Skip to main content
SpringerLink
Log in

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

  • Review
  • Published:
Archives of Pharmacal Research Aims and scope Submit manuscript

Abstract

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  • Baghdadi M, Jinushi M (2014) The impact of the TIM gene family on tumor immunity and immunosuppression. Cell Mol Immunol 11:41–48

    Article  CAS  PubMed  Google Scholar 

  • 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 62:629–637

    Article  CAS  PubMed  Google Scholar 

  • 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 118:2639–2643

    Article  CAS  PubMed  Google Scholar 

  • 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 7:1–14

    Article  CAS  Google Scholar 

  • 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 23:962–978

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Biswas SK, Mantovani A (2010) Macrophage plasticity and interaction with lymphocyte subsets: cancer as a paradigm. Nat Immunol 11:889–896

    Article  CAS  PubMed  Google Scholar 

  • 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 200:1157–1165

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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 418:200–203

    Article  CAS  PubMed  Google Scholar 

  • 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 142:699–713

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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 12:2367–2377

    Article  CAS  PubMed  Google Scholar 

  • 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 123:3231–3242

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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) 89:743–752

    Article  CAS  Google Scholar 

  • Davis HW, Hussain N, Qi X (2016) Detection of cancer cells using SapC-DOPS nanovesicles. Mol Cancer 15:33

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Davra V, Kimani SG, Calianese D, Birge RB (2016) Ligand activation of TAM family receptors-implications for tumor biology and therapeutic response. Cancers (Basel) 8:107

    Article  CAS  Google Scholar 

  • Derose P, Thorpe PE, Gerber DE (2011) Development of bavituximab, a vascular targeting agent with immune-modulating properties, for lung cancer treatment. Immunotherapy 3:933–944

    Article  CAS  PubMed  Google Scholar 

  • Elliott MR, Ravichandran KS (2010) Clearance of apoptotic cells: implications in health and disease. J Cell Biol 189:1059–1070

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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 44:264–277

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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 101:890–898

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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 112:2145–2150

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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 6:209–216

    Article  CAS  PubMed  Google Scholar 

  • 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 76:1746–1756

    Article  CAS  PubMed  Google Scholar 

  • 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 112:12800–12805

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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 13:967–970

    CAS  PubMed  Google Scholar 

  • Galluzzi L, Kroemer G (2017) Calreticulin and type I interferon: an unsuspected connection. Oncoimmunology 6:e1288334

    Article  PubMed  PubMed Central  Google Scholar 

  • Gamrekelashvili J, Greten TF, Korangy F (2015) Immunogenicity of necrotic cell death. Cell Mol Life Sci 72:273–283

    Article  CAS  PubMed  Google Scholar 

  • 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 123:321–334

    Article  CAS  PubMed  Google Scholar 

  • Garg AD, Agostinis P (2017) Cell death and immunity in cancer: from danger signals to mimicry of pathogen defense responses. Immunol Rev 280:126–148

    Article  CAS  PubMed  Google Scholar 

  • 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 117:1928–1937

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gordon S, Pluddemann A (2018) Macrophage clearance of apoptotic cells: a critical assessment. Front Immunol 9:127

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Graham DK, Deryckere D, Davies KD, Earp HS (2014) The TAM family: phosphatidylserine sensing receptor tyrosine kinases gone awry in cancer. Nat Rev Cancer 14:769–785

    Article  CAS  PubMed  Google Scholar 

  • Gray M, Botelho RJ (2017) Phagocytosis: hungry, hungry cells. Methods Mol Biol 1519:1–16

    Article  CAS  PubMed  Google Scholar 

  • 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 18:50

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Gregory CD, Pound JD (2011) Cell death in the neighbourhood: direct microenvironmental effects of apoptosis in normal and neoplastic tissues. J Pathol 223:177–194

    Article  CAS  PubMed  Google Scholar 

  • Hagiwara C, Tanaka M, Kudo H (2002) Increase in colorectal epithelial apoptotic cells in patients with ulcerative colitis ultimately requiring surgery. J Gastroenterol Hepatol 17:758–764

    Article  PubMed  Google Scholar 

  • Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144:646–674

    Article  CAS  PubMed  Google Scholar 

  • 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 5:181–183

    CAS  PubMed  Google Scholar 

  • 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 13:5211–5218

    Article  CAS  PubMed  Google Scholar 

  • 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 15:6871–6880

    Article  CAS  PubMed  Google Scholar 

  • 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 10:1009–1018

    Article  PubMed  CAS  Google Scholar 

  • 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 65:4408–4416

    Article  CAS  PubMed  Google Scholar 

  • Iwamoto M, Koji T, Makiyama K, Kobayashi N, Nakane PK (1996) Apoptosis of crypt epithelial cells in ulcerative colitis. J Pathol 180:152–159

    Article  CAS  PubMed  Google Scholar 

  • 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 10:977–983

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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 15:753–764

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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 162:19–27

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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 3:1269–1278

