Archives of Pharmacal Research

, Volume 42, Issue 8, pp 658–671 | Cite as

Apoptotic cell clearance in the tumor microenvironment: a potential cancer therapeutic target

  • Seong-Ah Shin
  • Sun Young Moon
  • Daeho Park
  • Jong Bae Park
  • Chang Sup LeeEmail author


Millions of cells in the human body undergo apoptosis not only under normal physiological conditions but also under pathological conditions such as infection or other diseases related to acute tissue injury. Swift apoptotic cell clearance is essential for tissue homeostasis. Defective clearance of dead cells is linked to pathogenesis of diseases such as inflammatory diseases, atherosclerosis, neurological disease, and cancer. Significance of apoptotic cell clearance has been emerging as an interesting field for disease treatment. Efficient apoptotic cell clearance plays an important role in reducing inflammation through the suppression of inappropriate inflammatory responses under healthy and diseased conditions. However, apoptotic cell clearance related to cancer pathogenesis is more complex in tumor microenvironments. Chronic inflammation resulting from the failure of apoptotic cell clearance can contribute to tumor progression. Conversely, tumor cells can exploit the anti-inflammatory effect of apoptotic cell clearance to generate an immunosuppressive tumor microenvironment. In this review, focus is on the current understanding of apoptotic cell clearance in the tumor microenvironment. Furthermore, we discuss how signaling molecules (PtdSer and PtdSer recognition receptor) mediating apoptotic cell clearance are aberrantly expressed in the tumor microenvironment and their current development state as potential therapeutic targets for clinical cancer therapy.


Apoptotic cell clearance Tumor microenvironment Phosphatidylserine Phosphatidylserine recognition receptor 



This research was supported by the National Research Foundation (NRF) grant funded by the Korea government (MSIT) (Grant Nos. NRF-2017R1A2B1005773 and NRF-2018R1A4A1025860).

Compliance with ethical standards

Conflicts of interest

The authors declare no conflicts of interest.


