肿瘤相关巨噬细胞的研究进展
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摘要
肿瘤相关巨噬细胞(tumor-associated macrophages, TAMs)在肿瘤微环境中扮演着重要的角色,TAMs的大量存在与不良预后密切相关。近年来,TAMs的相关问题成为研究的热点,该文就TAMs的募集、TAMs的极化状态及TAMs与肿瘤之间的相互作用问题进行了综述。该文对经典活化的M1型和替代活化的M2型巨噬细胞对肿瘤影响研究的最新进展进行了总结。此外,对TAMs的多种靶向治疗策略进行了总结和讨论。这些治疗策略中包含抑制TAMs的募集、直接清除TAMs、将M2型TAMs极化为M1型TAMs以及提高TAMs的吞噬能力等方法和手段。这些研究有助于深入理解TAMs与肿瘤相互作用的机理,并为肿瘤的联合治疗提供借鉴和参考。
Tumor-associated macrophages(TAMs) in microenvironment mediate many important biological functions in tumor progress. The abundance of TAMs in tumor is usually correlated with a worse patient prognosis.Significant attention has been drawn towards development of TAMs in recent years. In this paper, we discuss the recruitment of TAMs, two main kinds of polarization states and the interaction between TAMs and tumors respectively. Recent advances in the study of classically activated M1 and alternative activated M2 macrophages are summarized. In addition, a variety of targeted treatment strategies for TAMs are discussed. These therapeutic strategies include inhibition of TAMs recruitment, direct depletion of M2 TAMs, repolarization of M2 TAMs to Ml macrophages and enhancement of macrophage-mediated tumor cell killing or phagocytosis. The results of these studies may improve the understanding about the mechanism of TAMs-tumor interaction and provide inspiration for the combined treatment of tumor.
Tumor-associated macrophages(TAMs) in microenvironment mediate many important biological functions in tumor progress. The abundance of TAMs in tumor is usually correlated with a worse patient prognosis.Significant attention has been drawn towards development of TAMs in recent years. In this paper, we discuss the recruitment of TAMs, two main kinds of polarization states and the interaction between TAMs and tumors respectively. Recent advances in the study of classically activated M1 and alternative activated M2 macrophages are summarized. In addition, a variety of targeted treatment strategies for TAMs are discussed. These therapeutic strategies include inhibition of TAMs recruitment, direct depletion of M2 TAMs, repolarization of M2 TAMs to Ml macrophages and enhancement of macrophage-mediated tumor cell killing or phagocytosis. The results of these studies may improve the understanding about the mechanism of TAMs-tumor interaction and provide inspiration for the combined treatment of tumor.
引文
[1]Aras S,Zaidi MR.TAMeless traitors:macrophages in cancer progression and metastasis.Br J Cancer,2017,117:1583-91
[2]Evans R,Alexander P.Cooperation of immune lymphoid cells with macrophages in tumour immunity.Nature,1970,228:620-2
[3]Mantovani A,Marchesi F,Maliesci A,et al.Tumourassociated macrophages as treatment targets in oncology.Nat Rev Clin Oncol,2017,14:399-16
[4]Gordon S.Alternative activation of macrophages.Nat Rev Immunol,2003,3:23-35
[5]Long KB,Collier AI,Beatty GL.Macrophages:key orchestrators of a tumor microenvironment defined by therapeutic resistance.Mol Immunol,2017,pii:S0161-5890(17)30596-5
[6]Andon FT,Digifico E,Maeda A,et al.Targeting tumor associated macrophages:the new challenge for nanomedicine.Sem Immunol,2017,34:103-13
[7]Gordon S,MauteR,Dulken B,et al.PD-1 expression by tumour-associated macrophages inhibits phagocytosis and tumour immunity.Nature,2017,545:495-9
[8]Krishnan V,Schaar B,Tallapragada S,et al.Tumor associated macrophages in gynecologic cancers.Gynecol Oncol,2018,149:205-13