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kelsen JR, Sullivan KE (2017) Inflammatory bowel disease in primary immunodeficiencies. Curr Allergy Asthma Rep 17:57

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • 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 190:1433–1446

    Article  CAS  PubMed  Google Scholar 

  • 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 4:924–933

    Article  CAS  PubMed  Google Scholar 

  • 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 75:3699–3705

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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 16:1855–1865

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Kumar S, Calianese D, Birge RB (2017) Efferocytosis of dying cells differentially modulate immunological outcomes in tumor microenvironment. Immunol Rev 280:149–164

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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 44:807–820

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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 32:5359–5368

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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 28:3442–3455

    Article  CAS  PubMed  Google Scholar 

  • 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 22:77–82

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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 100:35–83

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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 32:3420–3431

    Article  CAS  PubMed  Google Scholar 

  • 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 280:39460–39467

    Article  CAS  PubMed  Google Scholar 

  • Mantovani A (2018) The inflammation - cancer connection. FEBS J 285:638–640

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mantovani A, Allavena P, Sica A, Balkwill F (2008) Cancer-related inflammation. Nature 454:436–444

    Article  CAS  PubMed  Google Scholar 

  • Mantovani A, Marchesi F, Malesci A, Laghi L, Allavena P (2017) Tumour-associated macrophages as treatment targets in oncology. Nat Rev Clin Oncol 14:399–416

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mates JM, Sanchez-Jimenez FM (2000) Role of reactive oxygen species in apoptosis: implications for cancer therapy. Int J Biochem Cell Biol 32:157–170

    Article  CAS  PubMed  Google Scholar 

  • 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 10:2891–2899

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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 111:81–86

    Article  PubMed  Google Scholar 

  • 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 139:1340–1349

    Article  CAS  PubMed  Google Scholar 

  • 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 14:271–277

    Article  CAS  PubMed  Google Scholar 

  • Murray PJ (2018) Nonresolving macrophage-mediated inflammation in malignancy. FEBS J 285:641–653

    Article  CAS  PubMed  Google Scholar 

  • Nam DH, Park K, Suh YL, Kim JH (2004) Expression of VEGF and brain specific angiogenesis inhibitor-1 in glioblastoma: prognostic significance. Oncol Rep 11:863–869

    CAS  PubMed  Google Scholar 

  • 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 134:189–196

    Article  PubMed  CAS  Google Scholar 

  • 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 387:58–63

    Article  CAS  PubMed  Google Scholar 

  • Noy R, Pollard JW (2014) Tumor-associated macrophages: from mechanisms to therapy. Immunity 41:49–61

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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 13:54–61

    Article  CAS  PubMed  Google Scholar 

  • 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 507:508–512

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Park SY, Kim IS (2017) Engulfment signals and the phagocytic machinery for apoptotic cell clearance. Exp Mol Med 49:e331

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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 450:430–434

    Article  CAS  PubMed  Google Scholar 

  • 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:e0156334

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Poon IK, Lucas CD, Rossi AG, Ravichandran KS (2014) Apoptotic cell clearance: basic biology and therapeutic potential. Nat Rev Immunol 14:166–180

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Porta C, Larghi P, Rimoldi M, Totaro MG, Allavena P, Mantovani A, Sica A (2009) Cellular and molecular pathways linking inflammation and cancer. Immunobiology 214:761–777

    Article  CAS  PubMed  Google Scholar 

  • Qian BZ, Pollard JW (2010) Macrophage diversity enhances tumor progression and metastasis. Cell 141:39–51

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ran S, Downes A, Thorpe PE (2002) Increased exposure of anionic phospholipids on the surface of tumor blood vessels. Cancer Res 62:6132–6140

    CAS  PubMed  Google Scholar 

  • 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 11:1551–1562

    Article  CAS  PubMed  Google Scholar 

  • Ravichandran KS (2010) Find-me and eat-me signals in apoptotic cell clearance: progress and conundrums. J Exp Med 207:1807–1817

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ray K (2018) Replenishing hepatocytes. Nat Rev Gastroenterol Hepatol 15:328

    Article  PubMed  Google Scholar 

  • 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 31:4171–4181

    Article  CAS  PubMed  Google Scholar 

  • Ruan GX, Kazlauskas A (2012) Axl is essential for VEGF-A-dependent activation of PI3 K/Akt. EMBO J 31:1692–1703

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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 32:480–489

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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 9:43

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • 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:e0145078

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Sarode GS, Sarode SC, Maniyar N, Sharma NK, Patil S (2017) Carcinogenesis-relevant biological events in the pathophysiology of the efferocytosis phenomenon. Oncol Rev 11:343

    PubMed  PubMed Central  Google Scholar 

  • 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 24:245–255

    Article  CAS  PubMed  Google Scholar 

  • Schrijvers DM, De Meyer GR, Herman AG, Martinet W (2007) Phagocytosis in atherosclerosis: molecular mechanisms and implications for plaque progression and stability. Cardiovasc Res 73:470–480

