Skip to main content

Advertisement

SpringerLink
Log in

The role of macrophages during breast cancer development and response to chemotherapy

  • Review Article
  • Published:
Clinical and Translational Oncology Aims and scope Submit manuscript

Abstract

Macrophages play an important role in the immune system as a key host defense against pathogens. Non-polarized macrophages can differentiate into pro-inflammatory classical pathway-activated macrophages or anti-inflammatory alternative pathway-activated macrophages, both of which play central roles in breast cancer growth and progression in a process called polarization of macrophages. Classical pathway-activated and alternative pathway-activated macrophages can transform into each other and their transformational properties and orientation are determined by cytokines in the tumor microenvironment. Tumor-associated macrophages display many functions, such as tissue reforming, participating in inflammation and tumor growth in breast cancer progression. Some cytokines, such as interleukins and transcriptional activators, reside in the tumor microenvironment and influence tumor-associated macrophages. Chemotherapy is a common treatment for breast cancer and macrophages play an important role in mammary tumor cell migration, cancer invasion, and angiogenesis. This review summarizes the activities of tumor-associated macrophages in the mammary tumor, chemotherapeutic processes and some potential strategies for breast 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
Fig. 5
Fig. 6

Similar content being viewed by others

Availability of data and materials

The datasets generated and/or analyzed during the current study are available in the NCBI PubMed repository.

References

  1. Sheikhpour E, Noorbakhsh P, Foroughi E, Farahnak S, Nasiri R, Neamatzadeh H. A survey on the role of interleukin-10 in breast cancer: a narrative. Rep Biochem Mol Biol. 2018;7(1):30–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Reddy JP, Atkinson RL, Larson R, Burks JK, Smith D, Debeb BG, Ruffell B, Creighton CJ, Bambhroliya A, Reuben JM, et al. Mammary stem cell and macrophage markers are enriched in normal tissue adjacent to inflammatory breast cancer. Breast Cancer Res Treat. 2018;171(2):283–93.

    Article  CAS  PubMed  Google Scholar 

  3. Zhao Y, Zheng J, Yu Y, Wang L. Panax notoginseng saponins regulate macrophage polarization under hyperglycemic condition via NF-kappaB signaling pathway. Biomed Res Int. 2018;2018:9239354.

    PubMed  PubMed Central  Google Scholar 

  4. Qiu SQ, Waaijer SJH, Zwager MC, de Vries EGE, van der Vegt B, Schroder CP. Tumor-associated macrophages in breast cancer: innocent bystander or important player? Cancer Treat Rev. 2018;70:178–89.

    Article  CAS  PubMed  Google Scholar 

  5. Qian BZ, Pollard JW. Macrophage diversity enhances tumor progression and metastasis. Cell. 2010;141(1):39–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. DeSantis CE, Ma J, Goding Sauer A, Newman LA, Jemal A. Breast cancer statistics, 2017, racial disparity in mortality by state. CA Cancer J Clin. 2017;67(6):439–48.

    Article  PubMed  Google Scholar 

  7. Linde N, Casanova-Acebes M, Sosa MS, Mortha A, Rahman A, Farias E, Harper K, Tardio E, Reyes Torres I, Jones J, et al. Macrophages orchestrate breast cancer early dissemination and metastasis. Nat Commun. 2018;9(1):21.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. Arlauckas SP, Garris CS, Kohler RH, Kitaoka M, Cuccarese MF, Yang KS, Miller MA, Carlson JC, Freeman GJ, Anthony RM, et al. In vivo imaging reveals a tumor-associated macrophage-mediated resistance pathway in anti-PD-1 therapy. Sci Transl Med. 2017;9(389):eaal3604.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Ring A, Nguyen C, Smbatyan G, Tripathy D, Yu M, Press M, Kahn M, Lang JE. CBP/beta-Catenin/FOXM1 is a novel therapeutic target in triple negative breast cancer. Cancers (Basel). 2018;10(12):525.

    Article  CAS  Google Scholar 

  10. Clark NM, Bos PD. Tumor-associated macrophage isolation and in vivo analysis of their tumor-promoting activity. Methods Mol Biol. 2019;1884:151–60.