[9]Kitamura T,Qian B,Soong D,et al.CCL2-induced chemokine cascade promotes breast cancer metastasis by enhancing retention of metastasis-associated macrophages.J Exp Med,2015,212:1043-59
[10]Halama N,Zoernig I,Berthel A,et al.Tumoral immune cell exploitation in colorectal cancer metastases can be targeted effectively by anti-CCR5 therapy in cancer patients.Cancer Cell,2016,29:587-601
[11]Martinez F,Helming L,Milde R,et al.Genetic programs expressed in resting and IL-4 alternatively activated mouse and human macrophages:similarities and differences.Blood,2013,121:e57-69
[12]Wynn TA,Chawla A,Pollard JW.Macrophage biology in development,homeostasis and disease.Nature,2013,496:445-55
[13]Strachan DC,Ruffell B,Oei Y,et al.CSF1R inhibition delays cervical and mammary tumor growth in murine models by attenuating the turnover of tumor-associated macrophages and enhancing infiltration by CD8+T cells.Oncoimmunology,2013,2:e26968
[14]Linde N,Lederle W,Depne S,et al.Vascular endothelial growth factor-induced skin carcinogenesis depends on recruitment and alternative activation of macrophages.JPathol,2012,227:17-28
[15]Johnson K,Wilgus T.Multiple roles for VEGF in nonmelanoma skin cancer:angiogenesis and beyond.J Skin Cancer,2012,2012:483439
[16]Imtiyaz HZ,Williams EP,Hickey MM,et al.Hypoxiainducible factor 2αregulates macrophage function in mouse models of acute and tumor inflammation.J Clin Invest,2010,120:2699-714
[17]Akhtar S,Hartmann P,Karshovska E,et al.Endothelial hypoxia-inducible factor-1αpromotes atherosclerosis and monocyte recruitment by upregulating microRNA-19a.Hypertension,2015,66:1220-6
[18]吴婷,周武雄.肿瘤微环境中肿瘤相关巨噬细胞的研究进展.细胞与分子免疫学杂志,2016,32:265-7
[19]Zhang B,Cao M,He Y,et al.Combination of plasma HAand circulating M2-like monocytes may serve as a diagnostic marker for breast cancer.J Cancer,2017,8:3522-30
[20]Kobayashi N,MiyoshiI S,Mikami T,et al.Hyaluronan deficiency in tumor stroma impairs macrophage trafficking and tumor neovascularization.Cancer Res,2010,70:7073-83
[21]Goswami KK,Ghosh T,Ghosh S,et al.Tumor promoting role of anti-tumor macrophages in tumor microenvironment.Cell Immunol,2017,316:1-10
[22]Shish SL,Ruffell B,Denardo DG,et al.Th2-polarized CD4+T cells and macrophages limit efficacy of radiation therapy.Cancer Immunol Res,2015,3:518-25
[23]Pedrozagonzalez A,Xu K,Wu TC,et al.Thymic stromal lymphopoietin fosters human breast tumor growth by promoting type 2 inflammation.J Exp Med,2011,208:479-90
[24]Fu XL,Duan W,Su CY,et al.Interleukin 6 induces M2macrophage differentiation by STAT3 activation that correlates with gastric cancer progression.Cancer Immunol Immun,2017,66:1-12
[25]Zhang Y,Feng J,Fu H,et al.Coagulation factor Xregulated by CASC2c recruited macrophages and induced M2 polarization in glioblastoma multiforme.Front Immunol,2018,9:1157
[26]Murray PJ,Allen JE,Biswas SK,et al.Macrophage activation and polarization:nomenclature and experimental guidelines.Immunity,2014,41:14-20
[27]Ferrante CJ,Leibovich SJ.Rerulation of macrophage polarization and wound healing.Adv Wound Care,2012,1:10-6
[28]Singh S,Mehta N,Jiang L,et al.Initiative action of tumor-associated macrophage during tumor metastasis.Biochim Open,2017,4:8-18
[29]Duluc D,Delneste Y,Tan F,et al.Tumor-associated leukemia inhibitory factor and IL-6 skew monocyte differentiation into tumor-associated macrophage-like cells.Blood,2007,110:4319-30
[30]Mantovani A,Marchesi F,Malesci A,et al.Tumourassociated macrophages as treatment targets in oncology.Nat Rev Cancer Clin Oncol,2017,7:399-416
