Monocytes and Macrophages in Cancer: Unsuspected Roles

  • Sofia Gouveia-Fernandes
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1219)


The behavior of cancer is undoubtedly affected by stroma. Macrophages belong to this microenvironment and their presence correlates with reduced survival in most cancers. After a tumor-induced “immunoediting”, these monocytes/macrophages, originally the first line of defense against tumor cells, undergo a phenotypic switch and become tumor-supportive and immunosuppressive.

The influence of these tumor-associated macrophages (TAMs) on cancer is present in all traits of carcinogenesis. These cells participate in tumor initiation and growth, migration, vascularization, invasion and metastasis. Although metastasis is extremely clinically relevant, this step is always reliant on the angiogenic ability of tumors. Therefore, the formation of new blood vessels in tumors assumes particular importance as a limiting step for disease progression.

Herein, the once unsuspected roles of macrophages in cancer will be discussed and their importance as a promising strategy to treat this group of diseases will be reminded.


Tumor stroma Immunoediting Tumor-associated macrophages (TAM) Metastasis Tumor vascularization 


  1. Abraham D, Zins K, Sioud M, Lucas T, Schafer R, Stanley ER, Aharinejad S (2010) Stromal cell-derived CSF-1 blockade prolongs xenograft survival of CSF-1-negative neuroblastoma. Int J Cancer 126(6):1339–1352. Scholar
  2. Ahn JB, Rha SY, Shin SJ, Jeung HC, Kim TS, Zhang X, Park KH, Noh SH, Roh JK, Chung HC (2010a) Circulating endothelial progenitor cells (EPC) for tumor vasculogenesis in gastric cancer patients. Cancer Lett 288(1):124–132. Scholar
  3. Ahn GO, Tseng D, Liao CH, Dorie MJ, Czechowicz A, Brown JM (2010b) Inhibition of Mac-1 (CD11b/CD18) enhances tumor response to radiation by reducing myeloid cell recruitment. Proc Natl Acad Sci U S A 107(18):8363–8368. Scholar
  4. Akhurst RJ, Derynck R (2001) TGF-beta signaling in cancer--a double-edged sword. Trends Cell Biol 11(11):S44–S51. Scholar
  5. Alahari SV, Dong S, Alahari SK (2015) Are macrophages in tumors good targets for novel therapeutic approaches? Mol Cells 38(2):95–104. Scholar
  6. Allavena P, Piemonti L, Longoni D, Bernasconi S, Stoppacciaro A, Ruco L, Mantovani A (1998) IL-10 prevents the differentiation of monocytes to dendritic cells but promotes their maturation to macrophages. Eur J Immunol 28(1):359–369.<359::AID-IMMU359>3.0.CO;2-4PubMedCrossRefPubMedCentralGoogle Scholar
  7. Antsiferova M, Piwko-Czuchra A, Cangkrama M, Wietecha M, Sahin D, Birkner K, Amann VC, Levesque M, Hohl D, Dummer R, Werner S (2017) Activin promotes skin carcinogenesis by attraction and reprogramming of macrophages. EMBO Mol Med 9(1):27–45. Scholar
  8. Aras S, Zaidi MR (2017) TAMeless traitors: macrophages in cancer progression and metastasis. Br J Cancer 117(11):1583–1591. Scholar
  9. Arenberg DA, Keane MP, DiGiovine B, Kunkel SL, Strom SR, Burdick MD, Iannettoni MD, Strieter RM (2000) Macrophage infiltration in human non-small-cell lung cancer: the role of CC chemokines. Cancer Immunol Immunother 49(2):63–70PubMedCrossRefGoogle Scholar
  10. Arts RJ, Plantinga TS, Tuit S, Ulas T, Heinhuis B, Tesselaar M, Sloot Y, Adema GJ, Joosten LA, Smit JW, Netea MG, Schultze JL, Netea-Maier RT (2016) Transcriptional and metabolic reprogramming induce an inflammatory phenotype in non-medullary thyroid carcinoma-induced macrophages. Oncoimmunology 5(12):e1229725. Scholar
  11. Asahara T, Murohara T, Sullivan A, Silver M, van der Zee R, Li T, Witzenbichler B, Schatteman G, Isner JM (1997) Isolation of putative progenitor endothelial cells for angiogenesis. Science 275(5302):964–967PubMedCrossRefGoogle Scholar
  12. Atanasov G, Potner C, Aust G, Schierle K, Dietel C, Benzing C, Krenzien F, Bartels M, Eichfeld U, Schmelzle M, Bahra M, Pascher A, Wiltberger G (2018) TIE2-expressing monocytes and M2-polarized macrophages impact survival and correlate with angiogenesis in adenocarcinoma of the pancreas. Oncotarget 9(51):29715–29726. Scholar
  13. Bak SP, Alonso A, Turk MJ, Berwin B (2008) Murine ovarian cancer vascular leukocytes require arginase-1 activity for T cell suppression. Mol Immunol 46(2):258–268. Scholar
  14. Balkwill F, Charles KA, Mantovani A (2005) Smoldering and polarized inflammation in the initiation and promotion of malignant disease. Cancer Cell 7(3):211–217. Scholar
  15. Barleon B, Sozzani S, Zhou D, Weich HA, Mantovani A, Marme D (1996) Migration of human monocytes in response to vascular endothelial growth factor (VEGF) is mediated via the VEGF receptor flt-1. Blood 87(8):3336–3343PubMedCrossRefGoogle Scholar