    Article  CAS  PubMed  Google Scholar 

  11. Zhuang X, Wang J. Correlations of MRP1 gene with serum TGF-beta1 and IL-8 in breast cancer patients during chemotherapy. J BUON. 2018;23(5):1302–8.

    PubMed  Google Scholar 

  12. Wang S, Liu X, Chen S, Liu Z, Zhang X, Liang XJ, Li L. Regulation of Ca(2+) signaling for drug-resistant breast cancer therapy with mesoporous silica nanocapsule encapsulated doxorubicin/siRNA cocktail. ACS Nano. 2019;13(1):274–83.

    Article  CAS  PubMed  Google Scholar 

  13. Zhao SC, Ma LS, Chu ZH, Xu H, Wu WQ, Liu F. Regulation of microglial activation in stroke. Acta Pharmacol Sin. 2017;38(4):445–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Advani R, Flinn I, Popplewell L, Forero A, Bartlett NL, Ghosh N, Kline J, Roschewski M, LaCasce A, Collins GP, et al. CD47 blockade by Hu5F9-G4 and rituximab in non-Hodgkin's lymphoma. N Engl J Med. 2018;379(18):1711–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Gholamin S, Mitra SS, Feroze AH, Liu J, Kahn SA, Zhang M, Esparza R, Richard C, Ramaswamy V, Remke M, et al. Disrupting the CD47-SIRPalpha anti-phagocytic axis by a humanized anti-CD47 antibody is an efficacious treatment for malignant pediatric brain tumors. Sci Transl Med. 2017;9(381):eaaf2968.

    Article  PubMed  CAS  Google Scholar 

  16. Mantovani A, Longo DL. Macrophage checkpoint blockade in cancer—back to the future. N Engl J Med. 2018;379(18):1777–9.

    Article  PubMed  Google Scholar 

  17. Mahlbacher G, Curtis LT, Lowengrub J, Frieboes HB. Mathematical modeling of tumor-associated macrophage interactions with the cancer microenvironment. J Immunother Cancer. 2018;6(1):10.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Cheng N, Watkins-Schulz R, Junkins RD, David CN, Johnson BM, Montgomery SA, Peine KJ, Darr DB, Yuan H, McKinnon KP, et al. A nanoparticle-incorporated STING activator enhances antitumor immunity in PD-L1-insensitive models of triple-negative breast cancer. JCI Insight. 2018;3(22):e120638.

    Article  PubMed Central  Google Scholar 

  19. Xie L, Yang Y, Meng J, Wen T, Liu J, Xu H. Cationic polysaccharide spermine-pullulan drives tumor associated macrophage towards M1 phenotype to inhibit tumor progression. Int J Biol Macromol. 2019;123:1012–9.

    Article  CAS  PubMed  Google Scholar 

  20. Xu Y, Chen L, Jiang YX, Yang Y, Zhang DD. Regulatory effect and relevant mechanisms of fraction from heat-clearing and detoxifying herb couplet on macrophage M1/M2 phenotypes. Zhongguo Zhong Yao Za Zhi. 2018;43(18):3722–8.

    PubMed  Google Scholar 

  21. Obeid E, Nanda R, Fu YX, Olopade OI. The role of tumor-associated macrophages in breast cancer progression (review). Int J Oncol. 2013;43(1):5–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Sharif O, Brunner JS, Vogel A, Schabbauer G. Macrophage rewiring by nutrient associated PI3K dependent pathways. Front Immunol. 2002;2019:10.

    Google Scholar 

  23. Guha M, Mackman N. The phosphatidylinositol 3-kinase-Akt pathway limits lipopolysaccharide activation of signaling pathways and expression of inflammatory mediators in human monocytic cells. J Biol Chem. 2002;277(35):32124–322.

    Article  CAS  PubMed  Google Scholar 

  24. 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.

    Article  CAS  PubMed  Google Scholar 

  25. Squadrito ML, De Palma M. Macrophage regulation of tumor angiogenesis: implications for cancer therapy. Mol Asp Med. 2011;32(2):123–45.