  1. Baghdadi M, Jinushi M (2014) The impact of the TIM gene family on tumor immunity and immunosuppression. Cell Mol Immunol 11:41–48Google Scholar
  2. Baghdadi M, Nagao H, Yoshiyama H, Akiba H, Yagita H, Dosaka-Akita H, Jinushi M (2013) Combined blockade of TIM-3 and TIM-4 augments cancer vaccine efficacy against established melanomas. Cancer Immunol Immunother 62:629–637Google Scholar
  3. Beck AW, Luster TA, Miller AF, Holloway SE, Conner CR, Barnett CC, Thorpe PE, Fleming JB, Brekken RA (2006) Combination of a monoclonal anti-phosphatidylserine antibody with gemcitabine strongly inhibits the growth and metastasis of orthotopic pancreatic tumors in mice. Int J Cancer 118:2639–2643Google Scholar
  4. Belzile O, Huang X, Gong J, Carlson J, Schroit AJ, Brekken RA, Freimark BD (2018) Antibody targeting of phosphatidylserine for the detection and immunotherapy of cancer. Immunotarg Ther 7:1–14Google Scholar
  5. Birge RB, Boeltz S, Kumar S, Carlson J, Wanderley J, Calianese D, Barcinski M, Brekken RA, Huang X, Hutchins JT, Freimark B, Empig C, Mercer J, Schroit AJ, Schett G, Herrmann M (2016) Phosphatidylserine is a global immunosuppressive signal in efferocytosis, infectious disease, and cancer. Cell Death Differ 23:962–978Google Scholar
  6. Biswas SK, Mantovani A (2010) Macrophage plasticity and interaction with lymphocyte subsets: cancer as a paradigm. Nat Immunol 11:889–896Google Scholar
  7. 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 (2004) Inhibition of phosphatidylserine recognition heightens the immunogenicity of irradiated lymphoma cells in vivo. J Exp Med 200:1157–1165Google Scholar
  8. Brown S, Heinisch I, Ross E, Shaw K, Buckley CD, Savill J (2002) Apoptosis disables CD31-mediated cell detachment from phagocytes promoting binding and engulfment. Nature 418:200–203Google Scholar
  9. 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 (2010) Anti-CD47 antibody synergizes with rituximab to promote phagocytosis and eradicate non-Hodgkin lymphoma. Cell 142:699–713Google Scholar
  10. Christoph S, Deryckere D, Schlegel J, Frazer JK, Batchelor LA, Trakhimets AY, Sather S, Hunter DM, Cummings CT, Liu J, Yang C, Kireev D, Simpson C, Norris-Drouin J, Hull-Ryde EA, Janzen WP, Johnson GL, Wang X, Frye SV, Earp HS III, Graham DK (2013) UNC569, a novel small-molecule mer inhibitor with efficacy against acute lymphoblastic leukemia in vitro and in vivo. Mol Cancer Ther 12:2367–2377Google Scholar
  11. Cook RS, Jacobsen KM, Wofford AM, Deryckere D, Stanford J, Prieto AL, Redente E, Sandahl M, Hunter DM, Strunk KE, Graham DK, Earp HS III (2013) MerTK inhibition in tumor leukocytes decreases tumor growth and metastasis. J Clin Invest 123:3231–3242Google Scholar
  12. Cork SM, Van Meir EG (2011) Emerging roles for the BAI1 protein family in the regulation of phagocytosis, synaptogenesis, neurovasculature, and tumor development. J Mol Med (Berl) 89:743–752Google Scholar
  13. Davis HW, Hussain N, Qi X (2016) Detection of cancer cells using SapC-DOPS nanovesicles. Mol Cancer 15:33Google Scholar
  14. Davra V, Kimani SG, Calianese D, Birge RB (2016) Ligand activation of TAM family receptors-implications for tumor biology and therapeutic response. Cancers (Basel) 8:107Google Scholar
  15. Derose P, Thorpe PE, Gerber DE (2011) Development of bavituximab, a vascular targeting agent with immune-modulating properties, for lung cancer treatment. Immunotherapy 3:933–944Google Scholar
  16. Elliott MR, Ravichandran KS (2010) Clearance of apoptotic cells: implications in health and disease. J Cell Biol 189:1059–1070Google Scholar
  17. Fadeel B, Xue D (2009) The ins and outs of phospholipid asymmetry in the plasma membrane: roles in health and disease. Crit Rev Biochem Mol Biol 44:264–277Google Scholar
  18. Fadok VA, Bratton DL, Konowal A, Freed PW, Westcott JY, Henson PM (1998) Macrophages that have ingested apoptotic cells in vitro inhibit proinflammatory cytokine production through autocrine/paracrine mechanisms involving TGF-beta, PGE2, and PAF. J Clin Invest 101:890–898Google Scholar