  16. Barnett FH, Rosenfeld M, Wood M, Kiosses WB, Usui Y, Marchetti V, Aguilar E, Friedlander M (2016) Macrophages form functional vascular mimicry channels in vivo. Sci Rep 6:36659. Scholar
  17. Bingle L, Lewis CE, Corke KP, Reed MW, Brown NJ (2006) Macrophages promote angiogenesis in human breast tumour spheroids in vivo. Br J Cancer 94(1):101–107. Scholar
  18. Bloch N, Harel D (2016) The tumor as an organ: comprehensive spatial and temporal modeling of the tumor and its microenvironment. BMC Bioinf 17(1):317. Scholar
  19. Bottazzi B, Walter S, Govoni D, Colotta F, Mantovani A (1992) Monocyte chemotactic cytokine gene transfer modulates macrophage infiltration, growth, and susceptibility to IL-2 therapy of a murine melanoma. J Immunol 148(4):1280–1285PubMedPubMedCentralGoogle Scholar
  20. Brown JM, Recht L, Strober S (2017) The promise of targeting macrophages in cancer therapy. Clin Cancer Res 23(13):3241–3250. Scholar
  21. Cebe-Suarez S, Zehnder-Fjallman A, Ballmer-Hofer K (2006) The role of VEGF receptors in angiogenesis; complex partnerships. Cell Mol Life Sci 63(5):601–615. Scholar
  22. Ceradini DJ, Kulkarni AR, Callaghan MJ, Tepper OM, Bastidas N, Kleinman ME, Capla JM, Galiano RD, Levine JP, Gurtner GC (2004) Progenitor cell trafficking is regulated by hypoxic gradients through HIF-1 induction of SDF-1. Nat Med 10(8):858–864. Scholar
  23. Chen Q, Zhang XH, Massague J (2011) Macrophage binding to receptor VCAM-1 transmits survival signals in breast cancer cells that invade the lungs. Cancer Cell 20(4):538–549. Scholar
  24. Chen W, Ma T, Shen XN, Xia XF, Xu GD, Bai XL, Liang TB (2012) Macrophage-induced tumor angiogenesis is regulated by the TSC2-mTOR pathway. Cancer Res 72(6):1363–1372. Scholar
  25. Coffelt SB, Hughes R, Lewis CE (2009) Tumor-associated macrophages: effectors of angiogenesis and tumor progression. Biochim Biophys Acta 1796(1):11–18. Scholar
  26. Condeelis J, Pollard JW (2006) Macrophages: obligate partners for tumor cell migration, invasion, and metastasis. Cell 124(2):263–266. Scholar
  27. Coussens LM, Zitvogel L, Palucka AK (2013) Neutralizing tumor-promoting chronic inflammation: a magic bullet? Science 339(6117):286–291. Scholar
  28. Cursiefen C, Chen L, Borges LP, Jackson D, Cao J, Radziejewski C, D’Amore PA, Dana MR, Wiegand SJ, Streilein JW (2004) VEGF-A stimulates lymphangiogenesis and hemangiogenesis in inflammatory neovascularization via macrophage recruitment. J Clin Invest 113(7):1040–1050. Scholar
  29. Dammeijer F, Lievense LA, Kaijen-Lambers ME, van Nimwegen M, Bezemer K, Hegmans JP, van Hall T, Hendriks RW, Aerts JG (2017) Depletion of tumor-associated macrophages with a CSF-1R kinase inhibitor enhances antitumor immunity and survival induced by DC immunotherapy. Cancer Immunol Res 5(7):535–546. Scholar
  30. De Palma M, Lewis CE (2011) Cancer: macrophages limit chemotherapy. Nature 472(7343):303–304. Scholar
  31. De Palma M, Venneri MA, Roca C, Naldini L (2003) Targeting exogenous genes to tumor angiogenesis by transplantation of genetically modified hematopoietic stem cells. Nat Med 9(6):789–795. Scholar
  32. De Palma M, Venneri MA, Galli R, Sergi Sergi L, Politi LS, Sampaolesi M, Naldini L (2005) Tie2 identifies a hematopoietic lineage of proangiogenic monocytes required for tumor vessel formation and a mesenchymal population of pericyte progenitors. Cancer Cell 8(3):211–226. Scholar
  33. DeNardo DG, Brennan DJ, Rexhepaj E, Ruffell B, Shiao SL, Madden SF, Gallagher WM, Wadhwani N, Keil SD, Junaid SA, Rugo HS, Hwang ES, Jirstrom K, West BL, Coussens LM (2011) Leukocyte complexity predicts breast cancer survival and functionally regulates response to chemotherapy. Cancer Discov 1(1):54–67. Scholar
  34. Derynck R, Zhang YE (2003) Smad-dependent and Smad-independent pathways in TGF-beta family signalling. Nature 425(6958):577–584. Scholar
  35. Dijkgraaf EM, Heusinkveld M, Tummers B, Vogelpoel LT, Goedemans R, Jha V, Nortier JW, Welters MJ, Kroep JR, van der Burg SH (2013) Chemotherapy alters monocyte differentiation to favor generation of cancer-supporting M2 macrophages in the tumor microenvironment. Cancer Res 73(8):2480–2492. Scholar
  36. Domingues G, Gouveia-Fernandes S, Salgado D, et al (2015) Monocytes/macrophages in cancer, from tumor aggressors to vascular components – a new insight for anti-angiogenic therapy. In: EACR-AACR-SIC special conference on anticancer drug action and drug resistance from cancer biology to the clinic, pp 98–99Google Scholar
  37. Dunn GP, Bruce AT, Ikeda H, Old LJ, Schreiber RD (2002) Cancer immunoediting: from immunosurveillance to tumor escape. Nat Immunol 3(11):991–998. Scholar