    Article  CAS  Google Scholar 

  26. Brown BN, Ratner BD, Goodman SB, Amar S, Badylak SF. Macrophage polarization: an opportunity for improved outcomes in biomaterials and regenerative medicine. Biomaterials. 2012;33(15):3792–802.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Chanmee T, Ontong P, Konno K, Itano N. Tumor-associated macrophages as major players in the tumor microenvironment. Cancers (Basel). 2014;6(3):1670–90.

    Article  CAS  Google Scholar 

  28. Martinez FO, Gordon S. The M1 and M2 paradigm of macrophage activation: time for reassessment. F1000Prime Rep. 2014;6:1–13.

    Article  CAS  Google Scholar 

  29. Solinas G, Germano G, Mantovani A, Allavena P. Tumor-associated macrophages (TAM) as major players of the cancer-related inflammation. J Leukoc Biol. 2009;86(5):1065–73.

    Article  CAS  PubMed  Google Scholar 

  30. Biswas SK, Lewis CE. NF-kappaB as a central regulator of macrophage function in tumors. J Leukoc Biol. 2010;88(5):877–84.

    Article  CAS  PubMed  Google Scholar 

  31. Tang X. Tumor-associated macrophages as potential diagnostic and prognostic biomarkers in breast cancer. Cancer Lett. 2013;332(1):3–10.

    Article  CAS  PubMed  Google Scholar 

  32. Mantovani A, Allavena P. The interaction of anticancer therapies with tumor-associated macrophages. J Exp Med. 2015;212(4):435–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  34. Noy R, Pollard JW. Tumor-associated macrophages: from mechanisms to therapy. Immunity. 2014;41(1):49–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Mantovani A, Marchesi F, Malesci A, Laghi L, Allavena P. Tumour-associated macrophages as treatment targets in oncology. Nat Rev Clin Oncol. 2017;14(7):399–416.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Mantovani A, Bottazzi B, Colotta F, Sozzani S, Ruco L. The origin and function of tumor-associated macrophages. Immunol Today. 1992;13(7):265–70.

    Article  CAS  PubMed  Google Scholar 

  37. Jinushi M, Komohara Y. Tumor-associated macrophages as an emerging target against tumors: creating a new path from bench to bedside. Biochim Biophys Acta. 2015;1855(2):123–30.

    CAS  PubMed  Google Scholar 

  38. Campbell MJ, Tonlaar NY, Garwood ER, Huo D, Moore DH, Khramtsov AI, Au A, Baehner F, Chen Y, Malaka DO, et al. Proliferating macrophages associated with high grade, hormone receptor negative breast cancer and poor clinical outcome. Breast Cancer Res Treat. 2011;128(3):703–11.

    Article  PubMed  Google Scholar 

  39. Kumar V, Cheng P, Condamine T, Mony S, Languino LR, McCaffrey JC, Hockstein N, Guarino M, Masters G, Penman E, et al. CD45 phosphatase inhibits STAT3 transcription factor activity in myeloid cells and promotes tumor-associated macrophage differentiation. Immunity. 2016;44(2):303–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Biswas SK, Mantovani A. Macrophage plasticity and interaction with lymphocyte subsets: cancer as a paradigm. Nat Immunol. 2010;11(10):889–96.

    Article  CAS  PubMed  Google Scholar 

  41. Murray PJ, Allen JE, Biswas SK, Fisher EA, Gilroy DW, Goerdt S, Gordon S, Hamilton JA, Ivashkiv LB, Lawrence T, et al. Macrophage activation and polarization: nomenclature and experimental guidelines. Immunity. 2014;41(1):14–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Kryczek I, Wei S, Zou L, Zhu G, Mottram P, Xu H, Chen L, Zou W. Cutting edge: induction of B7–H4 on APCs through IL-10: novel suppressive mode for regulatory T cells. J Immunol. 2006;177(1):40–4.