  19. Feng M, Chen JY, Weissman-Tsukamoto R, Volkmer JP, Ho PY, Mckenna KM, Cheshier S, Zhang M, Guo N, Gip P, Mitra SS, Weissman IL (2015) Macrophages eat cancer cells using their own calreticulin as a guide: roles of TLR and Btk. Proc Natl Acad Sci USA 112:2145–2150Google Scholar
  20. Frey B, Schildkopf P, Rodel F, Weiss EM, Munoz LE, Herrmann M, Fietkau R, Gaipl US (2009) AnnexinA5 renders dead tumor cells immunogenic–implications for multimodal cancer therapies. J Immunotoxicol 6:209–216Google Scholar
  21. Fucikova J, Becht E, Iribarren K, Goc J, Remark R, Damotte D, Alifano M, Devi P, Biton J, Germain C, Lupo A, Fridman WH, Dieu-Nosjean MC, Kroemer G, Sautes-Fridman C, Cremer I (2016) Calreticulin expression in human non-small cell lung cancers correlates with increased accumulation of antitumor immune cells and favorable prognosis. Cancer Res 76:1746–1756Google Scholar
  22. Fujii T, Sakata A, Nishimura S, Eto K, Nagata S (2015) TMEM16F is required for phosphatidylserine exposure and microparticle release in activated mouse platelets. Proc Natl Acad Sci USA 112:12800–12805Google Scholar
  23. Fukushima Y, Oshika Y, Tsuchida T, Tokunaga T, Hatanaka H, Kijima H, Yamazaki H, Ueyama Y, Tamaoki N, Nakamura M (1998) Brain-specific angiogenesis inhibitor 1 expression is inversely correlated with vascularity and distant metastasis of colorectal cancer. Int J Oncol 13:967–970Google Scholar
  24. Galluzzi L, Kroemer G (2017) Calreticulin and type I interferon: an unsuspected connection. Oncoimmunology 6:e1288334Google Scholar
  25. Gamrekelashvili J, Greten TF, Korangy F (2015) Immunogenicity of necrotic cell death. Cell Mol Life Sci 72:273–283Google Scholar
  26. Gardai SJ, Mcphillips KA, Frasch SC, Janssen WJ, Starefeldt A, Murphy-Ullrich JE, Bratton DL, Oldenborg PA, Michalak M, Henson PM (2005) Cell-surface calreticulin initiates clearance of viable or apoptotic cells through trans-activation of LRP on the phagocyte. Cell 123:321–334Google Scholar
  27. Garg AD, Agostinis P (2017) Cell death and immunity in cancer: from danger signals to mimicry of pathogen defense responses. Immunol Rev 280:126–148Google Scholar
  28. Ghosh AK, Secreto C, Boysen J, Sassoon T, Shanafelt TD, Mukhopadhyay D, Kay NE (2011) The novel receptor tyrosine kinase Axl is constitutively active in B-cell chronic lymphocytic leukemia and acts as a docking site of nonreceptor kinases: implications for therapy. Blood 117:1928–1937Google Scholar
  29. Gordon S, Pluddemann A (2018) Macrophage clearance of apoptotic cells: a critical assessment. Front Immunol 9:127Google Scholar
  30. Graham DK, Deryckere D, Davies KD, Earp HS (2014) The TAM family: phosphatidylserine sensing receptor tyrosine kinases gone awry in cancer. Nat Rev Cancer 14:769–785Google Scholar
  31. Gray M, Botelho RJ (2017) Phagocytosis: hungry, hungry cells. Methods Mol Biol 1519:1–16Google Scholar
  32. Gray MJ, Gong J, Hatch MM, Nguyen V, Hughes CC, Hutchins JT, Freimark BD (2016) Phosphatidylserine-targeting antibodies augment the anti-tumorigenic activity of anti-PD-1 therapy by enhancing immune activation and downregulating pro-oncogenic factors induced by T-cell checkpoint inhibition in murine triple-negative breast cancers. Breast Cancer Res 18:50Google Scholar
  33. Gregory CD, Pound JD (2011) Cell death in the neighbourhood: direct microenvironmental effects of apoptosis in normal and neoplastic tissues. J Pathol 223:177–194Google Scholar
  34. Hagiwara C, Tanaka M, Kudo H (2002) Increase in colorectal epithelial apoptotic cells in patients with ulcerative colitis ultimately requiring surgery. J Gastroenterol Hepatol 17:758–764Google Scholar
  35. Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144:646–674Google Scholar
  36. Hatanaka H, Oshika Y, Abe Y, Yoshida Y, Hashimoto T, Handa A, Kijima H, Yamazaki H, Inoue H, Ueyama Y, Nakamura M (2000) Vascularization is decreased in pulmonary adenocarcinoma expressing brain-specific angiogenesis inhibitor 1 (BAI1). Int J Mol Med 5:181–183Google Scholar