  38. Dunn GP, Old LJ, Schreiber RD (2004) The immunobiology of cancer immunosurveillance and immunoediting. Immunity 21(2):137–148. Scholar
  39. El-Serag HB (2012) Epidemiology of viral hepatitis and hepatocellular carcinoma. Gastroenterology 142(6):1264–1273.e1261. Scholar
  40. Erler JT, Bennewith KL, Cox TR, Lang G, Bird D, Koong A, Le QT, Giaccia AJ (2009) Hypoxia-induced lysyl oxidase is a critical mediator of bone marrow cell recruitment to form the premetastatic niche. Cancer Cell 15(1):35–44. Scholar
  41. Fadini GP, Baesso I, Albiero M, Sartore S, Agostini C, Avogaro A (2008) Technical notes on endothelial progenitor cells: ways to escape from the knowledge plateau. Atherosclerosis 197(2):496–503. Scholar
  42. Fernandez Pujol B, Lucibello FC, Gehling UM, Lindemann K, Weidner N, Zuzarte ML, Adamkiewicz J, Elsasser HP, Muller R, Havemann K (2000) Endothelial-like cells derived from human CD14 positive monocytes. Differentiation 65(5):287–300PubMedCrossRefGoogle Scholar
  43. Ferrara N, Gerber HP, LeCouter J (2003) The biology of VEGF and its receptors. Nat Med 9(6):669–676. Scholar
  44. Folkman J (1985) Tumor angiogenesis. Adv Cancer Res 43:175–203PubMedCrossRefGoogle Scholar
  45. Folkman J, Hanahan D (1991) Switch to the angiogenic phenotype during tumorigenesis. Princess Takamatsu Symp 22:339–347PubMedPubMedCentralGoogle Scholar
  46. Forget MA, Voorhees JL, Cole SL, Dakhlallah D, Patterson IL, Gross AC, Moldovan L, Mo X, Evans R, Marsh CB, Eubank TD (2014) Macrophage colony-stimulating factor augments Tie2-expressing monocyte differentiation, angiogenic function, and recruitment in a mouse model of breast cancer. PLoS One 9(6):e98623. Scholar
  47. Freire Valls A, Knipper K, Giannakouri E, Sarachaga V, Hinterkopf S, Wuehrl M, Shen Y, Radhakrishnan P, Klose J, Ulrich A, Schneider M, Augustin HG, Ruiz de Almodovar C, Schmidt T (2019) VEGFR1(+) metastasis-associated macrophages contribute to metastatic angiogenesis and influence colorectal cancer patient outcome. Clin Cancer Res 25(18):5674–5685. Scholar
  48. Fulton AM, Loveless SE, Heppner GH (1984) Mutagenic activity of tumor-associated macrophages in Salmonella typhimurium strains TA98 and TA 100. Cancer Res 44(10):4308–4311PubMedPubMedCentralGoogle Scholar
  49. Gabrusiewicz K, Liu D, Cortes-Santiago N, Hossain MB, Conrad CA, Aldape KD, Fuller GN, Marini FC, Alonso MM, Idoate MA, Gilbert MR, Fueyo J, Gomez-Manzano C (2014) Anti-vascular endothelial growth factor therapy-induced glioma invasion is associated with accumulation of Tie2-expressing monocytes. Oncotarget 5(8):2208–2220. Scholar
  50. Gao D, Nolan D, McDonnell K, Vahdat L, Benezra R, Altorki N, Mittal V (2009) Bone marrow-derived endothelial progenitor cells contribute to the angiogenic switch in tumor growth and metastatic progression. Biochim Biophys Acta 1796(1):33–40. Scholar
  51. Gazzaniga S, Bravo AI, Guglielmotti A, van Rooijen N, Maschi F, Vecchi A, Mantovani A, Mordoh J, Wainstok R (2007) Targeting tumor-associated macrophages and inhibition of MCP-1 reduce angiogenesis and tumor growth in a human melanoma xenograft. J Invest Dermatol 127(8):2031–2041. Scholar
  52. George AL, Bangalore-Prakash P, Rajoria S, Suriano R, Shanmugam A, Mittelman A, Tiwari RK (2011) Endothelial progenitor cell biology in disease and tissue regeneration. J Hematol Oncol 4:24. Scholar
  53. Gerber HP, Ferrara N (2003) The role of VEGF in normal and neoplastic hematopoiesis. J Mol Med (Berl) 81(1):20–31. Scholar
  54. Giraudo E, Inoue M, Hanahan D (2004) An amino-bisphosphonate targets MMP-9-expressing macrophages and angiogenesis to impair cervical carcinogenesis. J Clin Invest 114(5):623–633. Scholar
  55. Gocheva V, Wang HW, Gadea BB, Shree T, Hunter KE, Garfall AL, Berman T, Joyce JA (2010) IL-4 induces cathepsin protease activity in tumor-associated macrophages to promote cancer growth and invasion. Genes Dev 24(3):241–255. Scholar
  56. Goel S, Wong AH, Jain RK (2012) Vascular normalization as a therapeutic strategy for malignant and nonmalignant disease. Cold Spring Harb Perspect Med 2(3):a006486. Scholar
  57. Gorelik L, Flavell RA (2001) Immune-mediated eradication of tumors through the blockade of transforming growth factor-beta signaling in T cells. Nat Med 7(10):1118–1122. Scholar
  58. Gorelik L, Flavell RA (2002) Transforming growth factor-beta in T-cell biology. Nat Rev Immunol 2(1):46–53. Scholar
  59. Goswami S, Sahai E, Wyckoff JB, Cammer M, Cox D, Pixley FJ, Stanley ER, Segall JE, Condeelis JS (2005) Macrophages promote the invasion of breast carcinoma cells via a colony-stimulating factor-1/epidermal growth factor paracrine loop. Cancer Res 65(12):5278–5283. Scholar