    Article  CAS  PubMed  Google Scholar 

  43. Evans R, Alexander P. Cooperation of immune lymphoid cells with macrophages in tumour immunity. Nature. 1970;228(5272):620–2.

    Article  CAS  PubMed  Google Scholar 

  44. Vesely MD, Kershaw MH, Schreiber RD, Smyth MJ. Natural innate and adaptive immunity to cancer. Annu Rev Immunol. 2011;29:235–71.

    Article  CAS  PubMed  Google Scholar 

  45. Kratochvill F, Neale G, Haverkamp JM, Van de Velde LA, Smith AM, Kawauchi D, McEvoy J, Roussel MF, Dyer MA, Qualls JE, et al. TNF counterbalances the emergence of M2 tumor macrophages. Cell Rep. 2015;12(11):1902–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Tang X, Mo C, Wang Y, Wei D, Xiao H. Anti-tumour strategies aiming to target tumour-associated macrophages. Immunology. 2013;138(2):93–104.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Kessenbrock K, Plaks V, Werb Z. Matrix metalloproteinases: regulators of the tumor microenvironment. Cell. 2010;141(1):52–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Daurkin I, Eruslanov E, Stoffs T, Perrin GQ, Algood C, Gilbert SM, Rosser CJ, Su LM, Vieweg J, Kusmartsev S. Tumor-associated macrophages mediate immunosuppression in the renal cancer microenvironment by activating the 15-lipoxygenase-2 pathway. Cancer Res. 2011;71(20):6400–9.

    Article  CAS  PubMed  Google Scholar 

  49. Allavena P, Sica A, Solinas G, Porta C, Mantovani A. The inflammatory micro-environment in tumor progression: the role of tumor-associated macrophages. Crit Rev Oncol Hematol. 2008;66(1):1–9.

    Article  PubMed  Google Scholar 

  50. Chavez-Galan L, Olleros ML, Vesin D, Garcia I. Much more than M1 and M2 macrophages, there are also CD169(+) and TCR(+) macrophages. Front Immunol. 2015;6:263.

    PubMed  PubMed Central  Google Scholar 

  51. Bergenfelz C, Medrek C, Ekstrom E, Jirstrom K, Janols H, Wullt M, Bredberg A, Leandersson K. Wnt5a induces a tolerogenic phenotype of macrophages in sepsis and breast cancer patients. J Immunol. 2012;188(11):5448–58.

    Article  CAS  PubMed  Google Scholar 

  52. Prasad CP, Manchanda M, Mohapatra P, Andersson T. WNT5A as a therapeutic target in breast cancer. Cancer Metastasis Rev. 2018;37(4):767–78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Feliz-Mosquea YR, Christensen AA, Wilson AS, Westwood B, Varagic J, Melendez GC, Schwartz AL, Chen QR, Mathews Griner L, Guha R, et al. Combination of anthracyclines and anti-CD47 therapy inhibit invasive breast cancer growth while preventing cardiac toxicity by regulation of autophagy. Breast Cancer Res Treat. 2018;172(1):69–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Sawa-Wejksza K, Kandefer-Szerszen M. Tumor-associated macrophages as target for antitumor therapy. Arch Immunol Ther Exp (Warsz). 2018;66(2):97–111.

    Article  CAS  Google Scholar 

  55. Li J, Feng W, Lu H, Wei Y, Ma S, Wei L, Liu Q, Zhao J, Wei Q, Yao J. Artemisinin inhibits breast cancer-induced osteolysis by inhibiting osteoclast formation and breast cancer cell proliferation. J Cell Physiol. 2019;234(8):12663–75.

    Article  CAS  PubMed  Google Scholar 

  56. Talib WH, Al-Hadid SA, Ali MBW, Al-Yasari IH, Ali MRA. Role of curcumin in regulating p53 in breast cancer: an overview of the mechanism of action. Breast Cancer (Dove Med Press). 2018;10:207–17.

    CAS  Google Scholar 

  57. Hossain F, Sorrentino C, Ucar DA, Peng Y, Matossian M, Wyczechowska D, Crabtree J, Zabaleta J, Morello S, Del Valle L, et al. Notch signaling regulates mitochondrial metabolism and NF-kappaB activity in triple-negative breast cancer cells via IKKalpha-Dependent non-canonical pathways. Front Oncol. 2018;8:575.