  37. He J, Luster TA, Thorpe PE (2007) Radiation-enhanced vascular targeting of human lung cancers in mice with a monoclonal antibody that binds anionic phospholipids. Clin Cancer Res 13:5211–5218Google Scholar
  38. He J, Yin Y, Luster TA, Watkins L, Thorpe PE (2009) Antiphosphatidylserine antibody combined with irradiation damages tumor blood vessels and induces tumor immunity in a rat model of glioblastoma. Clin Cancer Res 15:6871–6880Google Scholar
  39. Hector A, Montgomery EA, Karikari C, Canto M, Dunbar KB, Wang JS, Feldmann G, Hong SM, Haffner MC, Meeker AK, Holland SJ, Yu J, Heckrodt TJ, Zhang J, Ding P, Goff D, Singh R, Roa JC, Marimuthu A, Riggins GJ, Eshleman JR, Nelkin BD, Pandey A, Maitra A (2010) The Axl receptor tyrosine kinase is an adverse prognostic factor and a therapeutic target in esophageal adenocarcinoma. Cancer Biol Ther 10:1009–1018Google Scholar
  40. Huang X, Bennett M, Thorpe PE (2005) A monoclonal antibody that binds anionic phospholipids on tumor blood vessels enhances the antitumor effect of docetaxel on human breast tumors in mice. Cancer Res 65:4408–4416Google Scholar
  41. Iwamoto M, Koji T, Makiyama K, Kobayashi N, Nakane PK (1996) Apoptosis of crypt epithelial cells in ulcerative colitis. J Pathol 180:152–159Google Scholar
  42. Kariolis MS, Miao YR, Jones DS 2nd, Kapur S, Mathews Ii, Giaccia AJ, Cochran JR (2014) An engineered Axl ‘decoy receptor’ effectively silences the Gas6-Axl signaling axis. Nat Chem Biol 10:977–983Google Scholar
  43. Kasikara C, Kumar S, Kimani S, Tsou WI, Geng K, Davra V, Sriram G, Devoe C, Nguyen KN, Antes A, Krantz A, Rymarczyk G, Wilczynski A, Empig C, Freimark B, Gray M, Schlunegger K, Hutchins J, Kotenko SV, Birge RB (2017) Phosphatidylserine sensing by TAM receptors regulates AKT-dependent chemoresistance and PD-L1 expression. Mol Cancer Res 15:753–764Google Scholar
  44. Kaur B, Brat DJ, Calkins CC, Van Meir EG (2003) Brain angiogenesis inhibitor 1 is differentially expressed in normal brain and glioblastoma independently of p53 expression. Am J Pathol 162:19–27Google Scholar
  45. Kelleher RJ Jr, Balu-Iyer S, Loyall J, Sacca AJ, Shenoy GN, Peng P, Iyer V, Fathallah AM, Berenson CS, Wallace PK, Tario J, Odunsi K, Bankert RB (2015) Extracellular vesicles present in human ovarian tumor microenvironments induce a phosphatidylserine-dependent arrest in the T-cell signaling cascade. Cancer Immunol Res 3:1269–1278Google Scholar
  46. Kelsen JR, Sullivan KE (2017) Inflammatory bowel disease in primary immunodeficiencies. Curr Allergy Asthma Rep 17:57Google Scholar
  47. Khan TN, Wong EB, Soni C, Rahman ZS (2013) Prolonged apoptotic cell accumulation in germinal centers of Mer-deficient mice causes elevated B cell and CD4+ Th cell responses leading to autoantibody production. J Immunol 190:1433–1446Google Scholar
  48. Kim R, Emi M, Tanabe K (2005) Cancer cell immune escape and tumor progression by exploitation of anti-inflammatory and pro-inflammatory responses. Cancer Biol Ther 4:924–933Google Scholar
  49. Kirane A, Ludwig KF, Sorrelle N, Haaland G, Sandal T, Ranaweera R, Toombs JE, Wang M, Dineen SP, Micklem D, Dellinger MT, Lorens JB, Brekken RA (2015) Warfarin blocks Gas6-mediated Axl activation required for pancreatic cancer epithelial plasticity and metastasis. Cancer Res 75:3699–3705Google Scholar
  50. Krais JJ, Virani N, Mckernan PH, Nguyen Q, Fung KM, Sikavitsas VI, Kurkjian C, Harrison RG (2017) Antitumor synergism and enhanced survival with a tumor vasculature-targeted enzyme prodrug system, rapamycin, and cyclophosphamide. Mol Cancer Ther 16:1855–1865Google Scholar
  51. Kroemer G, Galluzzi L, Kepp O, Zitvogel L (2013) Immunogenic cell death in cancer therapy. Annu Rev Immunol 31:51–72Google Scholar
  52. Kumar S, Calianese D, Birge RB (2017) Efferocytosis of dying cells differentially modulate immunological outcomes in tumor microenvironment. Immunol Rev 280:149–164Google Scholar