  60. Grunewald M, Avraham I, Dor Y, Bachar-Lustig E, Itin A, Jung S, Chimenti S, Landsman L, Abramovitch R, Keshet E (2006) VEGF-induced adult neovascularization: recruitment, retention, and role of accessory cells. Cell 124(1):175–189. Scholar
  61. Halin S, Rudolfsson SH, Van Rooijen N, Bergh A (2009) Extratumoral macrophages promote tumor and vascular growth in an orthotopic rat prostate tumor model. Neoplasia 11(2):177–186PubMedCrossRefGoogle Scholar
  62. Hanahan D, Folkman J (1996) Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell 86(3):353–364. Scholar
  63. Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144(5):646–674. Scholar
  64. Hao Q, Liu J, Pappu R, Su H, Rola R, Gabriel RA, Lee CZ, Young WL, Yang GY (2008) Contribution of bone marrow-derived cells associated with brain angiogenesis is primarily through leukocytes and macrophages. Arterioscler Thromb Vasc Biol 28(12):2151–2157. Scholar
  65. Harmey JH, Dimitriadis E, Kay E, Redmond HP, Bouchier-Hayes D (1998) Regulation of macrophage production of vascular endothelial growth factor (VEGF) by hypoxia and transforming growth factor beta-1. Ann Surg Oncol 5(3):271–278PubMedCrossRefGoogle Scholar
  66. Harney AS, Karagiannis GS, Pignatelli J, Smith BD, Kadioglu E, Wise SC, Hood MM, Kaufman MD, Leary CB, Lu WP, Al-Ani G, Chen X, Entenberg D, Oktay MH, Wang Y, Chun L, De Palma M, Jones JG, Flynn DL, Condeelis JS (2017) The selective Tie2 inhibitor rebastinib blocks recruitment and function of Tie2(Hi) macrophages in breast cancer and pancreatic neuroendocrine tumors. Mol Cancer Ther 16(11):2486–2501. Scholar
  67. Hirschi KK, Ingram DA, Yoder MC (2008) Assessing identity, phenotype, and fate of endothelial progenitor cells. Arterioscler Thromb Vasc Biol 28(9):1584–1595. Scholar
  68. Hou Z, Falcone DJ, Subbaramaiah K, Dannenberg AJ (2011) Macrophages induce COX-2 expression in breast cancer cells: role of IL-1beta autoamplification. Carcinogenesis 32(5):695–702. Scholar
  69. Hudson JD, Shoaibi MA, Maestro R, Carnero A, Hannon GJ, Beach DH (1999) A proinflammatory cytokine inhibits p53 tumor suppressor activity. J Exp Med 190(10):1375–1382PubMedCrossRefGoogle Scholar
  70. Hung JY, Horn D, Woodruff K, Prihoda T, LeSaux C, Peters J, Tio F, Abboud-Werner SL (2014) Colony-stimulating factor 1 potentiates lung cancer bone metastasis. Lab Investig 94(4):371–381. Scholar
  71. Ide H, Seligson DB, Memarzadeh S, Xin L, Horvath S, Dubey P, Flick MB, Kacinski BM, Palotie A, Witte ON (2002) Expression of colony-stimulating factor 1 receptor during prostate development and prostate cancer progression. Proc Natl Acad Sci U S A 99(22):14404–14409. Scholar
  72. Ingber DE (1992) Extracellular matrix as a solid-state regulator in angiogenesis: identification of new targets for anti-cancer therapy. Semin Cancer Biol 3(2):57–63PubMedPubMedCentralGoogle Scholar
  73. Jain RK (2005) Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science 307(5706):58–62. Scholar
  74. Ji J, Zhang G, Sun B, Yuan H, Huang Y, Zhang J, Wei X, Zhang X, Hou J (2013) The frequency of tumor-infiltrating Tie-2-expressing monocytes in renal cell carcinoma: its relationship to angiogenesis and progression. Urology 82(4):974.e979–974.e913. Scholar
  75. Jiang S, Yang Y, Fang M, Li X, Yuan X, Yuan J (2016) Co-evolution of tumor-associated macrophages and tumor neo-vessels during cervical cancer invasion. Oncol Lett 12(4):2625–2631. Scholar
  76. Kacinski BM (1997) CSF-1 and its receptor in breast carcinomas and neoplasms of the female reproductive tract. Mol Reprod Dev 46(1):71–74.<71::AID-MRD11>3.0.CO;2-6PubMedCrossRefPubMedCentralGoogle Scholar
  77. Kalka C, Masuda H, Takahashi T, Kalka-Moll WM, Silver M, Kearney M, Li T, Isner JM, Asahara T (2000) Transplantation of ex vivo expanded endothelial progenitor cells for therapeutic neovascularization. Proc Natl Acad Sci U S A 97(7):3422–3427. Scholar
  78. Kaplan RN, Psaila B, Lyden D (2007) Niche-to-niche migration of bone-marrow-derived cells. Trends Mol Med 13(2):72–81. Scholar
  79. Karin M, Greten FR (2005) NF-kappaB: linking inflammation and immunity to cancer development and progression. Nat Rev Immunol 5(10):749–759. Scholar
  80. Karin M, Lawrence T, Nizet V (2006) Innate immunity gone awry: linking microbial infections to chronic inflammation and cancer. Cell 124(4):823–835. Scholar
  81. Karlmark KR, Tacke F, Dunay IR (2012) Monocytes in health and disease – minireview. Eur J Microbiol Immunol (Bp) 2(2):97–102. Scholar
