摘要
包括乳腺癌在内的各种癌症类型中的肿瘤异质性在肿瘤标志的表现中是关键的。肿瘤异质性被视为一种常见的景观，其中包括细胞和非细胞因子的肿瘤内组分与外部环境形成界面，导致特定癌症类型的独特身份。在肿瘤异质性的各种贡献者中，细胞异质性极大地在抗药性和癌症复发中起作用。在肿瘤的细胞异质性中，肿瘤相关巨噬细胞（TAM）是促进乳腺癌和其他癌症类型中的生长，转移和药物抗性的促肿瘤类型的免疫细胞。揭示TAM的分子方面可以提供一个突破，以消除对现有药物的治疗阻断，并且这种理解在未来将为一类新的癌症免疫治疗铺平道路。本综述阐述了目前对TAM在乳腺癌标志中的作用的理解，并阐明了针对驯服癌症TAM的临床前药物的现状。
关键词: 生长，免疫反应，转移，肿瘤，治疗，耐药性。
图形摘要
[1]
Plummer MC, de Martel J, Vignat J, Ferlay F, Bray S. Franceschi. Global burden of cancers attributable to infections in 2012: a synthetic analysis. Lancet Glob Health 2016; 4(9): e609-16.
[2]
Torres L, Ribeiro FR, Pandis N, Andersen JA, Heim S, Teixeira MR. Intratumor genomic heterogeneity in breast cancer with clonal divergence between primary carcinomas and lymph node metastases. Breast Cancer Res Treat 2007; 102(2): 143-55.
[3]
Grivennikov SI, Greten FR, Karin M. Immunity, inflammation, and cancer. Cell 2010; 140(6): 883-99.
[4]
Stephens PJ, Tarpey PS, Davies H, et al. The landscape of cancer genes and mutational processes in breast cancer. Nature 2012; 486: 400-4.
[5]
Breitkreutz D, Hlatky L, Rietman E, Tuszynski JA. Molecular signaling network complexity is correlated with cancer patient survivability. Proc Natl Acad Sci USA 2012; 109(23): 9209-12.
[6]
Fisher R, Pusztai L, Swanton C. Cancer heterogeneity: implications for targeted therapeutics. Br J Cancer 2013; 108(3): 479-85.
[7]
Alizadeh AA, Aranda V, Bardelli A, et al. Toward understanding and exploiting tumor heterogeneity. Nat Med 2015; 21(8): 846-53.
[8]
Jahagirdar D, Purohit S, Jain A, Sharma NK. Export of short RNAs: A bridge between breast carcinoma and their neighboring cells. Front Oncol 2016; 6: 147.
[9]
Kim IS, Zhang XH. One microenvironment does not fit all: heterogeneity beyond cancer cells. Cancer Metastasis Rev 2016; 35(4): 601-29.
[10]
Nilendu P, Kumar A, Kumar A, Pal JK, Sharma NK. Breast cancer stem cells as last soldiers eluding therapeutic burn: A hard nut to crack. Int J Cancer 2017; 142(1): 7-17.
[11]
Augustin, H.G.; Koh, G.Y. Organotypic vasculature: From descriptive heterogeneity to functional pathophysiology. Science, 2017, eaal2379.
[13]
Shibue TRA. Weinberg. E.M.T. CSCs, and drug resistance: the mechanistic link and clinical implications. Nat Rev Clin Oncol 2017.
[http://dx.doi.org/10.1038/nrclinonc.2017.44]
[http://dx.doi.org/10.1038/nrclinonc.2017.44]
[14]
Tanaka A, Sakaguchi S. Regulatory T cells in cancer immunotherapy. Cell Res 2017; 27(1): 109-18.
[15]
Zhang M, Lee AV, Rosen JM. The cellular origin and evolution of breast cancer. cold spring harb perspect med. 2017, 7(3).
[17]
Schiarea S, Liguori M, Fabbri M, et al. Tumor-conditioned macrophages secrete migration-stimulating factor: a new marker for M2-polarization, influencing tumor cell motility. J Immunol 2010; 185(1): 642-52.
[18]
DeNardo DG, Brennan DJ, Rexhepaj E, et al. Leukocyte complexity predicts breast cancer survival and functionally regulates response to chemotherapy. Cancer Discov 2011; 54-67.
