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Giant Macrophages: Characteristics and Clinical Relevance

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Atlas of Liquid Biopsy

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Abstract

Tumor cell dissemination is mediated by a subpopulation of cells referred to as circulating tumor cells (CTCs), which have epithelial to mesenchymal properties and an inherent capacity to intravasate from the primary tumor, extravasate into secondary organs, and survive both in circulation and within the secondary organ. These properties have long been assumed to be cell autonomous; however, it is now clear that CTCs require the aid of secondary cells, such as macrophages. The role of tumor-associated macrophages (TAMs) as direct and indirect players in tumor cell dissemination will be discussed in this chapter. Special emphasis will be placed on the interplay between CTC and macrophages, focusing on the pro-tumorigenic function of TAMs at the level of secreted proteins, how TAMs enhance the invasive nature of tumor cells, the role of TAMs in promoting inflammation and a pro-tumor immune response, and the important role TAMs play in metastasis. Macrophages as therapeutic targets will also be discussed. Finally, the concept that macrophages can physically interact with CTCs or fuse with tumor cells to create giant macrophages or cell fusions that are invisible to the immune system and have enhanced migratory and metastatic capacities will be presented and detailed.

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References

  1. Condeelis J, Pollard JW. Minireview macrophages: obligate partners for tumor cell migration. Invasion Metastasis. 2006:263–6. https://doi.org/10.1016/j.cell.2006.01.007.

  2. Noy R, Pollard JW. Tumor-associated macrophages : from mechanisms to therapy. Immunity. 2015;41:49–61.

    Article  CAS  Google Scholar 

  3. Shih J-Y, Yuan A, Chen JJ-W, Yang P-C. Tumor-associated macrophage: its role in cancer invasion and metastasis. J Cancer Mol. 2006;2:101–6.

    CAS  Google Scholar 

  4. Yang L, Zhang Y. Tumor-associated macrophages: from basic research to clinical application. J Hematol Oncol. 2017;10:1–12. https://doi.org/10.1186/s13045-017-0430-2.

    Article  CAS  Google Scholar 

  5. Kitamura T, Qian B, Pollard JW, Avenue MP. Immune cell promotion of metastasis. Nat Rev Immunol. 2015;15:73–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Huang S, et al. Contributions of stromal metalloproteinase-9 to angiogenesis and growth of human ovarian carcinoma in mice. J Natl Cancer Inst. 2002;94:1134–42.

    Article  CAS  PubMed  Google Scholar 

  7. Solinas G, Germano G, Mantovani A, Allavena P. Tumor-associated macrophages (TAM) as major players of the cancer-related. Inflammation. 2009;86:1065–73.

    CAS  Google Scholar 

  8. Epelman S, Lavine KJ, Randolph GJ. Origin and functions of tissue macrophages. Immunity. 2015;41:21–35.

    Article  CAS  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Gordon S, Martinez FO. Alternative activation of macrophages: mechanism and functions. Immunity. 2010;32:593–604.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  12. Mosser DM, Edwards JP. Exploring the full spectrum of macrophage activation. Nat Rev Immunol. 2008;8:958–69.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Murray PJ, et al. Macrophage activation and polarization: nomenclature and experimental guidelines. Immunity. 2014;41:14–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Sica A, Mantovani A. Macrophage plasticity and polarization: in vivo veritas. J Clin Investig. 2012;122:787–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Heusinkveld M, van der Burg SH. Identification and manipulation of tumor associated macrophages in human cancers. J Transl Med. 2011;9:216.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Heusinkveld M, et al. M2 macrophages induced by prostaglandin E2 and IL-6 from cervical carcinoma are switched to activated M1 macrophages by CD4+ Th1 cells. J Immunol. 2011;187:1157–65.

    Article  CAS  PubMed  Google Scholar 

  17. Martinez FO, Helming L, Gordon S. Alternative activation of macrophages: an immunologic functional perspective. Annu Rev Immunol. 2009;27:451–83.

