, Levy R, Weissman IL, Majeti R. Anti-CD47 antibody synergizes with rituximab to promote phagocytosis and eradicate non-Hodgkin lymphoma. Cell. 2010;142:699–713.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Chao MP, Alizadeh AA, Tang C, Jan M, Weissman-Tsukamoto R, Zhao F, Park CY, Weissman IL, Majeti R. Therapeutic antibody targeting of CD47 eliminates human acute lymphoblastic leukemia. Cancer Res. 2011;71:1374–84.

    Article  CAS  PubMed  Google Scholar 

  103. Thery C, Ostrowski M, Segura E. Membrane vesicles as conveyors of immune responses. Nat Rev Immunol. 2009;9:581–93.

    Article  CAS  PubMed  Google Scholar 

  104. Buzas EI, Gyorgy B, Nagy G, Falus A, Gay S. Emerging role of extracellular vesicles in inflammatory diseases. Nat Rev Rheumatol. 2014;10:356–64.

    Article  CAS  PubMed  Google Scholar 

  105. Eken C, Martin PJ, Sadallah S, Treves S, Schaller M, Schifferli JA. Ectosomes released by polymorphonuclear neutrophils induce a MerTK-dependent anti-inflammatory pathway in macrophages. J Biol Chem. 2010;285:39914–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. D’Souza-Schorey C, Clancy JW. Tumor-derived microvesicles: shedding light on novel microenvironment modulators and prospective cancer biomarkers. Genes Dev. 2012;26:1287–99.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  107. Bonner C, Bacon S, Concannon CG, Rizvi SR, Baquie M, Farrelly AM, Kilbride SM, Dussmann H, Ward MW, Boulanger CM, Wollheim CB, Graf R, Byrne MM, Prehn JH. INS-1 cells undergoing caspase-dependent apoptosis enhance the regenerative capacity of neighboring cells. Diabetes. 2010;59:2799–808.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Peter C, Wesselborg S, Herrmann M, Lauber K. Dangerous attraction: phagocyte recruitment and danger signals of apoptotic and necrotic cells. Apoptosis. 2010;15(9):1007–28.

    Article  PubMed  Google Scholar 

  109. Arandjelovic S, Ravichandran KS. Phagocytosis of apoptotic cells in homeostasis. Nat Immunol. 2015;16:907–17.

    Article  CAS  PubMed  Google Scholar 

  110. Li F, Huang Q, Chen J, Peng Y, Roop DR, Bedford JS, Li CY. Apoptotic cells activate the “phoenix rising” pathway to promote wound healing and tissue regeneration. Sci Signal. 2010;3:ra13–13.

    PubMed  PubMed Central  Google Scholar 

  111. Ariel A, Fredman G, Sun YP, Kantarci A, Van Dyke TE, Luster AD, Serhan CN. Apoptotic neutrophils and T cells sequester chemokines during immune response resolution through modulation of CCR5 expression. Nat Immunol. 2006;7:1209–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Garrido C, Gurbuxani S, Ravagnan L, Kroemer G. Heat shock proteins: endogenous modulators of apoptotic cell death. Biochem Biophys Res Commun. 2001;286:433–42.

    Article  CAS  PubMed  Google Scholar 

  113. Baixauli F, Lopez-Otin C, Mittelbrunn M. Exosomes and autophagy: coordinated mechanisms for the maintenance of cellular fitness. Front Immunol. 2014;5:403.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  114. Coppe JP, Desprez PY, Krtolica A, Campisi J. The senescence-associated secretory phenotype: the dark side of tumor suppression. Annu Rev Pathol. 2010;5:99–118.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Birge RB, Ucker DS. Innate apoptotic immunity: the calming touch of death. Cell Death Differ. 2008;15:1096–102.

    Article  CAS  PubMed  Google Scholar 

  116. Cocco RE, Ucker DS. Distinct modes of macrophage recognition for apoptotic and necrotic cells are not specified exclusively by phosphatidylserine exposure. Mol Biol Cell. 2001;12:919–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Cvetanovic M, Mitchell JE, Patel V, Avner BS, Su Y, van der Saag PT, Witte PL, Fiore S, Levine JS, Ucker DS. Specific recognition of apoptotic cells reveals a ubiquitous and unconventional innate immunity. J Biol Chem. 2006;281:20055–67.