[19]
Lin EY, Nguyen AV, Russell RG, Pollard JW. Colony-stimulating factor 1 promotes progression of mammary tumors to malignancy. J Exp Med 2001; 193: 727-40.
[20]
Allavena P, Mantovani A. Immunology in the clinic review series; focus on cancer: tumour-associated macrophages: undisputed stars of the inflammatory tumour microenvironment. Clin Exp Immune 2012; 167(2): 195-205.
[21]
Rivera LB, Bergers G. Location, location, location: macrophage positioning within tumors determines pro- or antitumor activity. Cancer Cell 2013; 24(6): 687-9.
[22]
Chanmee T, Pawared O, Kenjiro K. Naoki, Itano. Tumor-associated macrophages as major players in the tumor microenvironment. Cancers (Basel) 2014; 6(3): 1670-90.
[23]
Graham DK, DeRyckere D, Davies KD, Earp HS. The TAM family: phosphatidylserine-sensing receptor tyrosine kinases gone awry in cancer. Nat Rev Cancer 2014; 14: 769-85.
[24]
Qian BZ, Li J, Zhang H, et al. CCL2 recruits inflammatory monocytes to facilitate breast-tumour metastasis. Nature 2011; 475: 222-5.
[25]
Franklin RA, Liao W, Sarkar A, et al. The cellular and molecular origin of tumor-associated macrophages. Science 2014; 344: 921-5.
[26]
Frankenberger C, Rabe D, Bainer R, et al. Metastasis Suppressors regulate the tumor microenvironment by blocking recruitment of prometastatic tumor-associated macrophages. Cancer Res 2015; 75(19): 4063-73.
[27]
Klingen TA, Chen Y, Aas H, Wik E, Akslen LA. Tumor-associated macrophages are strongly related to vascular invasion, non-luminal subtypes, and interval breast cancer. Hum Pathol 2017; 69: 72-80.
[28]
Hollmén M, Karaman S, Schwager S, et al. G-CSF regulates macrophage phenotype and associates with poor overall survival in human triple-negative breast cancer. OncoImmunology 2015; 5(3): e1115177.
[29]
Hollmén M, Roudnicky F, Karaman S, Detmar M. Characterization of macrophage-cancer cell crosstalk in estrogen receptor positive and triple-negative breast cancer. Sci Rep 2015; 5: 9188.
[30]
Shiao SL, Ruffell B, DeNardo DG, Faddegon BA, Park CC, Coussens LM. TH2-polarized CD4+ T Cells and macrophages limit efficacy of radiotherapy. Cancer Immunol Res 2015; 3: 518-25.
[31]
Henze A, Mazzone M. The impact of hypoxia on tumor-associated macrophages. J Clin Invest 2016; 126(10): 3672-9.
[32]
Walker ND, Patel J, Munoz JL, et al. The bone marrow niche in support of breast cancer dormancy. Cancer Lett 2016; 380(1): 263-71.
[33]
Yang L, Zhang Y. Tumor-associated macrophages: from basic research to clinical application. J Hematol Oncol 2017; 10: 58.
[34]
Zheng QF, Wang HM, Wang ZF, et al. Reprogramming of histone methylation controls the differentiation of monocytes into macrophages. FEBS J 2017; 284(9): 1309-23.
[35]
Zhang B, Cao M, He Y, et al. Combination of plasma HA and circulating M2-like monocytes may serve as a diagnostic marker for breast cancer. J Cancer 2017; 8(17): 3522-30.
[36]
Netea-Maier R, Smit J, Netea M. Metabolic changes in tumor cells and tumor-associated macrophages: A mutual relationship. Cancer Lett 2018; 413: 102-9.
[37]
Wang Z, Chen JQ, Liu JL, Tian L. Exosomes in tumor microenvironment: novel transporters and biomarkers. J Transl Med 2016; 14(1): 297.
[39]
Coscia M, Quaglino E, Iezzi M, et al. Zoledronic acid repolarizes tumor-associated macrophages and inhibits mammary carcinogenesis by targeting the mevalonate pathway. J Cell Mol Med 2010; 14(12): 2803-15.
[40]
Buhtoiarov IN, Sondel PM, Wigginton JM, et al. Anti-tumour synergy of cytotoxic chemotherapy and anti-CD40 plus CpG-ODN immunotherapy through repolarization of tumour-associated macrophages. J Immunol 2011; 132(2): 226-39.