    Article  PubMed  PubMed Central  Google Scholar 

  58. Mantovani A, Polentarutti N, Luini W, Peri G, Spreafico F. Role of host defense mechanisms in the antitumor activity of adriamycin and daunomycin in mice. J Natl Cancer Inst. 1979;63(1):61–6.

    CAS  PubMed  Google Scholar 

  59. Affara NI, Ruffell B, Medler TR, Gunderson AJ, Johansson M, Bornstein S, Bergsland E, Steinhoff M, Li Y, Gong Q, et al. B cells regulate macrophage phenotype and response to chemotherapy in squamous carcinomas. Cancer Cell. 2014;25(6):809–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Mitchem JB, Brennan DJ, Knolhoff BL, Belt BA, Zhu Y, Sanford DE, Belaygorod L, Carpenter D, Collins L, Piwnica-Worms D, et al. Targeting tumor-infiltrating macrophages decreases tumor-initiating cells, relieves immunosuppression, and improves chemotherapeutic responses. Cancer Res. 2013;73(3):1128–41.

    Article  CAS  PubMed  Google Scholar 

  61. Gabrilovich DI, Ostrand-Rosenberg S, Bronte V. Coordinated regulation of myeloid cells by tumours. Nat Rev Immunol. 2012;12(4):253–68.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Ma Y, Galluzzi L, Zitvogel L, Kroemer G. Autophagy and cellular immune responses. Immunity. 2013;39(2):211–27.

    Article  CAS  PubMed  Google Scholar 

  63. Pallasch CP, Leskov I, Braun CJ, Vorholt D, Drake A, Soto-Feliciano YM, Bent EH, Schwamb J, Iliopoulou B, Kutsch N, et al. Sensitizing protective tumor microenvironments to antibody-mediated therapy. Cell. 2014;156(3):590–602.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. De Palma M, Lewis CE. Macrophage regulation of tumor responses to anticancer therapies. Cancer Cell. 2013;23(3):277–86.

    Article  PubMed  CAS  Google Scholar 

  65. Zhang CC, Yan Z, Zhang Q, Kuszpit K, Zasadny K, Qiu M, Painter CL, Wong A, Kraynov E, Arango ME, et al. PF-03732010: a fully human monoclonal antibody against P-cadherin with antitumor and antimetastatic activity. Clin Cancer Res. 2010;16(21):5177–88.

    Article  CAS  PubMed  Google Scholar 

  66. DeNardo DG, Brennan DJ, Rexhepaj E, Ruffell B, Shiao SL, Madden SF, Gallagher WM, Wadhwani N, Keil SD, Junaid SA, et al. Leukocyte complexity predicts breast cancer survival and functionally regulates response to chemotherapy. Cancer Discov. 2011;1(1):54–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Ruffell B, Chang-Strachan D, Chan V, Rosenbusch A, Ho CM, Pryer N, Daniel D, Hwang ES, Rugo HS, Coussens LM. Macrophage IL-10 blocks CD8+ T cell-dependent responses to chemotherapy by suppressing IL-12 expression in intratumoral dendritic cells. Cancer Cell. 2014;26(5):623–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Galon J, Angell HK, Bedognetti D, Marincola FM. The continuum of cancer immunosurveillance: prognostic, predictive, and mechanistic signatures. Immunity. 2013;39(1):11–26.

    Article  CAS  PubMed  Google Scholar 

  69. Ruffell B, Coussens LM. Macrophages and therapeutic resistance in cancer. Cancer Cell. 2015;27(4):462–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Ino Y, Yamazaki-Itoh R, Shimada K, Iwasaki M, Kosuge T, Kanai Y, Hiraoka N. Immune cell infiltration as an indicator of the immune microenvironment of pancreatic cancer. Br J Cancer. 2013;108(4):914–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Williams CB, Yeh ES, Soloff AC. Tumor-associated macrophages: unwitting accomplices in breast cancer malignancy. NPJ Breast Cancer. 2016;2:12025.