    Article  CAS  PubMed  Google Scholar 

  18. Laoui D, et al. Tumor-associated macrophages in breast cancer: distinct subsets, distinct functions. Int J Dev Biol. 2011;55:861–7.

    Article  PubMed  Google Scholar 

  19. Martinez FO, Gordon S, Locati M, Mantovani A. Transcriptional profiling of the human monocyte-to-macrophage differentiation and polarization: new molecules and patterns of gene expression. J Immunol. 2006;177:7303–11.

    Article  CAS  PubMed  Google Scholar 

  20. 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;23:549–55.

    Article  CAS  PubMed  Google Scholar 

  21. Yan W, et al. Tim-3 fosters HCC development by enhancing TGF-β-mediated alternative activation of macrophages. Gut. 2015;64:1593–604.

    Article  CAS  PubMed  Google Scholar 

  22. Gocheva V, et al. IL-4 induces cathepsin protease activity in tumor-associated macrophages to promote cancer growth and invasion. Genes Dev. 2010;24:241–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Nagakawa Y, Aoki T, Kasuya K, Tsuchida A, Koyanagi Y. Histologic features of venous invasion, expression of vascular endothelial growth factor and matrix metalloproteinase-2 and matrix metalloproteinase-9, and the relation with liver metastasis in pancreatic cancer. Pancreas. 2002;24:169–78.

    Article  PubMed  Google Scholar 

  24. Sousa S, et al. Human breast cancer cells educate macrophages toward the M2 activation status. Breast Cancer Res. 2015;17:101.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. Wang R, et al. Tumor-associated macrophages provide a suitable microenvironment for non-small lung cancer invasion and progression. Lung Cancer. 2011;74:188–96.

    Article  PubMed  Google Scholar 

  26. Bohrer LR, Schwertfeger KL. Macrophages promote fibroblast growth factor receptor-driven tumor cell migration and invasion in a CXCR2-dependent manner. Mol Cancer Res. 2012;10:1294–305.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Fang W, et al. Tumor-associated macrophages promote the metastatic potential of thyroid papillary cancer by releasing CXCL8. Carcinogenesis. 2014;35:1780–7.

    Article  CAS  PubMed  Google Scholar 

  28. Ye X, et al. Tumor-associated microglia/macrophages enhance the invasion of glioma stem-like cells via TGF-β1 signaling pathway. J Immunol. 2012;189:444–53.

    Article  CAS  PubMed  Google Scholar 

  29. Singh R, Shankar BS, Sainis KB. TGF-β1-ROS-ATM-CREB signaling axis in macrophage mediated migration of human breast cancer MCF7 cells. Cell Signal. 2014;26:1604–15.

    Article  CAS  PubMed  Google Scholar 

  30. Sainz B, Martín B, Tatari M, Heeschen C, Guerra S. ISG15 is a critical microenvironmental factor for pancreatic cancer stem cells. Cancer Res. 2014;74:7309–20.

    Article  CAS  PubMed  Google Scholar 

  31. Li D, et al. Tumor-produced versican V1 enhances hCAP18/LL-37 expression in macrophages through activation of TLR2 and vitamin D3 signaling to promote ovarian cancer progression in vitro. PLoS One. 2013;8:e56616.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Sainz B, et al. Microenvironmental hCAP-18/LL-37 promotes pancreatic ductal adenocarcinoma by activating its cancer stem cell compartment. Gut. 2015;64:1921–35.

    Article  CAS  PubMed  Google Scholar 

  33. Lin EY, et al. Macrophages regulate the angiogenic switch in a mouse model of breast cancer. Cancer Res. 2006;66:11238–46.

    Article  CAS  PubMed  Google Scholar 

  34. Murdoch C, Muthana M, Coffelt SB, C L. The role of myeloid cells in the promotion of tumour angiogenesis. Nat Rev Cancer. 2008;8:618–31.