    Article  CAS  PubMed  Google Scholar 

  118. Cvetanovic M, Ucker DS. Innate immune discrimination of apoptotic cells: repression of proinflammatory macrophage transcription is coupled directly to specific recognition. J Immunol. 2004;172:880–9.

    Article  CAS  PubMed  Google Scholar 

  119. Lewis CE, Leek R, Harris A, McGee JO. Cytokine regulation of angiogenesis in breast cancer: the role of tumor-associated macrophages. J Leukoc Biol. 1995;57:747–51.

    CAS  PubMed  Google Scholar 

  120. Ong SM, Tan YC, Beretta O, Jiang D, Yeap WH, Tai JJ, Wong WC, Yang H, Schwarz H, Lim KH, Koh PK, Ling KL, Wong SC. Macrophages in human colorectal cancer are pro-inflammatory and prime T cells towards an anti-tumour type-1 inflammatory response. Eur J Immunol. 2012;42:89–100.

    Article  CAS  PubMed  Google Scholar 

  121. Zhang QW, Liu L, Gong CY, Shi HS, Zeng YH, Wang XZ, Zhao YW, Wei YQ. Prognostic significance of tumor-associated macrophages in solid tumor: a meta-analysis of the literature. PLoS One. 2012;7, e50946.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Stanford JC, Young C, Hicks D, Owens P, Williams A, Vaught DB, Morrison MM, Lim J, Williams M, Brantley-Sieders DM, Balko JM, Tonetti D, Earp HS, Cook RS. Efferocytosis produces a prometastatic landscape during postpartum mammary gland involution. J Clin Invest. 2014;124(11):4737–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Soki FN, Koh AJ, Jones JD, Kim YW, Dai J, Keller ET, Pienta KJ, Atabai K, Roca H, McCauley LK. Polarization of prostate cancer-associated macrophages is induced by milk fat globule-EGF factor 8 (MFG-E8)-mediated efferocytosis. J Biol Chem. 2014;289:24560–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Novak ML, Weinheimer-Haus EM, Koh TJ. Macrophage activation and skeletal muscle healing following traumatic injury. J Pathol. 2014;232:344–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Murray PJ, Allen JE, Biswas SK, Fisher EA, Gilroy DW, Goerdt S, Gordon S, Hamilton JA, Ivashkiv LB, Lawrence T, Locati M, Mantovani A, Martinez FO, Mege JL, Mosser DM, Natoli G, Saeij JP, Schultze JL, Shirey KA, Sica A, Suttles J, Udalova I, van Ginderachter JA, Vogel SN, Wynn TA. Macrophage activation and polarization: nomenclature and experimental guidelines. Immunity. 2014;41:14–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. A-Gonzalez N, Bensinger SJ, Hong C, Beceiro S, Bradley MN, Zelcer N, Deniz J, Ramirez C, Diaz M, Gallardo G, de Galarreta CR, Salazar J, Lopez F, Edwards P, Parks J, Andujar M, Tontonoz P, Castrillo A. Apoptotic cells promote their own clearance and immune tolerance through activation of the nuclear receptor LXR. Immunity. 2009;31:245–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Kondylis V, Polykratis A, Ehlken H, Ochoa-Callejero L, Straub BK, Krishna-Subramanian S, Van TM, Curth HM, Heise N, Weih F, Klein U, Schirmacher P, Kelliher M, Pasparakis M. NEMO prevents steatohepatitis and hepatocellular carcinoma by inhibiting RIPK1 kinase activity-mediated hepatocyte apoptosis. Cancer Cell. 2015;28:582–98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Fuchs Y, Steller H. Live to die another way: modes of programmed cell death and the signals emanating from dying cells. Nat Rev Mol Cell Biol. 2015;16:329–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Michalak EM, Vandenberg CJ, Delbridge AR, Wu L, Scott CL, Adams JM, Strasser A. Apoptosis-promoted tumorigenesis: gamma-irradiation-induced thymic lymphomagenesis requires Puma-driven leukocyte death. Genes Dev. 2010;24:1608–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Labi V, Erlacher M, Krumschnabel G, Manzl C, Tzankov A, Pinon J, Egle A, Villunger A. Apoptosis of leukocytes triggered by acute DNA damage promotes lymphoma formation. Genes Dev. 2010;24:1602–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Miura M. Apoptotic and nonapoptotic caspase functions in animal development. Cold Spring Harb Perspect Biol. 2012;4.