[31]Vesely MD,Kershaw MH,Schriber RD,et al.Natural innate and adaptive immunity to cancer.Ann Rev Immunol,2011,29:235-71
[32]Deanrdo DG,Barreto JB,Andeeu P,et al.CD4+T cells regulate pulmonary metastasis of mammary carcinomas by enhancing protumor properties of macrophages.Cancer Cell,2009,16:91-102
[33]Ruffell B.T2-polarized CD4 T cells and macrophages limit efficacy of radiotherapy.Cancer Immunol Res,2015,3:518-25
[34]De ML,Woermann S,Bunetto E,et al.Basophil recruitment into tumor draining lymph nodes correlates with Th2 inflammation and reduced survival in pancreatic cancer patients.Cancer Res,2016,76:1792-803
[35]Ma J,Liu L,Che G,et al.The M1 form of tumorassociated macrophages in non-small cell lung cancer is positively associated with survival time.BMC Cancer,2010,10:1-9
[36]Yuan X,Zhang J,Li D,et al.Prognostic significance of tumor-associated macrophages in ovarian cancer:a metaanalysis.Gynecol Oncol,2017,147:181-7
[37]Zhang Y,Yu G,Chu H,et al.Macrophage-associated PGK1 phosphorylation promotes aerobic glycolysis and tumorigenesis.Mol Cell,2018,71:201-15
[38]Sica A,Schioppa T,Mantovani A,et al.Tumourassociated macrophages are a distinct M2 polarised population promoting tumour progression:potential targets of anti-cancer therapy.Eur J Cancer,2006,42:717-27
[39]Hamanishi J,Mandai M,Iwaaki M,et al.Programmed cell death 1 ligand 1 and tumor-infiltrating CD8+Tlymphocytes are prognostic factors of human ovarian cancer.Proc Natl Acad Sci USA,2007,104:3360-5
[40]Santoni M,Romagnoli E,Saladino T,et al.Triple negative breast cancer:key role of tumor-associated macrophages in regulating the activity of anti-PD-1/PD-L1 agents.Biochim Biophys Acta,2017,1869:78-84
[41]Long K,Collier A,Beatty G.Macrophages:key orchestrators of a tumor microenvironment defined by therapeutic resistance.Mol Immunol,2017,12:003
[42]Coussens L,Tinkle C,Hanahan D,et al.MMP-9 supplied by bone marrow-derived cells contributes to skin carcinogenesis.Cell,2000,103:481-90
[43]Goswami S,Sahai E,Wyckoff JB,et al.Macrophages promote the invasion of breast carcinoma cells via a colony-stimulating factor-1/epidermal growth factor paracrine loop.Cancer Res,2005,65:5278-83
[44]Llental KR,Yu H,Kass L,et al.Matrix crosslinking forces tumor progression by enhancing integrin signaling.Cell,2009,139:891-906
[45]Kai K,Plaks V,Werb Z.Matrix metalloproteinases:regulators of the tumor microenvironment.Cell,2010,141:52-67
[46]Murdoch C,Muthana M,Coffelt SB,et al.The role of myeloid cells in the promotion of tumour angiogenesis.Nat Rev Cancer,2008,8:618-31
[47]Petty AJ,Yang Y.Tumor-associated macrophages:implications in cancer immunotherapy.Immunotherapy,2017,9:289-302
[48]Mojsilovic,SS,Mojsilovic S,Bjelica S,et al.Estramustine phosphate inhibits TGF-β-induced mouse macrophage migration and urokinase-type plasminogen activator production.Anal Cell Pathol(Amsterdam),2018,2018:3134102
[49]Liu T,Larionova I,Litviakov N,et al.Tumor-associated macrophages in human breast cancer produce new monocyte attracting and pro-angiogenic factor YKL-39indicative for increased metastasis after neoadjuvant chemotherapy.Oncoimmunology,2018,7:e1436922
[50]Sammarco G,Gadaleta CD,Zuccal V,et al.Tumorassociated macrophages and mast cells positive to tryptase are correlated with angiogenesis in surgically-treated gastric cancer patients.Int J Mol Sci,2018,19:1176