  82. Kawaguchi T (2005) Cancer metastasis: characterization and identification of the behavior of metastatic tumor cells and the cell adhesion molecules, including carbohydrates. Curr Drug Targets Cardiovasc Haematol Disord 5(1):39–64PubMedCrossRefGoogle Scholar
  83. Keith B, Johnson RS, Simon MC (2011) HIF1alpha and HIF2alpha: sibling rivalry in hypoxic tumour growth and progression. Nat Rev Cancer 12(1):9–22. Scholar
  84. Kemeny LV, Kurgyis Z, Buknicz T, Groma G, Jakab A, Zanker K, Dittmar T, Kemeny L, Nemeth IB (2016) Melanoma cells can adopt the phenotype of stromal fibroblasts and macrophages by spontaneous cell fusion in vitro. Int J Mol Sci 17(6). Scholar
  85. Kim SJ, Kim JS, Papadopoulos J, Wook Kim S, Maya M, Zhang F, He J, Fan D, Langley R, Fidler IJ (2009) Circulating monocytes expressing CD31: implications for acute and chronic angiogenesis. Am J Pathol 174(5):1972–1980. Scholar
  86. Kimura YN, Watari K, Fotovati A, Hosoi F, Yasumoto K, Izumi H, Kohno K, Umezawa K, Iguchi H, Shirouzu K, Takamori S, Kuwano M, Ono M (2007) Inflammatory stimuli from macrophages and cancer cells synergistically promote tumor growth and angiogenesis. Cancer Sci 98(12):2009–2018. Scholar
  87. Kioi M, Vogel H, Schultz G, Hoffman RM, Harsh GR, Brown JM (2010) Inhibition of vasculogenesis, but not angiogenesis, prevents the recurrence of glioblastoma after irradiation in mice. J Clin Invest 120(3):694–705. Scholar
  88. Kirschmann DA, Seftor EA, Hardy KM, Seftor RE, Hendrix MJ (2012) Molecular pathways: vasculogenic mimicry in tumor cells: diagnostic and therapeutic implications. Clin Cancer Res 18(10):2726–2732. Scholar
  89. Kitajima D, Kasamatsu A, Nakashima D, Miyamoto I, Kimura Y, Endo-Sakamoto Y, Shiiba M, Tanzawa H, Uzawa K (2018) Evidence for critical role of Tie2/Ang1 interaction in metastatic oral cancer. Oncol Lett 15(5):7237–7242. Scholar
  90. Knowles H, Leek R, Harris AL (2004) Macrophage infiltration and angiogenesis in human malignancy. Novartis Found Symp 256:189–200; discussion 200–184, 259–169Google Scholar
  91. Komohara Y, Ohnishi K, Kuratsu J, Takeya M (2008) Possible involvement of the M2 anti-inflammatory macrophage phenotype in growth of human gliomas. J Pathol 216(1):15–24. Scholar
  92. Komohara Y, Hasita H, Ohnishi K, Fujiwara Y, Suzu S, Eto M, Takeya M (2011) Macrophage infiltration and its prognostic relevance in clear cell renal cell carcinoma. Cancer Sci 102(7):1424–1431. Scholar
  93. Komohara Y, Horlad H, Ohnishi K, Fujiwara Y, Bai B, Nakagawa T, Suzu S, Nakamura H, Kuratsu J, Takeya M (2012) Importance of direct macrophage-tumor cell interaction on progression of human glioma. Cancer Sci 103(12):2165–2172. Scholar
  94. Koong AC, Denko NC, Hudson KM, Schindler C, Swiersz L, Koch C, Evans S, Ibrahim H, Le QT, Terris DJ, Giaccia AJ (2000) Candidate genes for the hypoxic tumor phenotype. Cancer Res 60(4):883–887PubMedPubMedCentralGoogle Scholar
  95. Koukourakis MI, Giatromanolaki A, Kakolyris S, O’Byrne KJ, Apostolikas N, Skarlatos J, Gatter KC, Harris AL (1998) Different patterns of stromal and cancer cell thymidine phosphorylase reactivity in non-small-cell lung cancer: impact on tumour neoangiogenesis and survival. Br J Cancer 77(10):1696–1703. Scholar
  96. Kovacic JC, Moore J, Herbert A, Ma D, Boehm M, Graham RM (2008) Endothelial progenitor cells, angioblasts, and angiogenesis--old terms reconsidered from a current perspective. Trends Cardiovasc Med 18(2):45–51. Scholar
  97. Kovaleva OV, Samoilova DV, Shitova MS, Gratchev A (2016) Tumor associated macrophages in kidney cancer. Anal Cell Pathol (Amst) 2016:9307549. Scholar
  98. Kubota Y, Takubo K, Shimizu T, Ohno H, Kishi K, Shibuya M, Saya H, Suda T (2009) M-CSF inhibition selectively targets pathological angiogenesis and lymphangiogenesis. J Exp Med 206(5):1089–1102. Scholar
  99. Kuwabara K, Ogawa S, Matsumoto M, Koga S, Clauss M, Pinsky DJ, Lyn P, Leavy J, Witte L, Joseph-Silverstein J et al (1995) Hypoxia-mediated induction of acidic/basic fibroblast growth factor and platelet-derived growth factor in mononuclear phagocytes stimulates growth of hypoxic endothelial cells. Proc Natl Acad Sci U S A 92(10):4606–4610PubMedCrossRefGoogle Scholar
  100. Lamagna C, Aurrand-Lions M, Imhof BA (2006) Dual role of macrophages in tumor growth and angiogenesis. J Leukoc Biol 80(4):705–713. Scholar
  101. Lee HW, Choi HJ, Ha SJ, Lee KT, Kwon YG (2013) Recruitment of monocytes/macrophages in different tumor microenvironments. Biochim Biophys Acta 1835(2):170–179. Scholar
  102. Leek RD, Lewis CE, Whitehouse R, Greenall M, Clarke J, Harris AL (1996) Association of macrophage infiltration with angiogenesis and prognosis in invasive breast carcinoma. Cancer Res 56(20):4625–4629PubMedGoogle Scholar