    Article  CAS  PubMed  Google Scholar 

  35. Mantovani A, Allavena P, Sica A, Balkwill F. Cancer-related inflammation. Nature. 2008;454:436–44.

    Article  CAS  PubMed  Google Scholar 

  36. Galdiero MR, et al. Tumor associated macrophages and neutrophils in cancer. Immunobiology. 2013;218:1402–10.

    Article  CAS  PubMed  Google Scholar 

  37. Bingle L, Brown NJ, Lewis CE. The role of tumour-associated macrophages in tumour progression: implications for new anticancer therapies. J Pathol. 2002;8:254–65.

    Article  Google Scholar 

  38. Lin EY, Gouon-Evans V, Nguyen AV, Pollard JW. The macrophage growth factor CSF-1 in mammary gland development and tumor progression. J Mammary Gland Biol Neoplasia. 2002;7:147–62.

    Article  PubMed  Google Scholar 

  39. Yang L, et al. CD163 + tumor-associated macrophage is a prognostic biomarker and is associated with therapeutic effect on malignant pleural effusion of lung cancer patients. Oncotarget. 2015;6:10592–603.

    Article  PubMed  PubMed Central  Google Scholar 

  40. D’Errico G, et al. Tumor-associated macrophage-secreted 14-3-3ζ signals via AXL to promote pancreatic cancer chemoresistance. Oncogene. 2019;38:5469–85.

    Article  PubMed  CAS  Google Scholar 

  41. Balkwill F, Charles KA, Mantovani A. Smoldering and polarized inflammation in the initiation and promotion of malignant disease. Cancer Cell. 2005;7:211–7.

    Article  CAS  PubMed  Google Scholar 

  42. Karin M, Greten FR. NF-κB: linking inflammation and immunity to cancer development and progression. Nat Rev Immunol. 2005;5:749–59.

    Article  CAS  PubMed  Google Scholar 

  43. Lin BEY, Nguyen AV, Russell RG, Pollard JW. Colony-stimulating factor 1 promotes progression of mammary tumors to malignancy. J Exp Med. 2001;193:727–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Pollard JW. Tumour-educated macrophages promote tumour progression and metastasis. Nat Rev Cancer. 2004;4:71–8.

    Article  CAS  PubMed  Google Scholar 

  45. Wu Y, et al. Stabilization of snail by NF-κB is required for inflammation- induced cell migration and invasion. Cancer Cell. 2010;15:416–28.

    Article  CAS  Google Scholar 

  46. Grivennikov SI, Wang K, Mucida D, Stewart CA, Schnabl B, Jauch D, Taniguchi K, Yu GY, Österreicher CH, Hung KE, Datz C. Adenoma-linked barrier defects and microbial products drive IL-23/IL-17-mediated tumour growth. Nature. 2012;491:254–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Krug S, et al. Therapeutic targeting of tumor-associated macrophages in pancreatic neuroendocrine tumors. Int J Cancer. 2018;143:1806–16.

    Article  CAS  PubMed  Google Scholar 

  48. Griesmann H, et al. Pharmacological macrophage inhibition decreases metastasis formation in a genetic model of pancreatic cancer. Gut. 2017;66:1278–85.

    Article  CAS  PubMed  Google Scholar 

  49. Finkernagel F, et al. The transcriptional signature of human ovarian carcinoma macrophages is associated with extracellular matrix reorganization. Oncotarget. 2016;7:75339–52.

    Article  PubMed  PubMed Central  Google Scholar 

  50. Pienta KJ, 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. Investig New Drugs. 2013;31:760–8.

    Article  CAS  Google Scholar 

  51. Sanford DE, et al. In pancreatic cancer: a role for targeting the CCL2/CCR2 axis. Clin Cancer Res. 2013;19:3404–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. 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;10:633–47.