[51]Wang R,Zhang J,Chen S,et al.Tumor-associated macrophages provide a suitable microenvironment for non-small lung cancer invasion and progression.Lung Cancer,2011,74:188-96
[52]Condeelis J,Pollard JW.Macrophages:obligate partners for tumor cell migration,invasion,and metastasis.Cell,2006,124:263-6
[53]Fan QN,Jing YY,Yu GF,et al.Tumor-associated macrophages promote cancer stem cell-like properties via transforming growth factor-β1-induced epithelialmesenchymal transition in hepatocellular carcinoma.Cancer Lett,2014,352:160-8
[54]Yang Z,Xie H,He D,et al.Infiltrating macrophages increase RCC epithelial mesenchymal transition(EMT)and stem cell-like populations via AKT and mTORsignaling.Oncotarget,2016,7:44478-91
[55]Zhang WJ,Wang XH,Gao ST,et al.Tumor-associated macrophages correlate with phenomenon of epithelialmesenchymal transition and contribute to poor prognosis in triple-negative breast cancer patients.J Surg Res,2018,222:93-101
[56]Morrison C.Immuno-oncologists eye up macrophage targets.Nat Rev Drug Discov,2016,15:373-4
[57]Pienta KJ,Machiels JP,Schrijvers D,et al.Phase 2 study of carlumab(CNTO 888),a human monoclonal antibody against CC-chemokine ligand 2(CCL2),in metastatic castration-resistant prostate cancer.Invest New Drugs,2013,31:760-8
[58]Sawa-Wejksza K,Kandefer-Szerszen M.Tumor-associated macrophages as target for antitumor therapy.Arch Immunl Ther Exp,2018,66:97-111
[59]Lao L,Fan S,Song E.Tumor associated macrophages as therapeutic targets for breast cancer.Adv Exp Med Biol,2017,1026:331-70
[60]Hughes R,Qian B,Rowan C,et al.Perivascular M2macrophages stimulate tumor relapse after chemotherapy.Cancer Res,2015,75:3479-91
[61]Van Acker HH,Anguills S,Willemen Y,et al.Bisphosphonates for cancer treatment:mechanisms of action and lessons from clinical trials.Pharmacol Therapeut,2016,158:24-40
[62]Germano G,Frapolli R,Belgiovine C,et al.Role of macrophage targeting in the antitumor activity of trabectedin.Cancer Cell,2013,23:249-62
[63]Cieslewicz M,Tang J,Yu J,et al.Targeted delivery of proapoptotic peptides to tumor-associated macrophages improves survival.Proc Natl Acad Sci USA,2013,110:15919-24
[64]Zhang X,Tian W,Cai X,et al.Hydrazinocurcumin encapsuled nanoparticles"Re-Educate"tumor-associated macrophages and exhibit anti-tumor effects on breast cancer following STAT3 suppression.PLoS One,2013,8:e65896
[65]Yuar R,Li S,Geng H,et al.Reversing the polarization of tumor-associated macrophages inhibits tumor metastasis.Int Immunopharmacol,2017,49:30-7
[66]Georgoudaki AM,Prokopec KE,Bour VF,et al.reprogramming tumor-associated macrophages by antibody targeting inhibits cancer progression and metastasis.Cell Rep,2016,15:2000-11
[67]Morrison C.Immunooncologists eye up macrophage targets.Nat Rev Drug Discov,2016,15:373-4
[68]Koh E,Lee EJ,Nam GH,et al.Exosome-SIRPα,a CD47blockade increases cancer cell phagocytosis.Biomaterials,2017,121:121-9
[69]Barkal A,Weiskopf K,Kao K,et al.Engagement of MHCclass I by the inhibitory receptor LILRB1 suppresses macrophages and is a target of cancer immunotherapy.Nat Immunol,2018,19:76-84
[2]Evans R,Alexander P.Cooperation of immune lymphoid cells with macrophages in tumour immunity.Nature,1970,228:620-2
[3]Mantovani A,Marchesi F,Maliesci A,et al.Tumourassociated macrophages as treatment targets in oncology.Nat Rev Clin Oncol,2017,14:399-16
[4]Gordon S.Alternative activation of macrophages.Nat Rev Immunol,2003,3:23-35
[5]Long KB,Collier AI,Beatty GL.Macrophages:key orchestrators of a tumor microenvironment defined by therapeutic resistance.Mol Immunol,2017,pii:S0161-5890(17)30596-5