  53. Lee CS, Penberthy KK, Wheeler KM, Juncadella IJ, Vandenabeele P, Lysiak JJ, Ravichandran KS (2016) Boosting apoptotic cell clearance by colonic epithelial cells attenuates inflammation in vivo. Immunity 44:807–820Google Scholar
  54. Lee-Sherick AB, Eisenman KM, Sather S, Mcgranahan A, Armistead PM, Mcgary CS, Hunsucker SA, Schlegel J, Martinson H, Cannon C, Keating AK, Earp HS, Liang X, Deryckere D, Graham DK (2013) Aberrant Mer receptor tyrosine kinase expression contributes to leukemogenesis in acute myeloid leukemia. Oncogene 32:5359–5368Google Scholar
  55. Li Y, Ye X, Tan C, Hongo JA, Zha J, Liu J, Kallop D, Ludlam MJ, Pei L (2009) Axl as a potential therapeutic target in cancer: role of Axl in tumor growth, metastasis and angiogenesis. Oncogene 28:3442–3455Google Scholar
  56. Li W, Li X, Xu S, Ma X, Zhang Q (2016) Expression of Tim4 in glioma and its regulatory role in LN-18 glioma cells. Med Sci Monit 22:77–82Google Scholar
  57. Linger RM, Keating AK, Earp HS, Graham DK (2008) TAM receptor tyrosine kinases: biologic functions, signaling, and potential therapeutic targeting in human cancer. Adv Cancer Res 100:35–83Google Scholar
  58. Linger RM, Cohen RA, Cummings CT, Sather S, Migdall-Wilson J, Middleton DH, Lu X, Baron AE, Franklin WA, Merrick DT, Jedlicka P, Deryckere D, Heasley LE, Graham DK (2013) Mer or Axl receptor tyrosine kinase inhibition promotes apoptosis, blocks growth and enhances chemosensitivity of human non-small cell lung cancer. Oncogene 32:3420–3431Google Scholar
  59. Mandal D, Mazumder A, Das P, Kundu M, Basu J (2005) Fas-, caspase 8-, and caspase 3-dependent signaling regulates the activity of the aminophospholipid translocase and phosphatidylserine externalization in human erythrocytes. J Biol Chem 280:39460–39467Google Scholar
  60. Mantovani A (2018) The inflammation - cancer connection. FEBS J 285:638–640Google Scholar
  61. Mantovani A, Allavena P, Sica A, Balkwill F (2008) Cancer-related inflammation. Nature 454:436–444Google Scholar
  62. Mantovani A, Marchesi F, Malesci A, Laghi L, Allavena P (2017) Tumour-associated macrophages as treatment targets in oncology. Nat Rev Clin Oncol 14:399–416Google Scholar
  63. Mates JM, Sanchez-Jimenez FM (2000) Role of reactive oxygen species in apoptosis: implications for cancer therapy. Int J Biochem Cell Biol 32:157–170Google Scholar
  64. Matharage JM, Minna JD, Brekken RA, Udugamasooriya DG (2015) Unbiased selection of peptide-peptoid hybrids specific for lung cancer compared to normal lung epithelial cells. ACS Chem Biol 10:2891–2899Google Scholar
  65. Mathema VB, Na-Bangchang K (2017) Regulatory roles of brain-specific angiogenesis inhibitor 1(BAI1) protein in inflammation, tumorigenesis and phagocytosis: a brief review. Crit Rev Oncol Hematol 111:81–86Google Scholar
  66. Moody G, Belmontes B, Masterman S, Wang W, King C, Murawsky C, Tsuruda T, Liu S, Radinsky R, Beltran PJ (2016) Antibody-mediated neutralization of autocrine Gas6 inhibits the growth of pancreatic ductal adenocarcinoma tumors in vivo. Int J Cancer 139:1340–1349Google Scholar
  67. Munoz LE, Frey B, Pausch F, Baum W, Mueller RB, Brachvogel B, Poschl E, Rodel F, Von Der Mark K, Herrmann M, Gaipl US (2007) The role of annexin A5 in the modulation of the immune response against dying and dead cells. Curr Med Chem 14:271–277Google Scholar
  68. Murray PJ (2018) Nonresolving macrophage-mediated inflammation in malignancy. FEBS J 285:641–653Google Scholar
  69. Nam DH, Park K, Suh YL, Kim JH (2004) Expression of VEGF and brain specific angiogenesis inhibitor-1 in glioblastoma: prognostic significance. Oncol Rep 11:863–869Google Scholar
  70. Nieminen U, Jussila A, Nordling S, Mustonen H, Farkkila MA (2014) Inflammation and disease duration have a cumulative effect on the risk of dysplasia and carcinoma in IBD: a case-control observational study based on registry data. Int J Cancer 134:189–196Google Scholar