[41]
Melissa RJ, Junttila J. Frederic, de Sauvage. Influence of tumour micro-environment heterogeneity on therapeutic response. Nature 2013; 501: 346-54.
[42]
Junttila M, Sauvage F. Influence of tumour micro-environment heterogeneity on therapeutic response. Nature 2013; 50: 346-54.
[43]
McGranahan N, Swanton C. Clonal heterogeneity and tumor evolution: past, present, and the future. Cell 2017; 168(4): 613-28.
[44]
Picco N, Sahai E, Maini PK, Anderson AR. Integrating models to quantify environment mediated drug resistance. Cancer Res., 2017, pii: canres.0835.
[45]
Balkwill FR, Capasso M, Hagemann T. The tumor microenvironment at a glance. J Cell Sci 2012; 125(Pt 23): 5591-6.
[46]
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 2018; 1869(1): 78-84.
[47]
Creixell P, Reimand J, Haider S, et al. Pathway and network analysis of cancer genomes. Nat Methods 2015; 12(7): 615-21.
[48]
Mantovani A, Sozzani S, Locati M, Allavena P, Sica A. Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol 2002; 23(11): 549-55.
[49]
Caso G, Barry C, Patejunas G. Dysregulation of CXCL9 and reduced tumor growth in Egr-1 deficient mice. J Hematol Oncol 2009; 2: 7.
[50]
Thoreau M, Leong Penny H, Tan KW, et al. Vaccine-induced tumor regression requires a dynamic cooperation between T cells and myeloid cells at the tumor site. Oncotarget J 2015; 6(29): 27832-46.
[51]
Gottfried E, Faust S, Fritsche J, et al. Identification of genes expressed in tumor-associated macrophages. Immunobiol J 2003; 207(5): 351-9.
[52]
Niu M, Valdes S, Naguib YW, Hursting SD, Cui Z. Tumor-associated macrophage-mediated targeted therapy of triple-negative breast cancer. Mol Pharm 2016; 13(6): 1833-42.
[53]
Na YR, Yoon YN, Son DI, Seok SH. Cyclooxygenase-2 inhibition blocks M2 macrophage differentiation and suppresses metastasis in murine breast cancer model. PLoS One 8(5): e63451.
[54]
Gan L, Qiu Z, Huang J, et al. Cyclooxygenase-2 in tumor-associated macrophages promotes metastatic potential of breast cancer cells through Akt pathway. Int J Biol Sci 2016; 12(12): 1533-43.
[55]
Ringleb J, Strack E, Angioni C, et al. Apoptotic cancer cells suppress 5-lipoxygenase in tumor-associated macrophages. J Immunol 2018; 200(2): 857-68.
[56]
Riabov V, Gudima A, Wang N, Mickley A, Orekhov A, Kzhyshkowska J. Role of tumor associated macrophages in tumor angiogenesis and lymphangiogenesis. Front Physiol 2014; 5(5): 75.
[57]
Sica A, Saccani A, Bottazzi B, et al. Autocrine production of IL-10 mediates defective IL-12 production and NF-kappa B activation in tumor-associated macrophages. J Immunol 2000; 164(2): 762-7.
[60]
Sassen S, Eric A, Miska CC. MicroRNA-implications for cancer. Virchows Arch 2008; 452(1): 1-10.
[61]
Berger SL, Kouzarides T, Shiekhattar R, Shilatifard A. An operational definition of epigenetics. Genes Dev 2009; 23: 781-3.
[62]
Graff JW, Dickson AM, Clay G, McCaffrey AP, Wilson ME. Identifying functional MicroRNAs in macrophages with polarized phenotypes. J Biol Chem 2012; 287(26): 21816-25.
[63]
Squadrito ML, Pucci F, Magri L, et al. miR-511-3p modulates genetic programs of tumor-associated macrophages. Cell Reports 2012; 1(2): 141-54.
[64]
Paladini L, Fabris L, Bottai G, et al. Targeting microRNAs as key modulators of tumor immune response. J Exp Clin Cancer Res 2016; 35: 103.
[65]
Kohlhapp F, Mitra A, Lengyel E, Peter M. microRNAs as mediators and communicators between cancer cells and the tumor micro-environment. Oncogene 2015; 34(48): 5857-68.
[66]
Yang M, Chen J, Su F, et al. Microvesicles secreted by macrophages shuttle invasion-potentiating microRNAs into breast cancer cells. Mol Cancer 2011; 10: 117.