    Article  CAS  PubMed  Google Scholar 

  53. Liu X, Kwon H, Li Z, Fu Y. Is CD47 an innate immune checkpoint for tumor evasion ? J Hematol Oncol. 2017:1–7. https://doi.org/10.1186/s13045-016-0381-z.

  54. Hughes R, et al. Perivascular M2 macrophages stimulate tumor relapse after chemotherapy. Microenviron Immunol. 2015;75:3479–92.

    CAS  Google Scholar 

  55. Deng YR, Liu WB, Lian ZX, Li X, Hou X. Sorafenib inhibits macrophage-mediated epithelial-mesenchymal transition in hepatocellular carcinoma. Oncotarget. 2016;7:38292–305.

    Article  PubMed  PubMed Central  Google Scholar 

  56. Wang F, et al. CD163+CD14+ macrophages, a potential immune biomarker for malignant pleural effusion. Cancer Immunol Immunother. 2015;64:965–76.

    Article  CAS  PubMed  Google Scholar 

  57. Li H, Meng QH, Noh H, Somaiah N, Torres KE. Cell-surface vimentin – positive macrophage-like circulating tumor cells as a novel biomarker of metastatic gastrointestinal stromal tumors. Oncoimmunology. 2018;7:e1420450.

    Google Scholar 

  58. Chang M, et al. Clinical significance of circulating tumor microemboli as a prognostic marker in patients with pancreatic ductal adenocarcinoma. Clin Chem. 2016;513:505–13.

    Article  CAS  Google Scholar 

  59. Aceto N, et al. Circulating tumor cell clusters are oligoclonal precursors of breast cancer metastasis. Cell. 2015;158:1110–22.

    Article  CAS  Google Scholar 

  60. Cohen SJ, et al. Relationship of circulating tumor cells to tumor response, progression-free survival , and overall survival in patients with metastatic colorectal cancer. J Clin Oncol. 2019;26:3213–21.

    Article  Google Scholar 

  61. Cho EH, et al. Characterization of circulating tumor cell aggregates identified in patients with epithelial tumors. Phys Biol. 2013;9:1–13.

    Google Scholar 

  62. Friedl P, Gilmour D. Collective cell migration in morphogenesis, regeneration and cancer. Nat Rev Mol Cell Biol. 2009;10:445.

    Article  CAS  PubMed  Google Scholar 

  63. Hou J, et al. Short communication circulating tumor cells as a window on metastasis biology in lung cancer. Am J Pathol. 2011;178:989–96.

    Article  PubMed  PubMed Central  Google Scholar 

  64. Lazova R, Chakraborty A, Pawelek JM. Leukocyte-cancer cell fusion: initiator of the Warburg effect in malignancy? Adv Exp Med Biol. 2011;714:151–72.

    Article  CAS  PubMed  Google Scholar 

  65. Dittmar T, Zänker KS. Introduction. Adv Exp Med Biol. 2011;950:1–3.

    Article  CAS  Google Scholar 

  66. Dittmar T, et al. Recurrence cancer stem cells – made by cell fusion? Med Hypotheses. 2009;73:542–7.

    Google Scholar 

  67. Duelli D, Lazebnik Y. Cell fusion: A hidden enemy ? Cancer Cell. 2003;3:445–8.

    Article  CAS  PubMed  Google Scholar 

  68. Silvestris F, Ciavarella S, Strippoli S, Dammacco F. Cell fusion and hyperactive osteoclastogenesis in multiple myeloma. Adv Exp Med Biol. 2011;714:113–28.

    Article  CAS  PubMed  Google Scholar 

  69. Sutton TL, Walker BS, Wong MH. Circulating hybrid cells join the fray of circulating cellular biomarkers. Cell Mol Gastroenterol Hepatol. 2019;8:595–607.