  71. Nilsson A, Oldenborg PA (2009) CD47 promotes both phosphatidylserine-independent and phosphatidylserine-dependent phagocytosis of apoptotic murine thymocytes by non-activated macrophages. Biochem Biophys Res Commun 387:58–63Google Scholar
  72. Noy R, Pollard JW (2014) Tumor-associated macrophages: from mechanisms to therapy. Immunity 41:49–61Google Scholar
  73. Obeid M, Tesniere A, Ghiringhelli F, Fimia GM, Apetoh L, Perfettini JL, Castedo M, Mignot G, Panaretakis T, Casares N, Metivier D, Larochette N, Van Endert P, Ciccosanti F, Piacentini M, Zitvogel L, Kroemer G (2007) Calreticulin exposure dictates the immunogenicity of cancer cell death. Nat Med 13:54–61Google Scholar
  74. Paolino M, Choidas A, Wallner S, Pranjic B, Uribesalgo I, Loeser S, Jamieson AM, Langdon WY, Ikeda F, Fededa JP, Cronin SJ, Nitsch R, Schultz-Fademrecht C, Eickhoff J, Menninger S, Unger A, Torka R, Gruber T, Hinterleitner R, Baier G, Wolf D, Ullrich A, Klebl BM, Penninger JM (2014) The E3 ligase Cbl-b and TAM receptors regulate cancer metastasis via natural killer cells. Nature 507:508–512Google Scholar
  75. Park SY, Kim IS (2017) Engulfment signals and the phagocytic machinery for apoptotic cell clearance. Exp Mol Med 49:e331Google Scholar
  76. Park D, Tosello-Trampont AC, Elliott MR, Lu M, Haney LB, Ma Z, Klibanov AL, Mandell JW, Ravichandran KS (2007) BAI1 is an engulfment receptor for apoptotic cells upstream of the ELMO/Dock180/Rac module. Nature 450:430–434Google Scholar
  77. Park JH, Kotani T, Konno T, Setiawan J, Kitamura Y, Imada S, Usui Y, Hatano N, Shinohara M, Saito Y, Murata Y, Matozaki T (2016) Promotion of intestinal epithelial cell turnover by commensal bacteria: role of short-chain fatty acids. PLoS ONE 11:e0156334Google Scholar
  78. Poon IK, Lucas CD, Rossi AG, Ravichandran KS (2014) Apoptotic cell clearance: basic biology and therapeutic potential. Nat Rev Immunol 14:166–180Google Scholar
  79. Porta C, Larghi P, Rimoldi M, Totaro MG, Allavena P, Mantovani A, Sica A (2009) Cellular and molecular pathways linking inflammation and cancer. Immunobiology 214:761–777Google Scholar
  80. Qian BZ, Pollard JW (2010) Macrophage diversity enhances tumor progression and metastasis. Cell 141:39–51Google Scholar
  81. Ran S, Downes A, Thorpe PE (2002) Increased exposure of anionic phospholipids on the surface of tumor blood vessels. Cancer Res 62:6132–6140Google Scholar
  82. Ran S, He J, Huang X, Soares M, Scothorn D, Thorpe PE (2005) Antitumor effects of a monoclonal antibody that binds anionic phospholipids on the surface of tumor blood vessels in mice. Clin Cancer Res 11:1551–1562Google Scholar
  83. Ravichandran KS (2010) Find-me and eat-me signals in apoptotic cell clearance: progress and conundrums. J Exp Med 207:1807–1817Google Scholar
  84. Ray K (2018) Replenishing hepatocytes. Nat Rev Gastroenterol Hepatol 15:328Google Scholar
  85. Rogers AE, Le JP, Sather S, Pernu BM, Graham DK, Pierce AM, Keating AK (2012) Mer receptor tyrosine kinase inhibition impedes glioblastoma multiforme migration and alters cellular morphology. Oncogene 31:4171–4181Google Scholar
  86. Ruan GX, Kazlauskas A (2012) Axl is essential for VEGF-A-dependent activation of PI3 K/Akt. EMBO J 31:1692–1703Google Scholar
  87. Russ A, Hua AB, Montfort WR, Rahman B, Riaz IB, Khalid MU, Carew JS, Nawrocki ST, Persky D, Anwer F (2018) Blocking “don’t eat me” signal of CD47-SIRPalpha in hematological malignancies, an in-depth review. Blood Rev 32:480–489Google Scholar
  88. Ryu JR, Hong CJ, Kim JY, Kim EK, Sun W, Yu SW (2016) Control of adult neurogenesis by programmed cell death in the mammalian brain. Mol Brain 9:43Google Scholar
  89. Santulli-Marotto S, Gervais A, Fisher J, Strake B, Ogden CA, Riveley C, Giles-Komar J (2015) Discovering molecules that regulate efferocytosis using primary human macrophages and high content imaging. PLoS ONE 10:e0145078Google Scholar
  90. Sarode GS, Sarode SC, Maniyar N, Sharma NK, Patil S (2017) Carcinogenesis-relevant biological events in the pathophysiology of the efferocytosis phenomenon. Oncol Rev 11:343Google Scholar