    Article  Google Scholar 

  72. Germano G, Frapolli R, Belgiovine C, Anselmo A, Pesce S, Liguori M, Erba E, Uboldi S, Zucchetti M, Pasqualini F, et al. Role of macrophage targeting in the antitumor activity of trabectedin. Cancer Cell. 2013;23(2):249–62.

    Article  CAS  PubMed  Google Scholar 

  73. Drake MT, Clarke BL, Khosla S. Bisphosphonates: mechanism of action and role in clinical practice. Mayo Clin Proc. 2008;83(9):1032–45.

    Article  CAS  PubMed  Google Scholar 

  74. Belgiovine C, D'Incalci M, Allavena P, Frapolli R. Tumor-associated macrophages and anti-tumor therapies: complex links. Cell Mol Life Sci. 2016;73(13):2411–24.

    Article  CAS  PubMed  Google Scholar 

  75. Mukhtar RA, Nseyo O, Campbell MJ, Esserman LJ. Tumor-associated macrophages in breast cancer as potential biomarkers for new treatments and diagnostics. Expert Rev Mol Diagn. 2011;11(1):91–100.

    Article  CAS  PubMed  Google Scholar 

  76. Brownlow N, Mol C, Hayford C, Ghaem-Maghami S, Dibb NJ. Dasatinib is a potent inhibitor of tumour-associated macrophages, osteoclasts and the FMS receptor. Leukemia. 2009;23(3):590–4.

    Article  CAS  PubMed  Google Scholar 

  77. Weigelt B, Bissell MJ. Unraveling the microenvironmental influences on the normal mammary gland and breast cancer. Semin Cancer Biol. 2008;18(5):311–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. D'Incalci M, Badri N, Galmarini CM, Allavena P. Trabectedin, a drug acting on both cancer cells and the tumour microenvironment. Br J Cancer. 2014;111(4):646–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Avila-Arroyo S, Nunez GS, Garcia-Fernandez LF, Galmarini CM. Synergistic effect of trabectedin and olaparib combination regimen in breast cancer cell lines. J Breast Cancer. 2015;18(4):329–38.

    Article  PubMed  PubMed Central  Google Scholar 

  80. Casneuf T, Axel AE, King P, Alvarez JD, Werbeck JL, Verhulst T, Verstraeten K, Hall BM, Sasser AK. Interleukin-6 is a potential therapeutic target in interleukin-6 dependent, estrogen receptor-alpha-positive breast cancer. Breast Cancer (Dove Med Press). 2016;8:13–27.

    CAS  Google Scholar 

  81. Mitchell LA, Hansen RJ, Beaupre AJ, Gustafson DL, Dow SW. Optimized dosing of a CCR2 antagonist for amplification of vaccine immunity. Int Immunopharmacol. 2013;15(2):357–63.

    Article  CAS  PubMed  Google Scholar 

  82. Panni RZ, Linehan DC, DeNardo DG. Targeting tumor-infiltrating macrophages to combat cancer. Immunotherapy. 2013;5(10):1075–87.

    Article  CAS  PubMed  Google Scholar 

  83. Zhu XD, Zhang JB, Zhuang PY, Zhu HG, Zhang W, Xiong YQ, Wu WZ, Wang L, Tang ZY, Sun HC. High expression of macrophage colony-stimulating factor in peritumoral liver tissue is associated with poor survival after curative resection of hepatocellular carcinoma. J Clin Oncol. 2008;26(16):2707–16.

    Article  PubMed  Google Scholar 

  84. Russo J, Russo IH. The pathway of neoplastic transformation of human breast epithelial cells. Radiat Res. 2001;155(1 Pt 2):151–4.