[6]Andon FT,Digifico E,Maeda A,et al.Targeting tumor associated macrophages:the new challenge for nanomedicine.Sem Immunol,2017,34:103-13
[7]Gordon S,MauteR,Dulken B,et al.PD-1 expression by tumour-associated macrophages inhibits phagocytosis and tumour immunity.Nature,2017,545:495-9
[8]Krishnan V,Schaar B,Tallapragada S,et al.Tumor associated macrophages in gynecologic cancers.Gynecol Oncol,2018,149:205-13
[9]Kitamura T,Qian B,Soong D,et al.CCL2-induced chemokine cascade promotes breast cancer metastasis by enhancing retention of metastasis-associated macrophages.J Exp Med,2015,212:1043-59
[10]Halama N,Zoernig I,Berthel A,et al.Tumoral immune cell exploitation in colorectal cancer metastases can be targeted effectively by anti-CCR5 therapy in cancer patients.Cancer Cell,2016,29:587-601
[11]Martinez F,Helming L,Milde R,et al.Genetic programs expressed in resting and IL-4 alternatively activated mouse and human macrophages:similarities and differences.Blood,2013,121:e57-69
[12]Wynn TA,Chawla A,Pollard JW.Macrophage biology in development,homeostasis and disease.Nature,2013,496:445-55
[13]Strachan DC,Ruffell B,Oei Y,et al.CSF1R inhibition delays cervical and mammary tumor growth in murine models by attenuating the turnover of tumor-associated macrophages and enhancing infiltration by CD8+T cells.Oncoimmunology,2013,2:e26968
[14]Linde N,Lederle W,Depne S,et al.Vascular endothelial growth factor-induced skin carcinogenesis depends on recruitment and alternative activation of macrophages.JPathol,2012,227:17-28
[15]Johnson K,Wilgus T.Multiple roles for VEGF in nonmelanoma skin cancer:angiogenesis and beyond.J Skin Cancer,2012,2012:483439
[16]Imtiyaz HZ,Williams EP,Hickey MM,et al.Hypoxiainducible factor 2αregulates macrophage function in mouse models of acute and tumor inflammation.J Clin Invest,2010,120:2699-714
[17]Akhtar S,Hartmann P,Karshovska E,et al.Endothelial hypoxia-inducible factor-1αpromotes atherosclerosis and monocyte recruitment by upregulating microRNA-19a.Hypertension,2015,66:1220-6
[18]吴婷,周武雄.肿瘤微环境中肿瘤相关巨噬细胞的研究进展.细胞与分子免疫学杂志,2016,32:265-7
[19]Zhang B,Cao M,He Y,et al.Combination of plasma HAand circulating M2-like monocytes may serve as a diagnostic marker for breast cancer.J Cancer,2017,8:3522-30
[20]Kobayashi N,MiyoshiI S,Mikami T,et al.Hyaluronan deficiency in tumor stroma impairs macrophage trafficking and tumor neovascularization.Cancer Res,2010,70:7073-83
[21]Goswami KK,Ghosh T,Ghosh S,et al.Tumor promoting role of anti-tumor macrophages in tumor microenvironment.Cell Immunol,2017,316:1-10
[22]Shish SL,Ruffell B,Denardo DG,et al.Th2-polarized CD4+T cells and macrophages limit efficacy of radiation therapy.Cancer Immunol Res,2015,3:518-25
[23]Pedrozagonzalez A,Xu K,Wu TC,et al.Thymic stromal lymphopoietin fosters human breast tumor growth by promoting type 2 inflammation.J Exp Med,2011,208:479-90
[24]Fu XL,Duan W,Su CY,et al.Interleukin 6 induces M2macrophage differentiation by STAT3 activation that correlates with gastric cancer progression.Cancer Immunol Immun,2017,66:1-12
[25]Zhang Y,Feng J,Fu H,et al.Coagulation factor Xregulated by CASC2c recruited macrophages and induced M2 polarization in glioblastoma multiforme.Front Immunol,2018,9:1157
[26]Murray PJ,Allen JE,Biswas SK,et al.Macrophage activation and polarization:nomenclature and experimental guidelines.Immunity,2014,41:14-20
[27]Ferrante CJ,Leibovich SJ.Rerulation of macrophage polarization and wound healing.Adv Wound Care,2012,1:10-6