  91. Schcolnik-Cabrera A, Oldak B, Juarez M, Cruz-Rivera M, Flisser A, Mendlovic F (2019) Calreticulin in phagocytosis and cancer: opposite roles in immune response outcomes. Apoptosis 24:245–255Google Scholar
  92. Schrijvers DM, De Meyer GR, Herman AG, Martinet W (2007) Phagocytosis in atherosclerosis: molecular mechanisms and implications for plaque progression and stability. Cardiovasc Res 73:470–480Google Scholar
  93. Schroeder GM, An Y, Cai ZW, Chen XT, Clark C, Cornelius LA, Dai J, Gullo-Brown J, Gupta A, Henley B, Hunt JT, Jeyaseelan R, Kamath A, Kim K, Lippy J, Lombardo LJ, Manne V, Oppenheimer S, Sack JS, Schmidt RJ, Shen G, Stefanski K, Tokarski JS, Trainor GL, Wautlet BS, Wei D, Williams DK, Zhang Y, Zhang Y, Fargnoli J, Borzilleri RM (2009) Discovery of N-(4-(2-amino-3-chloropyridin-4-yloxy)-3-fluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (BMS-777607), a selective and orally efficacious inhibitor of the Met kinase superfamily. J Med Chem 52:1251–1254Google Scholar
  94. Sharma B, Kanwar SS (2018) Phosphatidylserine: a cancer cell targeting biomarker. Semin Cancer Biol 52:17–25Google Scholar
  95. Sharma R, Huang X, Brekken RA, Schroit AJ (2017) Detection of phosphatidylserine-positive exosomes for the diagnosis of early-stage malignancies. Br J Cancer 117:545–552Google Scholar
  96. Shukla KK, Mahdi AA, Rajender S (2012) Apoptosis, spermatogenesis and male infertility. Front Biosci (Elite Ed) 4:746–754Google Scholar
  97. Simon HU, Haj-Yehia A, Levi-Schaffer F (2000) Role of reactive oxygen species (ROS) in apoptosis induction. Apoptosis 5:415–418Google Scholar
  98. Solinas G, Germano G, Mantovani A, Allavena P (2009) Tumor-associated macrophages (TAM) as major players of the cancer-related inflammation. J Leukoc Biol 86:1065–1073Google Scholar
  99. Stach CM, Turnay X, Voll RE, Kern PM, Kolowos W, Beyer TD, Kalden JR, Herrmann M (2000) Treatment with annexin V increases immunogenicity of apoptotic human T-cells in Balb/c mice. Cell Death Differ 7:911–915Google Scholar
  100. 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 3rd, Cook RS (2014) Efferocytosis produces a prometastatic landscape during postpartum mammary gland involution. J Clin Invest 124:4737–4752Google Scholar
  101. Suarez RM, Chevot F, Cavagnino A, Saettel N, Radvanyi F, Piguel S, Bernard-Pierrot I, Stoven V, Legraverend M (2013) Inhibitors of the TAM subfamily of tyrosine kinases: synthesis and biological evaluation. Eur J Med Chem 61:2–25Google Scholar
  102. Suzuki J, Fujii T, Imao T, Ishihara K, Kuba H, Nagata S (2013) Calcium-dependent phospholipid scramblase activity of TMEM16 protein family members. J Biol Chem 288:13305–13316Google Scholar
  103. Taylor DD, Gercel-Taylor C (2011) Exosomes/microvesicles: mediators of cancer-associated immunosuppressive microenvironments. Semin Immunopathol 33:441–454Google Scholar
  104. Torr EE, Gardner DH, Thomas L, Goodall DM, Bielemeier A, Willetts R, Griffiths HR, Marshall LJ, Devitt A (2012) Apoptotic cell-derived ICAM-3 promotes both macrophage chemoattraction to and tethering of apoptotic cells. Cell Death Differ 19:671–679Google Scholar
  105. Tsai WH, Shih CH, Feng SY, Li IT, Chang SC, Lin YC, Hsu HC (2014) CX3CL1(+) microparticles mediate the chemoattraction of alveolar macrophages toward apoptotic acute promyelocytic leukemic cells. Cell Physiol Biochem 33:594–604Google Scholar
  106. Tworkoski KA, Platt JT, Bacchiocchi A, Bosenberg M, Boggon TJ, Stern DF (2013) MERTK controls melanoma cell migration and survival and differentially regulates cell behavior relative to AXL. Pigment Cell Melanoma Res 26:527–541Google Scholar
  107. Utsugi T, Schroit AJ, Connor J, Bucana CD, Fidler IJ (1991) Elevated expression of phosphatidylserine in the outer membrane leaflet of human tumor cells and recognition by activated human blood monocytes. Cancer Res 51:3062–3066Google Scholar
  108. Van Vre EA, Ait-Oufella H, Tedgui A, Mallat Z (2012) Apoptotic cell death and efferocytosis in atherosclerosis. Arterioscler Thromb Vasc Biol 32:887–893Google Scholar