    Google Scholar 

  132. Connolly PF, Jager R, Fearnhead HO. New roles for old enzymes: killer caspases as the engine of cell behavior changes. Front Physiol. 2014;5:149.

    Article  PubMed  PubMed Central  Google Scholar 

  133. Zhao X, Wang D, Zhao Z, Xiao Y, Sengupta S, Xiao Y, Zhang R, Lauber K, Wesselborg S, Feng L, Rose TM, Shen Y, Zhang J, Prestwich G, Xu Y. Caspase-3-dependent activation of calcium-independent phospholipase A2 enhances cell migration in non-apoptotic ovarian cancer cells. J Biol Chem. 2006;281:29357–68.

    Article  CAS  PubMed  Google Scholar 

  134. Ran S, Thorpe PE. Phosphatidylserine is a marker of tumor vasculature and a potential target for cancer imaging and therapy. Int J Radiat Oncol Biol Phys. 2002;54:1479–84.

    Article  CAS  PubMed  Google Scholar 

  135. Riboldi E, Porta C, Morlacchi S, Viola A, Mantovani A, Sica A. Hypoxia-mediated regulation of macrophage functions in pathophysiology. Int Immunol. 2013;25:67–75.

    Article  CAS  PubMed  Google Scholar 

  136. Kaelin Jr WG, Ratcliffe PJ. Oxygen sensing by metazoans: the central role of the HIF hydroxylase pathway. Mol Cell. 2008;30:393–402.

    Article  CAS  PubMed  Google Scholar 

  137. Cummins EP, Berra E, Comerford KM, Ginouves A, Fitzgerald KT, Seeballuck F, Godson C, Nielsen JE, Moynagh P, Pouyssegur J, Taylor CT. Prolyl hydroxylase-1 negatively regulates IkappaB kinase-beta, giving insight into hypoxia-induced NFkappaB activity. Proc Natl Acad Sci U S A. 2006;103:18154–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Sendoel A, Hengartner MO. Apoptotic cell death under hypoxia. Physiology (Bethesda). 2014;29:168–76.

    CAS  Google Scholar 

  139. Schioppa T, Uranchimeg B, Saccani A, Biswas SK, Doni A, Rapisarda A, Bernasconi S, Saccani S, Nebuloni M, Vago L, Mantovani A, Melillo G, Sica A. Regulation of the chemokine receptor CXCR4 by hypoxia. J Exp Med. 2003;198:1391–402.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Biswas SK, Allavena P, Mantovani A. Tumor-associated macrophages: functional diversity, clinical significance, and open questions. Semin Immunopathol. 2013;35:585–600.

    Article  CAS  PubMed  Google Scholar 

  141. Movahedi K, Laoui D, Gysemans C, Baeten M, Stange G, Van den Bossche J, Mack M, Pipeleers D, In’t Veld P, De Baetselier P, Van Ginderachter JA. Different tumor microenvironments contain functionally distinct subsets of macrophages derived from Ly6C(high) monocytes. Cancer Res. 2010;70:5728–39.

    Article  CAS  PubMed  Google Scholar 

  142. Obeid E, Nanda R, Fu YX, Olopade OI. The role of tumor-associated macrophages in breast cancer progression (review). Int J Oncol. 2013;43:5–12.

    CAS  PubMed  PubMed Central  Google Scholar 

  143. Solinas G, Germano G, Mantovani A, Allavena P. Tumor-associated macrophages (TAM) as major players of the cancer-related inflammation. J Leukoc Biol. 2009;86:1065–73.

    Article  CAS  PubMed  Google Scholar 

  144. Hartnett L, Egan LJ. Inflammation, DNA methylation and colitis-associated cancer. Carcinogenesis. 2012;33:723–31.

    Article  CAS  PubMed  Google Scholar 

  145. Walter ND, Rice PL, Redente EF, Kauvar EF, Lemond L, Aly T, Wanebo K, Chan ED. Wound healing after trauma may predispose to lung cancer metastasis: review of potential mechanisms. Am J Respir Cell Mol Biol. 2011;44:591–6.

    Article  CAS  PubMed  Google Scholar 

  146. Wang XW, Hussain SP, Huo TI, Wu CG, Forgues M, Hofseth LJ, Brechot C, Harris CC. Molecular pathogenesis of human hepatocellular carcinoma. Toxicology. 2002;181–182:43–7.