    Article  PubMed  PubMed Central  Google Scholar 

  70. Adams DL, et al. Circulating giant macrophages as a potential biomarker of solid tumors. Proc Natl Acad Sci U S A. 2014;111:3514–9. https://doi.org/10.1073/pnas.1320198111.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Zhang L-N, Huang Y-H, Zhao L. Fusion of macrophages promotes breast cancer cell proliferation, migration and invasion through activating epithelial-mesenchymal transition and Wnt/β-catenin signaling pathway. Arch Biochem Biophys. 2019;676:108137.

    Article  CAS  PubMed  Google Scholar 

  72. Shabo I, et al. Macrophage traits in cancer cells are induced by macrophage-cancer cell fusion and cannot be explained by cellular interaction. BMC Cancer. 2015;15:1–11.

    Article  Google Scholar 

  73. Clawson GA, et al. ‘Stealth dissemination’ of macrophage-tumor cell fusions cultured from blood of patients with pancreatic ductal adenocarcinoma. PLoS One. 2017;12(9):e0184451.

    Google Scholar 

  74. Clawson GA, et al. Circulating tumor cells in melanoma patients. PLoS One. 2017;28:12(9):e0184451.

    Google Scholar 

  75. Clawson GA, et al. Macrophage-tumor cell fusions from peripheral blood of melanoma patients. PLoS One. 2015;10:e0134320.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  76. Lindström A, Midtbö K, Arnesson L-G, Garvin S, Shabo I. Fusion between M2-macrophages and cancer cells results in a subpopulation of radioresistant cells with enhanced DNA-repair capacity. Oncotarget. 2017;8:51370–86.

    Article  PubMed  PubMed Central  Google Scholar 

  77. Ding J, Jin W, Chen C, Shao Z, Wu J. Tumor associated macrophage × cancer cell hybrids may acquire cancer stem cell properties in breast cancer. PLoS One. 2012;7:e41942.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Lizier M, et al. Fusion between cancer cells and macrophages occurs in a murine model of spontaneous neu+ breast cancer without increasing its metastatic potential. Oncotarget. 2016;7:60793–806.

    Article  PubMed  PubMed Central  Google Scholar 

  79. Martin-Padura I, et al. Spontaneous cell fusion of acute leukemia cells and macrophages observed in cells with leukemic potential. Neoplasia. 2012;14:1057–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Powell AE, et al. Fusion between intestinal epithelial cells and macrophages in a cancer context results in nuclear reprogramming. Cancer Res. 2011;71:1497–505.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Clawson GA, et al. “Stealth dissemination” of macrophage-tumor cell fusions cultured from blood of patients with pancreatic ductal adenocarcinoma. PLoS One. 2017;12:e0184451.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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Authors and Affiliations

  1. Chronic Diseases and Cancer Area 3 – Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain

    Julie Earl & Bruno Sainz Jr.

  2. Molecular Epidemiology and Predictive Tumor Markers Group, Ramón y Cajal Health Research Institute (IRYCIS), Carretera Colmenar Km 9,100. 28034, Madrid, Spain

    Julie Earl

  3. Biomedical Research Network in Cancer (CIBERONC CB16/12/00446), C/ Monforte de Lemos 3-5. Pabellón 11, 28029 CIBERONC, Madrid, Spain

    Julie Earl

  4. Department of Biochemistry, Universidad Autónoma de Madrid (UAM) and Instituto de Investigaciones Biomédicas “Alberto Sols” (IIBM), CSIC-UAM, Madrid, Spain

    Bruno Sainz Jr.

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  1. Julie Earl
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  2. Bruno Sainz Jr.
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Correspondence to Bruno Sainz Jr. .

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Editors and Affiliations

  1. AC Camargo Cancer Center, São Paulo, São Paulo, Brazil

    Ludmilla Thomé Domingos Chinen

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Earl, J., Sainz, B. (2021). Giant Macrophages: Characteristics and Clinical Relevance. In: Chinen, L.T.D. (eds) Atlas of Liquid Biopsy. Springer, Cham. https://doi.org/10.1007/978-3-030-69879-9_11

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  • DOI: https://doi.org/10.1007/978-3-030-69879-9_11

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