  109. Vandivier RW, Henson PM, Douglas IS (2006) Burying the dead: the impact of failed apoptotic cell removal (efferocytosis) on chronic inflammatory lung disease. Chest 129:1673–1682Google Scholar
  110. Vuckovic S, Vandyke K, Rickards DA, Mccauley Winter P, Brown SHJ, Mitchell TW, Liu J, Lu J, Askenase PW, Yuriev E, Capuano B, Ramsland PA, Hill GR, Zannettino ACW, Hutchinson AT (2017) The cationic small molecule GW4869 is cytotoxic to high phosphatidylserine-expressing myeloma cells. Br J Haematol 177:423–440Google Scholar
  111. Waldner MJ, Neurath MF (2015) Mechanisms of immune signaling in colitis-associated cancer. Cell Mol Gastroenterol Hepatol 1:6–16Google Scholar
  112. Wang H, Zhang X, Sun W, Hu X, Li X, Fu S, Liu C (2016) Activation of TIM1 induces colon cancer cell apoptosis via modulating Fas ligand expression. Biochem Biophys Res Commun 473:377–381Google Scholar
  113. Wang M, Zhao J, Zhang L, Wei F, Lian Y, Wu Y, Gong Z, Zhang S, Zhou J, Cao K, Li X, Xiong W, Li G, Zeng Z, Guo C (2017) Role of tumor microenvironment in tumorigenesis. J Cancer 8:761–773Google Scholar
  114. Werfel TA, Cook RS (2018) Efferocytosis in the tumor microenvironment. Semin Immunopathol 40:545–554Google Scholar
  115. Willingham SB, Volkmer JP, Gentles AJ, Sahoo D, Dalerba P, Mitra SS, Wang J, Contreras-Trujillo H, Martin R, Cohen JD, Lovelace P, Scheeren FA, Chao MP, Weiskopf K, Tang C, Volkmer AK, Naik TJ, Storm TA, Mosley AR, Edris B, Schmid SM, Sun CK, Chua MS, Murillo O, Rajendran P, Cha AC, Chin RK, Kim D, Adorno M, Raveh T, Tseng D, Jaiswal S, Enger PO, Steinberg GK, Li G, So SK, Majeti R, Harsh GR, Van De Rijn M, Teng NN, Sunwoo JB, Alizadeh AA, Clarke MF, Weissman IL (2012) The CD47-signal regulatory protein alpha (SIRPa) interaction is a therapeutic target for human solid tumors. Proc Natl Acad Sci USA 109:6662–6667Google Scholar
  116. Wu G, Ma Z, Cheng Y, Hu W, Deng C, Jiang S, Li T, Chen F, Yang Y (2018) Targeting Gas6/TAM in cancer cells and tumor microenvironment. Mol Cancer 17:20Google Scholar
  117. Yin Y, Huang X, Lynn KD, Thorpe PE (2013) Phosphatidylserine-targeting antibody induces M1 macrophage polarization and promotes myeloid-derived suppressor cell differentiation. Cancer Immunol Res 1:256–268Google Scholar
  118. Zhang L, Zhou H, Belzile O, Thorpe P, Zhao D (2014a) Phosphatidylserine-targeted bimodal liposomal nanoparticles for in vivo imaging of breast cancer in mice. J Control Release 183:114–123Google Scholar
  119. Zhang W, Deryckere D, Hunter D, Liu J, Stashko MA, Minson KA, Cummings CT, Lee M, Glaros TG, Newton DL, Sather S, Zhang D, Kireev D, Janzen WP, Earp HS, Graham DK, Frye SV, Wang X (2014b) UNC2025, a potent and orally bioavailable MER/FLT3 dual inhibitor. J Med Chem 57:7031–7041Google Scholar
  120. Zhu D, Osuka S, Zhang Z, Reichert ZR, Yang L, Kanemura Y, Jiang Y, You S, Zhang H, Devi NS, Bhattacharya D, Takano S, Gillespie GY, Macdonald T, Tan C, Nishikawa R, Nelson WG, Olson JJ, Van Meir EG (2018) BAI1 suppresses medulloblastoma formation by protecting p53 from Mdm2-mediated degradation. Cancer Cell 33(1004–1016):e1005Google Scholar
  121. Zwaal RF, Comfurius P, Bevers EM (2005) Surface exposure of phosphatidylserine in pathological cells. Cell Mol Life Sci 62:971–988Google Scholar

Copyright information

© The Pharmaceutical Society of Korea 2019

Authors and Affiliations

  1. 1.College of Pharmacy and Research Institute of Pharmaceutical SciencesGyeongsang National UniversityJinjuRepublic of Korea
  2. 2.School of Life Sciences and Aging Research InstituteGwangju Institute of Science and TechnologyGwangjuRepublic of Korea
  3. 3.Specific Organs Cancer Branch, Research Institute and HospitalNational Cancer CenterGoyangRepublic of Korea
  4. 4.Department of System Cancer Science, Graduate School of Cancer Science and PolicyNational Cancer CenterGoyangRepublic of Korea

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