    Article  PubMed  Google Scholar 

  147. Jung Y, Witek RP, Syn WK, Choi SS, Omenetti A, Premont R, Guy CD, Diehl AM. Signals from dying hepatocytes trigger growth of liver progenitors. Gut. 2010;59:655–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Lu WY, Bird TG, Boulter L, Tsuchiya A, Cole AM, Hay T, Guest RV, Wojtacha D, Man TY, Mackinnon A, Ridgway RA, Kendall T, Williams MJ, Jamieson T, Raven A, Hay DC, Iredale JP, Clarke AR, Sansom OJ, Forbes SJ. Hepatic progenitor cells of biliary origin with liver repopulation capacity. Nat Cell Biol. 2015;17(8):971–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Lu H, Clauser KR, Tam WL, Frose J, Ye X, Eaton EN, Reinhardt F, Donnenberg VS, Bhargava R, Carr SA, Weinberg RA. A breast cancer stem cell niche supported by juxtacrine signalling from monocytes and macrophages. Nat Cell Biol. 2014;16:1105–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Koh TJ, DiPietro LA. Inflammation and wound healing: the role of the macrophage. Expert Rev Mol Med. 2011;13, e23.

    Article  PubMed  PubMed Central  Google Scholar 

  151. Novak ML, Koh TJ. Phenotypic transitions of macrophages orchestrate tissue repair. Am J Pathol. 2013;183:1352–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Schafer M, Werner S. Cancer as an overhealing wound: an old hypothesis revisited. Nat Rev Mol Cell Biol. 2008;9:628–38.

    Article  CAS  PubMed  Google Scholar 

  153. Byun JS, Gardner K. Wounds that will not heal: pervasive cellular reprogramming in cancer. Am J Pathol. 2013;182:1055–64.

    Article  PubMed  PubMed Central  Google Scholar 

  154. Mantovani A, Sica A. Macrophages, innate immunity and cancer: balance, tolerance, and diversity. Curr Opin Immunol. 2010;22:231–7.

    Article  CAS  PubMed  Google Scholar 

  155. Wynn TA, Chawla A, Pollard JW. Macrophage biology in development, homeostasis and disease. Nature. 2013;496:445–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Khanna S, Biswas S, Shang Y, Collard E, Azad A, Kauh C, Bhasker V, Gordillo GM, Sen CK, Roy S. Macrophage dysfunction impairs resolution of inflammation in the wounds of diabetic mice. PLoS One. 2010;5, e9539.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  157. Swift ME, Burns AL, Gray KL, DiPietro LA. Age-related alterations in the inflammatory response to dermal injury. J Invest Dermatol. 2001;117:1027–35.

    Article  CAS  PubMed  Google Scholar 

  158. Kroemer G, Galluzzi L, Kepp O, Zitvogel L. Immunogenic cell death in cancer therapy. Annu Rev Immunol. 2013;31:51–72.

    Article  CAS  PubMed  Google Scholar 

  159. Murdoch C, Giannoudis A, Lewis CE. Mechanisms regulating the recruitment of macrophages into hypoxic areas of tumors and other ischemic tissues. Blood. 2004;104:2224–34.

    Article  CAS  PubMed  Google Scholar 

  160. DeNardo DG, Brennan DJ, Rexhepaj E, Ruffell B, Shiao SL, Madden SF, Gallagher WM, Wadhwani N, Keil SD, Junaid SA, Rugo HS, Hwang ES, Jirstrom K, West BL, Coussens LM. Leukocyte complexity predicts breast cancer survival and functionally regulates response to chemotherapy. Cancer Discov. 2011;1:54–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Xu J, Escamilla J, Mok S, David J, Priceman S, West B, Bollag G, McBride W, Wu L. CSF1R signaling blockade stanches tumor-infiltrating myeloid cells and improves the efficacy of radiotherapy in prostate cancer. Cancer Res. 2013;73:2782–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Loberg RD, Ying C, Craig M, Day LL, Sargent E, Neeley C, Wojno K, Snyder LA, Yan L, Pienta KJ. Targeting CCL2 with systemic delivery of neutralizing antibodies induces prostate cancer tumor regression in vivo. Cancer Res. 2007;67:9417–24.