  103. Leek RD, Hunt NC, Landers RJ, Lewis CE, Royds JA, Harris AL (2000) Macrophage infiltration is associated with VEGF and EGFR expression in breast cancer. J Pathol 190(4):430–436.<430::AID-PATH538>3.0.CO;2-6PubMedCrossRefGoogle Scholar
  104. Leung SY, Wong MP, Chung LP, Chan AS, Yuen ST (1997) Monocyte chemoattractant protein-1 expression and macrophage infiltration in gliomas. Acta Neuropathol 93(5):518–527PubMedCrossRefGoogle Scholar
  105. Lewis C, Murdoch C (2005) Macrophage responses to hypoxia: implications for tumor progression and anti-cancer therapies. Am J Pathol 167(3):627–635. Scholar
  106. Lewis CE, De Palma M, Naldini L (2007) Tie2-expressing monocytes and tumor angiogenesis: regulation by hypoxia and angiopoietin-2. Cancer Res 67(18):8429–8432. Scholar
  107. Li MO, Wan YY, Sanjabi S, Robertson AK, Flavell RA (2006) Transforming growth factor-beta regulation of immune responses. Annu Rev Immunol 24:99–146. Scholar
  108. Lin WW, Karin M (2007) A cytokine-mediated link between innate immunity, inflammation, and cancer. J Clin Invest 117(5):1175–1183. Scholar
  109. Lin EY, Nguyen AV, Russell RG, Pollard JW (2001) Colony-stimulating factor 1 promotes progression of mammary tumors to malignancy. J Exp Med 193(6):727–740PubMedCrossRefGoogle Scholar
  110. Lin EY, Gouon-Evans V, Nguyen AV, Pollard JW (2002) The macrophage growth factor CSF-1 in mammary gland development and tumor progression. J Mammary Gland Biol Neoplasia 7(2):147–162PubMedCrossRefGoogle Scholar
  111. Lin EY, Li JF, Bricard G, Wang W, Deng Y, Sellers R, Porcelli SA, Pollard JW (2007) Vascular endothelial growth factor restores delayed tumor progression in tumors depleted of macrophages. Mol Oncol 1(3):288–302. Scholar
  112. Lindstrom A, Midtbo K, Arnesson LG, Garvin S, Shabo I (2017) Fusion between M2-macrophages and cancer cells results in a subpopulation of radioresistant cells with enhanced DNA-repair capacity. Oncotarget 8(31):51370–51386. Scholar
  113. Lissbrant IF, Stattin P, Wikstrom P, Damber JE, Egevad L, Bergh A (2000) Tumor associated macrophages in human prostate cancer: relation to clinicopathological variables and survival. Int J Oncol 17(3):445–451. Scholar
  114. Liu Q, Qiao L, Liang N, Xie J, Zhang J, Deng G, Luo H (2016) The relationship between vasculogenic mimicry and epithelial-mesenchymal transitions. J Cell Mol Med 20(9):1761–1769. Scholar
  115. Locati M, Deuschle U, Massardi ML, Martinez FO, Sironi M, Sozzani S, Bartfai T, Mantovani A (2002) Analysis of the gene expression profile activated by the CC chemokine ligand 5/RANTES and by lipopolysaccharide in human monocytes. J Immunol 168(7):3557–3562PubMedCrossRefGoogle Scholar
  116. Lopes-Coelho F, Gouveia-Fernandes S, Serpa J (2018) Metabolic cooperation between cancer and non-cancerous stromal cells is pivotal in cancer progression. Tumour Biol 40(2):1010428318756203. Scholar
  117. Maeda H, Akaike T (1998) Nitric oxide and oxygen radicals in infection, inflammation, and cancer. Biochemistry (Mosc) 63(7):854–865Google Scholar
  118. Mancuso P, Burlini A, Pruneri G, Goldhirsch A, Martinelli G, Bertolini F (2001) Resting and activated endothelial cells are increased in the peripheral blood of cancer patients. Blood 97(11):3658–3661PubMedCrossRefGoogle Scholar
  119. Mantovani A (2010) Molecular pathways linking inflammation and cancer. Curr Mol Med 10(4):369–373. Scholar
  120. Mantovani A, Sica A (2010) Macrophages, innate immunity and cancer: balance, tolerance, and diversity. Curr Opin Immunol 22(2):231–237. Scholar
  121. Mantovani A, Schioppa T, Porta C, Allavena P, Sica A (2006) Role of tumor-associated macrophages in tumor progression and invasion. Cancer Metastasis Rev 25(3):315–322. Scholar
  122. Mantovani A, Allavena P, Sica A, Balkwill F (2008) Cancer-related inflammation. Nature 454(7203):436–444. Scholar
  123. Martin-Padura I, Marighetti P, Gregato G, Agliano A, Malazzi O, Mancuso P, Pruneri G, Viale A, Bertolini F (2012) Spontaneous cell fusion of acute leukemia cells and macrophages observed in cells with leukemic potential. Neoplasia 14(11):1057–1066PubMedCrossRefGoogle Scholar
  124. Matsubara T, Kanto T, Kuroda S, Yoshio S, Higashitani K, Kakita N, Miyazaki M, Sakakibara M, Hiramatsu N, Kasahara A, Tomimaru Y, Tomokuni A, Nagano H, Hayashi N, Takehara T (2013) TIE2-expressing monocytes as a diagnostic marker for hepatocellular carcinoma correlates with angiogenesis. Hepatology 57(4):1416–1425. Scholar
  125. McDonnell CO, Bouchier-Hayes DJ, Toomey D, Foley D, Kay EW, Leen E, Walsh TN (2003) Effect of neoadjuvant chemoradiotherapy on angiogenesis in oesophageal cancer. Br J Surg 90(11):1373–1378. Scholar