[67]
Xi J, Huang Q, Wang L, et al. miR-21 depletion in macrophages promotes tumoricidal polarization and enhances PD-1 immunotherapy. Oncogene 2018; 37(23): 3151.
[68]
Korabecna M, Koutova L, Tesarova P. The potential roles of vesicle-enclosed miRNAs in communication between macrophages and cancer cells in tumor microenvironment. Neoplasma 2017; 64(3): 406-11.
[69]
Huang F, Zhao JL, Wang L, et al. miR-148a-3p mediates notch signaling to promote the differentiation and M1 activation of macrophages. Front Immunol 2017; 8: 1327.
[70]
Chen MT, Lin HS, Shen C, et al. 1-regulated long noncoding rna lnc-mc controls human monocyte/macrophage differentiation through interaction with MicroRNA 199a-5p. Mol Cell Biol 2015; 35(18): 3212-24.
[71]
Louafi F, Martinez-Nunez R, Sanchez-Elsner T. MicroRNA-155 targets SMAD2 and modulates the response of macrophages to transforming growth factor-β. J Biol Chem 2010; 285(53): 41328-36.
[72]
Banerjee S, Cui H, Xie N, et al. miR-125a-5p regulates differential activation of macrophages and inflammation. J Biol Chem 2013; 288(49): 35428-36.
[73]
Zhong Y, Yi C. MicroRNA-720 suppresses M2 macrophage polarization by targeting GATA3. Biosci Rep 2016; 36(4): BSR20160105.
[74]
Nilsson S, Möller C, Jirström K, et al. Downregulation of miR-92a is associated with aggressive breast cancer features and increased tumor macrophage infiltration. PLoS One 2012; 7(4): e36051.
[75]
Li Y, Zhao L, Shi B, et al. Functions of miR-146a and miR-222 in tumor-associated macrophages in breast cancer. Sci Rep 2015; 5: 18648.
[76]
Nilendu P, Sharma NK. Epigenomic hard drive imprinting: a hidden code beyond the biological death of cancer patients. J Cancer Prev 2017; 22(4): 211-8.
[77]
Sparmann A, Bar-Sagi D. Ras-induced interleukin-8 expression plays a critical role in tumor growth and angiogenesis. Cancer Cell 2004; 6: 447-58.
[78]
Liu S, Jin K, Hui Y, et al. HOXB7 promotes malignant progression by activating the TGFβ signaling pathway. Cancer Res 2015; 75(4): 709-19.
[79]
Cassetta L, Pollard JW. Repolarizing macrophages improves breast cancer therapy. Cell Res 2017; 7(8): 963-4.
[80]
Kroemer G, Senovilla L, Galluzzi L, Andre F, Zitvogel L. Natural and therapy-induced immunosurveillance in breast cancer. Nat Med 2015; 21: 1128-3118.
[81]
Galluzzi L, Kroemer G. An epigenetic modifier triggers therapeutic immune responses against breast cancer. OncoImmunology 2017; 6(5): e1313376.
[82]
Tevis KM, Cecchi RJ, Colson YL, Grinstaff MW. Mimicking the tumor microenvironment to regulate macrophage phenotype and assessing chemotherapeutic efficacy in embedded cancer cell/macrophage spheroid models. Acta Biomater 2017; 50: 271-9.
[83]
Lei X, Chen M, Li X, et al. A vascular disrupting agent overcomes tumor multidrug resistance by skewing macrophage polarity toward the M1 phenotype. Cancer Lett 2018; 418: 239-49.
[84]
Vallerand D. Characterization of breast cancer preclinical models reveals a specific pattern of macrophage polarization. PLoS One 2016; 11(7): e0157670.
[85]
Wang J, Chen H, Chen X, Lin H. Expression of tumor-related macrophages and cytokines after surgery of triple-negative breast cancer patients and its implications. Med Sci Monit 2016; 22: 115-20.
[86]
Tariq M, Zhang J, Liang G, Ding L, He Q, Yang B. Macrophage polarization: anti-cancer strategies to target tumor-associated macrophage in breast cancer. J Cell Biochem 2017; 118(9): 2484-501.
[87]
Weitsman G. Detecting intratumoral heterogeneity of EGFR activity by liposome-based in vivo transfection of a fluorescent biosensor. Oncogene 2017; 36(25): 3618-28.