[28]Singh S,Mehta N,Jiang L,et al.Initiative action of tumor-associated macrophage during tumor metastasis.Biochim Open,2017,4:8-18
[29]Duluc D,Delneste Y,Tan F,et al.Tumor-associated leukemia inhibitory factor and IL-6 skew monocyte differentiation into tumor-associated macrophage-like cells.Blood,2007,110:4319-30
[30]Mantovani A,Marchesi F,Malesci A,et al.Tumourassociated macrophages as treatment targets in oncology.Nat Rev Cancer Clin Oncol,2017,7:399-416
[31]Vesely MD,Kershaw MH,Schriber RD,et al.Natural innate and adaptive immunity to cancer.Ann Rev Immunol,2011,29:235-71
[32]Deanrdo DG,Barreto JB,Andeeu P,et al.CD4+T cells regulate pulmonary metastasis of mammary carcinomas by enhancing protumor properties of macrophages.Cancer Cell,2009,16:91-102
[33]Ruffell B.T2-polarized CD4 T cells and macrophages limit efficacy of radiotherapy.Cancer Immunol Res,2015,3:518-25
[34]De ML,Woermann S,Bunetto E,et al.Basophil recruitment into tumor draining lymph nodes correlates with Th2 inflammation and reduced survival in pancreatic cancer patients.Cancer Res,2016,76:1792-803
[35]Ma J,Liu L,Che G,et al.The M1 form of tumorassociated macrophages in non-small cell lung cancer is positively associated with survival time.BMC Cancer,2010,10:1-9
[36]Yuan X,Zhang J,Li D,et al.Prognostic significance of tumor-associated macrophages in ovarian cancer:a metaanalysis.Gynecol Oncol,2017,147:181-7
[37]Zhang Y,Yu G,Chu H,et al.Macrophage-associated PGK1 phosphorylation promotes aerobic glycolysis and tumorigenesis.Mol Cell,2018,71:201-15
[38]Sica A,Schioppa T,Mantovani A,et al.Tumourassociated macrophages are a distinct M2 polarised population promoting tumour progression:potential targets of anti-cancer therapy.Eur J Cancer,2006,42:717-27
[39]Hamanishi J,Mandai M,Iwaaki M,et al.Programmed cell death 1 ligand 1 and tumor-infiltrating CD8+Tlymphocytes are prognostic factors of human ovarian cancer.Proc Natl Acad Sci USA,2007,104:3360-5
[40]Santoni M,Romagnoli E,Saladino T,et al.Triple negative breast cancer:key role of tumor-associated macrophages in regulating the activity of anti-PD-1/PD-L1 agents.Biochim Biophys Acta,2017,1869:78-84
[41]Long K,Collier A,Beatty G.Macrophages:key orchestrators of a tumor microenvironment defined by therapeutic resistance.Mol Immunol,2017,12:003
[42]Coussens L,Tinkle C,Hanahan D,et al.MMP-9 supplied by bone marrow-derived cells contributes to skin carcinogenesis.Cell,2000,103:481-90
[43]Goswami S,Sahai E,Wyckoff JB,et al.Macrophages promote the invasion of breast carcinoma cells via a colony-stimulating factor-1/epidermal growth factor paracrine loop.Cancer Res,2005,65:5278-83
[44]Llental KR,Yu H,Kass L,et al.Matrix crosslinking forces tumor progression by enhancing integrin signaling.Cell,2009,139:891-906
[45]Kai K,Plaks V,Werb Z.Matrix metalloproteinases:regulators of the tumor microenvironment.Cell,2010,141:52-67
[46]Murdoch C,Muthana M,Coffelt SB,et al.The role of myeloid cells in the promotion of tumour angiogenesis.Nat Rev Cancer,2008,8:618-31
[47]Petty AJ,Yang Y.Tumor-associated macrophages:implications in cancer immunotherapy.Immunotherapy,2017,9:289-302
[48]Mojsilovic,SS,Mojsilovic S,Bjelica S,et al.Estramustine phosphate inhibits TGF-β-induced mouse macrophage migration and urokinase-type plasminogen activator production.Anal Cell Pathol(Amsterdam),2018,2018:3134102