  126. Medina RJ, O’Neill CL, Sweeney M, Guduric-Fuchs J, Gardiner TA, Simpson DA, Stitt AW (2010) Molecular analysis of endothelial progenitor cell (EPC) subtypes reveals two distinct cell populations with different identities. BMC Med Genet 3:18. Scholar
  127. Menetrier-Caux C, Montmain G, Dieu MC, Bain C, Favrot MC, Caux C, Blay JY (1998) Inhibition of the differentiation of dendritic cells from CD34(+) progenitors by tumor cells: role of interleukin-6 and macrophage colony-stimulating factor. Blood 92(12):4778–4791PubMedCrossRefGoogle Scholar
  128. Metallo CM, Gameiro PA, Bell EL, Mattaini KR, Yang J, Hiller K, Jewell CM, Johnson ZR, Irvine DJ, Guarente L, Kelleher JK, Vander Heiden MG, Iliopoulos O, Stephanopoulos G (2011) Reductive glutamine metabolism by IDH1 mediates lipogenesis under hypoxia. Nature 481(7381):380–384. Scholar
  129. Metinko AP, Kunkel SL, Standiford TJ, Strieter RM (1992) Anoxia-hyperoxia induces monocyte-derived interleukin-8. J Clin Invest 90(3):791–798. Scholar
  130. Mills CD, Ley K (2014) M1 and M2 macrophages: the chicken and the egg of immunity. J Innate Immun 6(6):716–726. Scholar
  131. Moldovan NI (2002) Role of monocytes and macrophages in adult angiogenesis: a light at the tunnel’s end. J Hematother Stem Cell Res 11(2):179–194. Scholar
  132. Monestiroli S, Mancuso P, Burlini A, Pruneri G, Dell’Agnola C, Gobbi A, Martinelli G, Bertolini F (2001) Kinetics and viability of circulating endothelial cells as surrogate angiogenesis marker in an animal model of human lymphoma. Cancer Res 61(11):4341–4344PubMedPubMedCentralGoogle Scholar
  133. Mroczko B, Groblewska M, Wereszczynska-Siemiatkowska U, Okulczyk B, Kedra B, Laszewicz W, Dabrowski A, Szmitkowski M (2007) Serum macrophage-colony stimulating factor levels in colorectal cancer patients correlate with lymph node metastasis and poor prognosis. Clin Chim Acta 380(1–2):208–212. Scholar
  134. Murdoch C, Lewis CE (2005) Macrophage migration and gene expression in response to tumor hypoxia. Int J Cancer 117(5):701–708. Scholar
  135. Murdoch C, Giannoudis A, Lewis CE (2004) Mechanisms regulating the recruitment of macrophages into hypoxic areas of tumors and other ischemic tissues. Blood 104(8):2224–2234. Scholar
  136. Murdoch C, Muthana M, Coffelt SB, Lewis CE (2008) The role of myeloid cells in the promotion of tumour angiogenesis. Nat Rev Cancer 8(8):618–631. Scholar
  137. Negus RP, Stamp GW, Hadley J, Balkwill FR (1997) Quantitative assessment of the leukocyte infiltrate in ovarian cancer and its relationship to the expression of C-C chemokines. Am J Pathol 150(5):1723–1734PubMedPubMedCentralGoogle Scholar
  138. Nielsen SR, Schmid MC (2017) Macrophages as key drivers of cancer progression and metastasis. Mediat Inflamm 2017:9624760. Scholar
  139. Nishida N, Yano H, Nishida T, Kamura T, Kojiro M (2006) Angiogenesis in cancer. Vasc Health Risk Manag 2(3):213–219PubMedCrossRefGoogle Scholar
  140. Nolan DJ, Ciarrocchi A, Mellick AS, Jaggi JS, Bambino K, Gupta S, Heikamp E, McDevitt MR, Scheinberg DA, Benezra R, Mittal V (2007) Bone marrow-derived endothelial progenitor cells are a major determinant of nascent tumor neovascularization. Genes Dev 21(12):1546–1558. Scholar
  141. Oguma K, Oshima H, Aoki M, Uchio R, Naka K, Nakamura S, Hirao A, Saya H, Taketo MM, Oshima M (2008) Activated macrophages promote Wnt signalling through tumour necrosis factor-alpha in gastric tumour cells. EMBO J 27(12):1671–1681. Scholar
  142. Ohno S, Ohno Y, Suzuki N, Kamei T, Koike K, Inagawa H, Kohchi C, Soma G, Inoue M (2004) Correlation of histological localization of tumor-associated macrophages with clinicopathological features in endometrial cancer. Anticancer Res 24(5C):3335–3342Google Scholar
  143. Pages G, Pouyssegur J (2005) Transcriptional regulation of the Vascular Endothelial Growth Factor gene--a concert of activating factors. Cardiovasc Res 65(3):564–573. Scholar
  144. Pahl HL (1999) Activators and target genes of Rel/NF-kappaB transcription factors. Oncogene 18(49):6853–6866. Scholar
  145. Parsonnet J, Friedman GD, Vandersteen DP, Chang Y, Vogelman JH, Orentreich N, Sibley RK (1991) Helicobacter pylori infection and the risk of gastric carcinoma. N Engl J Med 325(16):1127–1131. Scholar
  146. Peichev M, Naiyer AJ, Pereira D, Zhu Z, Lane WJ, Williams M, Oz MC, Hicklin DJ, Witte L, Moore MA, Rafii S (2000) Expression of VEGFR-2 and AC133 by circulating human CD34(+) cells identifies a population of functional endothelial precursors. Blood 95(3):952–958PubMedCrossRefGoogle Scholar