[88]
Yang C, He L, He P, et al. Increased drug resistance in breast cancer by tumor-associated macrophages through IL-10/STAT3/bcl-2 signaling pathway. Med Oncol 2015; 32(2): 352.
[89]
Gocheva V, Wang HW, Gadea BB, et al. IL-4 induces cathepsin protease activity in tumor-associated macrophages to promote cancer growth and invasion. Genes Dev 2010; 24(3): 241-55.
[90]
Shree T, Olson OC, Elie BT, et al. Macrophages and cathepsin proteases blunt chemotherapeutic response in breast cancer. Genes Dev 2011; 25(23): 2465-79.
[91]
Kersten K, Coffelt SB, Hoogstraat M, et al. Mammary tumor-derived CCL2 enhances pro-metastatic systemic inflammation through upregulation of IL1β in tumor-associated macrophages. OncoImmunology 2017; 6(8): e1334744.
[92]
Belgiovine C, Bello E, Liguori M, Craparotta I, Mannarino L, Paracchini L. Lurbinectedin reduces tumour-associated macrophages and the inflammatory tumour microenvironment in preclinical models. Br J Cancer 2017; 117(5): 628-38.
[93]
Xu M, Liu M, Du X, Li S, Li H, Li X. Intratumoral delivery of il-21 overcomes anti-her2/neu resistance through shifting tumor-associated macrophages from M2 to M1 phenotype. J Immunol 2015; 194(10): 4997-5006.
[94]
Dang W, Tang H, Cao H, et al. Strategy of STAT3β cell-specific expression in macrophages exhibits antitumor effects on mouse breast cancer. Gene Ther 2015; 22(12): 977-83.
[95]
Guo H, Liu Y, Gu J, et al. Endostatin inhibits the growth and migration of 4T1 mouse breast cancer cells by skewing macrophage polarity toward the M1 phenotype. Cancer Immunol Immunother 2016; 65(6): 677-88.
[96]
Binnemars-Postma K, Bansal R, Storm G, Prakash J. Targeting the Stat6 pathway in tumor-associated macrophages reduces tumor growth and metastatic niche formation in breast cancer. FASEB J 2018; 32(2): 969-78.
[97]
Harney AS, Karagiannis GS, Pignatelli J, et al. The selective Tie2 inhibitor rebastinib blocks recruitment and function of Tie2Hi macrophages in breast cancer and pancreatic neuroendocrine tumors. Mol Cancer Ther 2017; 16(11): 2486-501.
[98]
Zhu Y, Knolhoff BL, Meyer MA, Nywening TM, West BL, Luo J. CSF1/CSF1R blockade reprograms tumor-infiltrating macrophages and improves response to T-cell checkpoint immunotherapy in pancreatic cancer models. Cancer Res 2014; 74(18): 5057-69.
[99]
Meyers, M. A phase 1, open-label, dose escalation trial to investigate SNDX-6352 in patients with solid tumors. National Institute of Health, Bathesda. USA, 2017, NCT03238027
[100]
Georgoudaki AM, Prokopec KE, Boura VF, Hellqvist E, Sohn S, Östling J. Reprogramming tumor-associated macrophages by antibody targeting inhibits cancer progression and metastasis. Cell Reports 2016; 15(9): 2000-11.
[101]
Chen G, Gupta R, Petrik S, et al. A feasibility study of cyclophosphamide, trastuzumab, and an allogeneic GM-CSF-secreting breast tumor vaccine for HER2+ metastatic breast cancer. Cancer Immunol Res 2014; 2(10): 949-61.
[102]
Penn C, Yang K, Zong H, Lim JY, Cole A, Yang D. Therapeutic impact of nanoparticle therapy targeting tumor associate macrophages. Mol Cancer Ther 2017; 17(1): 96-106.
[103]
Song M, Liu T, Shi C, Zhang X, Chen X. Bioconjugated manganese dioxide nanoparticles enhance chemotherapy response by priming tumor-associated macrophages toward M1-like phenotype and attenuating tumor hypoxia. ACS Nano 2016; 10(1): 633-47.
[104]
Iwanowycz S, Wang J, Hodge J, Wang Y, Yu F, Fan D. Emodin inhibits breast cancer growth by blocking the tumor-promoting feedforward loop between cancer cells and macrophages. Mol Cancer Ther 2016; 15(8): 1931-42.
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