    Article  CAS  PubMed  Google Scholar 

  163. Rozel S, Galban CJ, Nicolay K, Lee KC, Sud S, Neeley C, Snyder LA, Chenevert TL, Rehemtulla A, Ross BD, Pienta KJ. Synergy between anti-CCL2 and docetaxel as determined by DW-MRI in a metastatic bone cancer model. J Cell Biochem. 2009;107:58–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Sanford DE, Belt BA, Panni RZ, Mayer A, Deshpande AD, Carpenter D, Mitchem JB, Plambeck-Suess SM, Worley LA, Goetz BD, Wang-Gillam A, Eberlein TJ, Denardo DG, Goedegebuure SP, Linehan DC. Inflammatory monocyte mobilization decreases patient survival in pancreatic cancer: a role for targeting the CCL2/CCR2 axis. Clin Cancer Res. 2013;19:3404–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Kitamura T, Qian BZ, Soong D, Cassetta L, Noy R, Sugano G, Kato Y, Li J, Pollard JW. CCL2-induced chemokine cascade promotes breast cancer metastasis by enhancing retention of metastasis-associated macrophages. J Exp Med. 2015;212:1043–59.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Germano G, Frapolli R, Belgiovine C, Anselmo A, Pesce S, Liguori M, Erba E, Uboldi S, Zucchetti M, Pasqualini F, Nebuloni M, van Rooijen N, Mortarini R, Beltrame L, Marchini S, Fuso Nerini I, Sanfilippo R, Casali PG, Pilotti S, Galmarini CM, Anichini A, Mantovani A, D’Incalci M, Allavena P. Role of macrophage targeting in the antitumor activity of trabectedin. Cancer Cell. 2013;23:249–62.

    Article  CAS  PubMed  Google Scholar 

  167. Zeisberger SM, Odermatt B, Marty C, Zehnder-Fjallman AH, Ballmer-Hofer K, Schwendener RA. Clodronate-liposome-mediated depletion of tumour-associated macrophages: a new and highly effective antiangiogenic therapy approach. Br J Cancer. 2006;95:272–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Coscia M, Quaglino E, Iezzi M, Curcio C, Pantaleoni F, Riganti C, Holen I, Monkkonen H, Boccadoro M, Forni G, Musiani P, Bosia A, Cavallo F, Massaia M. Zoledronic acid repolarizes tumour-associated macrophages and inhibits mammary carcinogenesis by targeting the mevalonate pathway. J Cell Mol Med. 2010;14:2803–15.

    Article  CAS  PubMed  Google Scholar 

  169. Hiraoka K, Zenmyo M, Watari K, Iguchi H, Fotovati A, Kimura YN, Hosoi F, Shoda T, Nagata K, Osada H, Ono M, Kuwano M. Inhibition of bone and muscle metastases of lung cancer cells by a decrease in the number of monocytes/macrophages. Cancer Sci. 2008;99:1595–602.

    Article  CAS  PubMed  Google Scholar 

  170. Pulaski HL, Spahlinger G, Silva IA, McLean K, Kueck AS, Reynolds RK, Coukos G, Conejo-Garcia JR, Buckanovich RJ. Identifying alemtuzumab as an anti-myeloid cell antiangiogenic therapy for the treatment of ovarian cancer. J Transl Med. 2009;7:49.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  171. Bak SP, Walters JJ, Takeya M, Conejo-Garcia JR, Berwin BL. Scavenger receptor-A-targeted leukocyte depletion inhibits peritoneal ovarian tumor progression. Cancer Res. 2007;67:4783–9.

    Article  CAS  PubMed  Google Scholar 

  172. Nagai T, Tanaka M, Tsuneyoshi Y, Xu B, Michie SA, Hasui K, Hirano H, Arita K, Matsuyama T. Targeting tumor-associated macrophages in an experimental glioma model with a recombinant immunotoxin to folate receptor beta. Cancer Immunol Immunother. 2009;58:1577–86.

    Article  CAS  PubMed  Google Scholar 

  173. Petrillo M, Zannoni GF, Martinelli E, Pedone Anchora L, Ferrandina G, Tropeano G, Fagotti A, Scambia G. Polarisation of tumor-associated macrophages toward M2 phenotype correlates with poor response to chemoradiation and reduced survival in patients with locally advanced cervical cancer. PLoS One. 2015;10, e0136654.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  174. Pantano F, Berti P, Guida FM, Perrone G, Vincenzi B, Amato MM, Righi D, Dell’aquila E, Graziano F, Catalano V, Caricato M, Rizzo S, Muda AO, Russo A, Tonini G, Santini D. The role of macrophages polarization in predicting prognosis of radically resected gastric cancer patients. J Cell Mol Med. 2013;17:1415–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Biswas SK, Lewis CE. NF-kappaB as a central regulator of macrophage function in tumors. J Leukoc Biol. 2010;88:877–84.