    Article  CAS  PubMed  Google Scholar 

  85. Nakasone ES, Askautrud HA, Kees T, Park JH, Plaks V, Ewald AJ, Fein M, Rasch MG, Tan YX, Qiu J, et al. Imaging tumor-stroma interactions during chemotherapy reveals contributions of the microenvironment to resistance. Cancer Cell. 2012;21(4):488–503.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Shree T, Olson OC, Elie BT, Kester JC, Garfall AL, Simpson K, Bell-McGuinn KM, Zabor EC, Brogi E, Joyce JA. Macrophages and cathepsin proteases blunt chemotherapeutic response in breast cancer. Genes Dev. 2011;25(23):2465–79.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Relation T, Yi T, Guess AJ, La Perle K, Otsuru S, Hasgur S, Dominici M, Breuer C, Horwitz EM. Intratumoral delivery of interferon gamma-secreting mesenchymal stromal cells repolarizes tumor-associated macrophages and suppresses neuroblastoma proliferation in vivo. Stem Cells. 2018;36(6):915–24.

    Article  CAS  PubMed  Google Scholar 

  88. Mantovani A, Germano G, Marchesi F, Locatelli M, Biswas SK. Cancer-promoting tumor-associated macrophages: new vistas and open questions. Eur J Immunol. 2011;41(9):2522–5.

    Article  CAS  PubMed  Google Scholar 

  89. Downey CM, Aghaei M, Schwendener RA, Jirik FR. DMXAA causes tumor site-specific vascular disruption in murine non-small cell lung cancer, and like the endogenous non-canonical cyclic dinucleotide STING agonist, 2′3′-cGAMP, induces M2 macrophage repolarization. PLoS One. 2014;9(6):e99988.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  90. Corrales L, Glickman LH, McWhirter SM, Kanne DB, Sivick KE, Katibah GE, Woo SR, Lemmens E, Banda T, Leong JJ, et al. Direct activation of STING in the tumor microenvironment leads to potent and systemic tumor regression and immunity. Cell Rep. 2015;11(7):1018–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Lin T, Bost KL. STAT3 activation in macrophages following infection with Salmonella. Biochem Biophys Res Commun. 2004;321(4):828–34.

    Article  CAS  PubMed  Google Scholar 

  92. Lee HT, Xue J, Chou PC, Zhou A, Yang P, Conrad CA, Aldape KD, Priebe W, Patterson C, Sawaya R, et al. Stat3 orchestrates interaction between endothelial and tumor cells and inhibition of Stat3 suppresses brain metastasis of breast cancer cells. Oncotarget. 2015;6(12):10016–29.

    Article  PubMed  PubMed Central  Google Scholar 

  93. Edwards JP, Emens LA. The multikinase inhibitor sorafenib reverses the suppression of IL-12 and enhancement of IL-10 by PGE(2) in murine macrophages. Int Immunopharmacol. 2010;10(10):1220–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Schmieder A, Michel J, Schonhaar K, Goerdt S, Schledzewski K. Differentiation and gene expression profile of tumor-associated macrophages. Semin Cancer Biol. 2012;22(4):289–97.

    Article  CAS  PubMed  Google Scholar 

  95. Mandal PK, Morlacchi P, Knight JM, Link TM, Lee GR, Nurieva R, Singh D, Dhanik A, Kavraki L, Corry DB, et al. Targeting the Src homology 2 (SH2) domain of signal transducer and activator of transcription 6 (STAT6) with cell-permeable, phosphatase-stable phosphopeptide mimics potently inhibits Tyr641 phosphorylation and transcriptional activity. J Med Chem. 2015;58(22):8970–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Liu L, Kritsanida M, Magiatis P, Gaboriaud N, Wang Y, Wu J, Buettner R, Yang F, Nam S, Skaltsounis L, et al. A novel 7-bromoindirubin with potent anticancer activity suppresses survival of human melanoma cells associated with inhibition of STAT3 and Akt signaling. Cancer Biol Ther. 2012;13(13):1255–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Furth PA. STAT signaling in different breast cancer sub-types. Mol Cell Endocrinol. 2014;382(1):612–5.

    Article  CAS  PubMed  Google Scholar 

  98. Chauhan P, Sodhi A, Shrivastava A. Cisplatin primes murine peritoneal macrophages for enhanced expression of nitric oxide, proinflammatory cytokines, TLRs, transcription factors and activation of MAP kinases upon co-incubation with L929 cells. Immunobiology. 2009;214(3):197–209.