    Article  CAS  PubMed  Google Scholar 

  • 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 52:1251–1254

    Article  CAS  PubMed  Google Scholar 

  • Sharma B, Kanwar SS (2018) Phosphatidylserine: a cancer cell targeting biomarker. Semin Cancer Biol 52:17–25

    Article  CAS  PubMed  Google Scholar 

  • Sharma R, Huang X, Brekken RA, Schroit AJ (2017) Detection of phosphatidylserine-positive exosomes for the diagnosis of early-stage malignancies. Br J Cancer 117:545–552

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shukla KK, Mahdi AA, Rajender S (2012) Apoptosis, spermatogenesis and male infertility. Front Biosci (Elite Ed) 4:746–754

    Article  Google Scholar 

  • Simon HU, Haj-Yehia A, Levi-Schaffer F (2000) Role of reactive oxygen species (ROS) in apoptosis induction. Apoptosis 5:415–418

    Article  CAS  PubMed  Google Scholar 

  • Solinas G, Germano G, Mantovani A, Allavena P (2009) Tumor-associated macrophages (TAM) as major players of the cancer-related inflammation. J Leukoc Biol 86:1065–1073

    Article  CAS  PubMed  Google Scholar 

  • 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 7:911–915

    Article  CAS  PubMed  Google Scholar 

  • 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 124:4737–4752

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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 61:2–25

    Article  CAS  PubMed  Google Scholar 

  • 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 288:13305–13316

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Taylor DD, Gercel-Taylor C (2011) Exosomes/microvesicles: mediators of cancer-associated immunosuppressive microenvironments. Semin Immunopathol 33:441–454

    Article  CAS  PubMed  Google Scholar 

  • 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 19:671–679

    Article  CAS  PubMed  Google Scholar 

  • 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 33:594–604

    Article  CAS  PubMed  Google Scholar 

  • 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 26:527–541

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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 51:3062–3066

    CAS  PubMed  Google Scholar 

  • Van Vre EA, Ait-Oufella H, Tedgui A, Mallat Z (2012) Apoptotic cell death and efferocytosis in atherosclerosis. Arterioscler Thromb Vasc Biol 32:887–893

    Article  PubMed  CAS  Google Scholar 

  • Vandivier RW, Henson PM, Douglas IS (2006) Burying the dead: the impact of failed apoptotic cell removal (efferocytosis) on chronic inflammatory lung disease. Chest 129:1673–1682

    Article  PubMed  Google Scholar 

  • 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 177:423–440

    Article  CAS  PubMed  Google Scholar 

  • Waldner MJ, Neurath MF (2015) Mechanisms of immune signaling in colitis-associated cancer. Cell Mol Gastroenterol Hepatol 1:6–16

    Article  PubMed  Google Scholar 

  • 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 473:377–381

    Article  CAS  PubMed  Google Scholar 

  • 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 8:761–773

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Werfel TA, Cook RS (2018) Efferocytosis in the tumor microenvironment. Semin Immunopathol 40:545–554

    Article  PubMed  PubMed Central  Google Scholar 

  • 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 109:6662–6667

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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 17:20

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • 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 1:256–268

    Article  CAS  PubMed  Google Scholar 

  • 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 183:114–123

    Article  CAS  PubMed  Google Scholar 

  • 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 57:7031–7041

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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):e1005

    Google Scholar 

  • Zwaal RF, Comfurius P, Bevers EM (2005) Surface exposure of phosphatidylserine in pathological cells. Cell Mol Life Sci 62:971–988

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

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

Author information

Authors and Affiliations

  1. College of Pharmacy and Research Institute of Pharmaceutical Sciences, Gyeongsang National University, 501 Jinju-daero, Jinju, Gyeongnam, 52828, Republic of Korea

    Seong-Ah Shin, Sun Young Moon & Chang Sup Lee

  2. School of Life Sciences and Aging Research Institute, Gwangju Institute of Science and Technology, Gwangju, 61005, Republic of Korea

    Daeho Park

  3. Specific Organs Cancer Branch, Research Institute and Hospital, National Cancer Center, Goyang, Gyeonggi, 10408, Republic of Korea

    Jong Bae Park

  4. Department of System Cancer Science, Graduate School of Cancer Science and Policy, National Cancer Center, Goyang, Gyeonggi, 10408, Republic of Korea

    Jong Bae Park

Authors
  1. Seong-Ah Shin
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sun Young Moon
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Daeho Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jong Bae Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Chang Sup Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Chang Sup Lee.

Ethics declarations

Conflicts of interest

The authors declare no conflicts of interest.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Shin, SA., Moon, S.Y., Park, D. et al. Apoptotic cell clearance in the tumor microenvironment: a potential cancer therapeutic target. Arch. Pharm. Res. 42, 658–671 (2019). https://doi.org/10.1007/s12272-019-01169-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12272-019-01169-2

Keywords

Search

Navigation