    Article  CAS  PubMed  Google Scholar 

  176. Guiducci C, Vicari AP, Sangaletti S, Trinchieri G, Colombo MP. Redirecting in vivo elicited tumor infiltrating macrophages and dendritic cells towards tumor rejection. Cancer Res. 2005;65:3437–46.

    CAS  PubMed  Google Scholar 

  177. Buhtoiarov IN, Sondel PM, Wigginton JM, Buhtoiarova TN, Yanke EM, Mahvi DA, Rakhmilevich AL. Anti-tumour synergy of cytotoxic chemotherapy and anti-CD40 plus CpG-ODN immunotherapy through repolarization of tumour-associated macrophages. Immunology. 2011;132:226–39.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Weber JS, Zarour H, Redman B, Trefzer U, O’Day S, van den Eertwegh AJ, Marshall E, Wagner S. Randomized phase 2/3 trial of CpG oligodeoxynucleotide PF-3512676 alone or with dacarbazine for patients with unresectable stage III and IV melanoma. Cancer. 2009;115:3944–54.

    Article  CAS  PubMed  Google Scholar 

  179. Carpentier A, Metellus P, Ursu R, Zohar S, Lafitte F, Barrie M, Meng Y, Richard M, Parizot C, Laigle-Donadey F, Gorochov G, Psimaras D, Sanson M, Tibi A, Chinot O, Carpentier AF. Intracerebral administration of CpG oligonucleotide for patients with recurrent glioblastoma: a phase II study. Neuro Oncol. 2010;12:401–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. Zent CS, Smith BJ, Ballas ZK, Wooldridge JE, Link BK, Call TG, Shanafelt TD, Bowen DA, Kay NE, Witzig TE, Weiner GJ. Phase I clinical trial of CpG oligonucleotide 7909 (PF-03512676) in patients with previously treated chronic lymphocytic leukemia. Leuk Lymphoma. 2012;53:211–7.

    Article  CAS  PubMed  Google Scholar 

  181. Beatty GL, Chiorean EG, Fishman MP, Saboury B, Teitelbaum UR, Sun W, Huhn RD, Song W, Li D, Sharp LL, Torigian DA, O’Dwyer PJ, Vonderheide RH. CD40 agonists alter tumor stroma and show efficacy against pancreatic carcinoma in mice and humans. Science. 2011;331:1612–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. Beatty GL, Torigian DA, Chiorean EG, Saboury B, Brothers A, Alavi A, Troxel AB, Sun W, Teitelbaum UR, Vonderheide RH, O’Dwyer PJ. A phase I study of an agonist CD40 monoclonal antibody (CP-870,893) in combination with gemcitabine in patients with advanced pancreatic ductal adenocarcinoma. Clin Cancer Res. 2013;19:6286–95.

    Article  CAS  PubMed  Google Scholar 

  183. Pyonteck SM, Akkari L, Schuhmacher AJ, Bowman RL, Sevenich L, Quail DF, Olson OC, Quick ML, Huse JT, Teijeiro V, Setty M, Leslie CS, Oei Y, Pedraza A, Zhang J, Brennan CW, Sutton JC, Holland EC, Daniel D, Joyce JA. CSF-1R inhibition alters macrophage polarization and blocks glioma progression. Nat Med. 2013;19(10):1264–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. Xu M, Liu M, Du X, Li S, Li H, Li X, Li Y, Wang Y, Qin Z, Fu YX, Wang S. Intratumoral delivery of IL-21 overcomes anti-Her2/Neu resistance through shifting tumor-associated macrophages from M2 to M1 phenotype. J Immunol. 2015;194:4997–5006.

    Article  CAS  PubMed  Google Scholar 

  185. Klug F, Prakash H, Huber PE, Seibel T, Bender N, Halama N, Pfirschke C, Voss RH, Timke C, Umansky L, Klapproth K, Schakel K, Garbi N, Jager D, Weitz J, Schmitz-Winnenthal H, Hammerling GJ, Beckhove P. Low-dose irradiation programs macrophage differentiation to an iNOS(+)/M1 phenotype that orchestrates effective T cell immunotherapy. Cancer Cell. 2013;24:589–602.