    Article  CAS  PubMed  Google Scholar 

  99. Khabbazi S, Goumon Y, Parat MO. Morphine modulates interleukin-4- or breast cancer cell-induced pro-metastatic activation of macrophages. Sci Rep. 2015;5:11389.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Funding

This study was funded by the Jilin Province Science and Technology Development Project (Grant number 20170623033TC and 20170623035TC to YD). This research was supported by National Natural Science Foundation of China (no. 81603460, to Q.L.).

Author information

Author notes

    Authors and Affiliations

    1. Department of Laboratory Animals, College of Animal Sciences, Jilin University, Changchun, 130062, China

      S. Tao, X. Guan, J. Wei, B. Yuan, S. He, D. Zhao, J. Zhang & Y. Ding

    2. The Second Clinical School of Medicine, Guangdong Provincial Hospital of Chinese Medicine, Guangdong Provincial Hospital of Chinese Medicine-Zhuhai Hospital, Guangzhou University of Chinese Medicine, Guangzhou, 510120, Guangdong, China

      Z. Zhao & Q. Liu

    3. College of Animal Science and Technology, Jilin Agricultural University, Changchun, 130118, China

      X. Zhang

    4. Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China

      Q. Liu

    5. The 2nd Clinical School of Medicine, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, 510120, China

      Z. Zhao & Q. Liu

    6. The 85th Hospital of CPLA, Shanghai, 200040, China

      Z. Zhao

    7. Guangdong Provincial Hospital of Chinese Medicine-Zhuhai Hospital, Zhuhai, 519015, China

      Z. Zhao & Q. Liu

    Authors
    1. S. Tao
      View author publications

      You can also search for this author in PubMed Google Scholar

    2. Z. Zhao
      View author publications

      You can also search for this author in PubMed Google Scholar

    3. X. Zhang
      View author publications

      You can also search for this author in PubMed Google Scholar

    4. X. Guan
      View author publications

      You can also search for this author in PubMed Google Scholar

    5. J. Wei
      View author publications

      You can also search for this author in PubMed Google Scholar

    6. B. Yuan
      View author publications

      You can also search for this author in PubMed Google Scholar

    7. S. He
      View author publications

      You can also search for this author in PubMed Google Scholar

    8. D. Zhao
      View author publications

      You can also search for this author in PubMed Google Scholar

    9. J. Zhang
      View author publications

      You can also search for this author in PubMed Google Scholar

    10. Q. Liu
      View author publications

      You can also search for this author in PubMed Google Scholar

    11. Y. Ding
      View author publications

      You can also search for this author in PubMed Google Scholar

    Contributions

    The study was designed by QL. The initial search, literature organization, and manuscript writing were performed by ST, ZZ, XZ, XG, JW, SH, and DZ. Critical comments and typesetting corrections on the final version were made by JZ, YD, and QL. The manuscript was finalized by YD and QL. All authors have read and revised the manuscript critically.

    Corresponding authors

    Correspondence to J. Zhang, Q. Liu or Y. Ding.

    Ethics declarations

    Conflict of interest

    The authors declare that they have no competing interests.

    Ethics approval and consent to participate

    Not applicable.

    Informed consent

    Not applicable.

    Research involving human and animal rights

    All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards.

    Additional information

    Publisher's Note

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

    S. Tao and Z. Zhao have contributed equally to this work.

    Rights and permissions

    Reprints and permissions

    About this article

    Check for updates. Verify currency and authenticity via CrossMark

    Cite this article

    Tao, S., Zhao, Z., Zhang, X. et al. The role of macrophages during breast cancer development and response to chemotherapy. Clin Transl Oncol 22, 1938–1951 (2020). https://doi.org/10.1007/s12094-020-02348-0

    Download citation

    • Received:

    • Accepted:

    • Published:

    • Issue Date:

    • DOI: https://doi.org/10.1007/s12094-020-02348-0

    Keywords

    Search

    Navigation