[49]Liu T,Larionova I,Litviakov N,et al.Tumor-associated macrophages in human breast cancer produce new monocyte attracting and pro-angiogenic factor YKL-39indicative for increased metastasis after neoadjuvant chemotherapy.Oncoimmunology,2018,7:e1436922
[50]Sammarco G,Gadaleta CD,Zuccal V,et al.Tumorassociated macrophages and mast cells positive to tryptase are correlated with angiogenesis in surgically-treated gastric cancer patients.Int J Mol Sci,2018,19:1176
[51]Wang R,Zhang J,Chen S,et al.Tumor-associated macrophages provide a suitable microenvironment for non-small lung cancer invasion and progression.Lung Cancer,2011,74:188-96
[52]Condeelis J,Pollard JW.Macrophages:obligate partners for tumor cell migration,invasion,and metastasis.Cell,2006,124:263-6
[53]Fan QN,Jing YY,Yu GF,et al.Tumor-associated macrophages promote cancer stem cell-like properties via transforming growth factor-β1-induced epithelialmesenchymal transition in hepatocellular carcinoma.Cancer Lett,2014,352:160-8
[54]Yang Z,Xie H,He D,et al.Infiltrating macrophages increase RCC epithelial mesenchymal transition(EMT)and stem cell-like populations via AKT and mTORsignaling.Oncotarget,2016,7:44478-91
[55]Zhang WJ,Wang XH,Gao ST,et al.Tumor-associated macrophages correlate with phenomenon of epithelialmesenchymal transition and contribute to poor prognosis in triple-negative breast cancer patients.J Surg Res,2018,222:93-101
[56]Morrison C.Immuno-oncologists eye up macrophage targets.Nat Rev Drug Discov,2016,15:373-4
[57]Pienta KJ,Machiels JP,Schrijvers D,et al.Phase 2 study of carlumab(CNTO 888),a human monoclonal antibody against CC-chemokine ligand 2(CCL2),in metastatic castration-resistant prostate cancer.Invest New Drugs,2013,31:760-8
[58]Sawa-Wejksza K,Kandefer-Szerszen M.Tumor-associated macrophages as target for antitumor therapy.Arch Immunl Ther Exp,2018,66:97-111
[59]Lao L,Fan S,Song E.Tumor associated macrophages as therapeutic targets for breast cancer.Adv Exp Med Biol,2017,1026:331-70
[60]Hughes R,Qian B,Rowan C,et al.Perivascular M2macrophages stimulate tumor relapse after chemotherapy.Cancer Res,2015,75:3479-91
[61]Van Acker HH,Anguills S,Willemen Y,et al.Bisphosphonates for cancer treatment:mechanisms of action and lessons from clinical trials.Pharmacol Therapeut,2016,158:24-40
[62]Germano G,Frapolli R,Belgiovine C,et al.Role of macrophage targeting in the antitumor activity of trabectedin.Cancer Cell,2013,23:249-62
[63]Cieslewicz M,Tang J,Yu J,et al.Targeted delivery of proapoptotic peptides to tumor-associated macrophages improves survival.Proc Natl Acad Sci USA,2013,110:15919-24
[64]Zhang X,Tian W,Cai X,et al.Hydrazinocurcumin encapsuled nanoparticles"Re-Educate"tumor-associated macrophages and exhibit anti-tumor effects on breast cancer following STAT3 suppression.PLoS One,2013,8:e65896
[65]Yuar R,Li S,Geng H,et al.Reversing the polarization of tumor-associated macrophages inhibits tumor metastasis.Int Immunopharmacol,2017,49:30-7
[66]Georgoudaki AM,Prokopec KE,Bour VF,et al.reprogramming tumor-associated macrophages by antibody targeting inhibits cancer progression and metastasis.Cell Rep,2016,15:2000-11
[67]Morrison C.Immunooncologists eye up macrophage targets.Nat Rev Drug Discov,2016,15:373-4
[68]Koh E,Lee EJ,Nam GH,et al.Exosome-SIRPα,a CD47blockade increases cancer cell phagocytosis.Biomaterials,2017,121:121-9
[69]Barkal A,Weiskopf K,Kao K,et al.Engagement of MHCclass I by the inhibitory receptor LILRB1 suppresses macrophages and is a target of cancer immunotherapy.Nat Immunol,2018,19:76-84