    Article  CAS  PubMed  Google Scholar 

  186. O’Connell RM, Taganov KD, Boldin MP, Cheng G, Baltimore D. MicroRNA-155 is induced during the macrophage inflammatory response. Proc Natl Acad Sci U S A. 2007;104:1604–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  187. Chaudhuri AA, So AY, Sinha N, Gibson WS, Taganov KD, O’Connell RM, Baltimore D. MicroRNA-125b potentiates macrophage activation. J Immunol. 2011;187:5062–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  188. Asano K, Miwa M, Miwa K, Hanayama R, Nagase H, Nagata S, Tanaka M. Masking of phosphatidylserine inhibits apoptotic cell engulfment and induces autoantibody production in mice. J Exp Med. 2004;200:459–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  189. Bondanza A, Zimmermann VS, Rovere-Querini P, Turnay J, Dumitriu IE, Stach CM, Voll RE, Gaipl US, Bertling W, Poschl E, Kalden JR, Manfredi AA, Herrmann M. Inhibition of phosphatidylserine recognition heightens the immunogenicity of irradiated lymphoma cells in vivo. J Exp Med. 2004;200:1157–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  190. He J, Yin Y, Luster TA, Watkins L, Thorpe PE. Antiphosphatidylserine antibody combined with irradiation damages tumor blood vessels and induces tumor immunity in a rat model of glioblastoma. Clin Cancer Res. 2009;15:6871–80.

    Article  CAS  PubMed  Google Scholar 

  191. Yin Y, Huang X, Lynn KD, Thorpe PE. Phosphatidylserine-targeting antibody induces M1 macrophage polarization and promotes myeloid-derived suppressor cell differentiation. Cancer Immunol Res. 2013;1:256–68.

    Article  CAS  PubMed  Google Scholar 

  192. Chalasani P, Marron M, Roe D, Clarke K, Iannone M, Livingston RB, Shan JS, Stopeck AT. A phase I clinical trial of bavituximab and paclitaxel in patients with HER2 negative metastatic breast cancer. Cancer Med. 2015;4:1051–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  193. Verma A, Warner SL, Vankayalapati H, Bearss DJ, Sharma S. Targeting Axl and Mer kinases in cancer. Mol Cancer Ther. 2011;10:1763–73.

    Article  CAS  PubMed  Google Scholar 

  194. Sheridan C. First Axl inhibitor enters clinical trials. Nat Biotechnol. 2013;31:775–6.

    Article  CAS  PubMed  Google Scholar 

  195. Bosurgi L, Bernink JH, Delgado Cuevas V, Gagliani N, Joannas L, Schmid ET, Booth CJ, Ghosh S, Rothlin CV. Paradoxical role of the proto-oncogene Axl and Mer receptor tyrosine kinases in colon cancer. Proc Natl Acad Sci U S A. 2013;110(32):13091–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  196. Montalvao F, Garcia Z, Celli S, Breart B, Deguine J, Van Rooijen N, Bousso P. The mechanism of anti-CD20-mediated B cell depletion revealed by intravital imaging. J Clin Invest. 2013;123:5098–103.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  197. Gul N, Babes L, Siegmund K, Korthouwer R, Bogels M, Braster R, Vidarsson G, Ten Hagen TL, Kubes P, van Egmond M. Macrophages eliminate circulating tumor cells after monoclonal antibody therapy. J Clin Invest. 2014;124:812–23.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  198. Donato AL, Huang Q, Liu X, Li F, Zimmerman MA, Li CY. Caspase 3 promotes surviving melanoma tumor cell growth after cytotoxic therapy. J Invest Dermatol. 2014;134:1686–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  199. Kruiswijk F, Labuschagne CF, Vousden KH. p53 in survival, death and metabolic health: a lifeguard with a licence to kill. Nat Rev Mol Cell Biol. 2015;16:393–405.

    Article  CAS  PubMed  Google Scholar 

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Correspondence to Christopher D. Gregory .

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Gregory, C.D., Ford, C.A., Voss, J.J.L.P. (2016). Microenvironmental Effects of Cell Death in Malignant Disease. In: Gregory, C. (eds) Apoptosis in Cancer Pathogenesis and Anti-cancer Therapy. Advances in Experimental Medicine and Biology, vol 930. Springer, Cham. https://doi.org/10.1007/978-3-319-39406-0_3

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