  147. Penny HL, Sieow JL, Adriani G, Yeap WH, See Chi Ee P, San Luis B, Lee B, Lee T, Mak SY, Ho YS, Lam KP, Ong CK, Huang RY, Ginhoux F, Rotzschke O, Kamm RD, Wong SC (2016) Warburg metabolism in tumor-conditioned macrophages promotes metastasis in human pancreatic ductal adenocarcinoma. Oncoimmunology 5(8):e1191731. Scholar
  148. Pircher A, Kahler CM, Skvortsov S, Dlaska M, Kawaguchi G, Schmid T, Gunsilius E, Hilbe W (2008) Increased numbers of endothelial progenitor cells in peripheral blood and tumor specimens in non-small cell lung cancer: a methodological challenge and an ongoing debate on the clinical relevance. Oncol Rep 19(2):345–352PubMedPubMedCentralGoogle Scholar
  149. Pogoda K, Pyszniak M, Rybojad P, Tabarkiewicz J (2016) Monocytic myeloid-derived suppressor cells as a potent suppressor of tumor immunity in non-small cell lung cancer. Oncol Lett 12(6):4785–4794. Scholar
  150. Polette M, Nawrocki-Raby B, Gilles C, Clavel C, Birembaut P (2004) Tumour invasion and matrix metalloproteinases. Crit Rev Oncol Hematol 49(3):179–186. Scholar
  151. Pollard JW (2004) Tumour-educated macrophages promote tumour progression and metastasis. Nat Rev Cancer 4(1):71–78. Scholar
  152. Pollard JW (2009) Trophic macrophages in development and disease. Nat Rev Immunol 9(4):259–270. Scholar
  153. Powell AE, Anderson EC, Davies PS, Silk AD, Pelz C, Impey S, Wong MH (2011) Fusion between Intestinal epithelial cells and macrophages in a cancer context results in nuclear reprogramming. Cancer Res 71(4):1497–1505. Scholar
  154. Prenen H, Mazzone M (2019) Tumor-associated macrophages: a short compendium. Cell Mol Life Sci 76(8):1447–1458. Scholar
  155. Psaila B, Lyden D (2009) The metastatic niche: adapting the foreign soil. Nat Rev Cancer 9(4):285–293. Scholar
  156. Purhonen S, Palm J, Rossi D, Kaskenpaa N, Rajantie I, Yla-Herttuala S, Alitalo K, Weissman IL, Salven P (2008) Bone marrow-derived circulating endothelial precursors do not contribute to vascular endothelium and are not needed for tumor growth. Proc Natl Acad Sci U S A 105(18):6620–6625. Scholar
  157. Qian BZ, Pollard JW (2010) Macrophage diversity enhances tumor progression and metastasis. Cell 141(1):39–51. Scholar
  158. Qian BZ, Li J, Zhang H, Kitamura T, Zhang J, Campion LR, Kaiser EA, Snyder LA, Pollard JW (2011) CCL2 recruits inflammatory monocytes to facilitate breast-tumour metastasis. Nature 475(7355):222–225. Scholar
  159. Qiu B, Zhang D, Wang C, Tao J, Tie X, Qiao Y, Xu K, Wang Y, Wu A (2011) IL-10 and TGF-beta2 are overexpressed in tumor spheres cultured from human gliomas. Mol Biol Rep 38(5):3585–3591. Scholar
  160. Real C, Remedio L, Caiado F, Igreja C, Borges C, Trindade A, Pinto-do OP, Yagita H, Duarte A, Dias S (2011) Bone marrow-derived endothelial progenitors expressing Delta-like 4 (Dll4) regulate tumor angiogenesis. PLoS One 6(4):e18323. Scholar
  161. Rehman J, Li J, Orschell CM, March KL (2003) Peripheral blood “endothelial progenitor cells” are derived from monocyte/macrophages and secrete angiogenic growth factors. Circulation 107(8):1164–1169PubMedCrossRefGoogle Scholar
  162. Ribatti D (2007) The discovery of endothelial progenitor cells. An historical review. Leuk Res 31(4):439–444. Scholar
  163. Ribatti D (2009) The paracrine role of Tie-2-expressing monocytes in tumor angiogenesis. Stem Cells Dev 18(5):703–706. Scholar
  164. Ribatti D, Nico B, Crivellato E, Vacca A (2005) Endothelial progenitor cells in health and disease. Histol Histopathol 20(4):1351–1358PubMedPubMedCentralGoogle Scholar
  165. Richter-Ehrenstein C, Rentzsch J, Runkel S, Schneider A, Schonfelder G (2007) Endothelial progenitor cells in breast cancer patients. Breast Cancer Res Treat 106(3):343–349. Scholar
  166. Rigo A, Gottardi M, Zamo A, Mauri P, Bonifacio M, Krampera M, Damiani E, Pizzolo G, Vinante F (2010) Macrophages may promote cancer growth via a GM-CSF/HB-EGF paracrine loop that is enhanced by CXCL12. Mol Cancer 9:273. Scholar
  167. Robinson CJ, Stringer SE (2001) The splice variants of vascular endothelial growth factor (VEGF) and their receptors. J Cell Sci 114(Pt 5):853–865PubMedPubMedCentralGoogle Scholar
  168. Robinson SC, Scott KA, Balkwill FR (2002) Chemokine stimulation of monocyte matrix metalloproteinase-9 requires endogenous TNF-alpha. Eur J Immunol 32(2):404–412.<404::AID-IMMU404>3.0.CO;2-XPubMedCrossRefPubMedCentralGoogle Scholar
  169. Robinson-Smith TM, Isaacsohn I, Mercer CA, Zhou M, Van Rooijen N, Husseinzadeh N, McFarland-Mancini MM, Drew AF (2007) Macrophages mediate inflammation-enhanced metastasis of ovarian tumors in mice. Cancer Res 67(12):5708–5716. Scholar
  170. Rodriguez PC, Zea AH, DeSalvo J, Culotta KS, Zabaleta J, Quiceno DG, Ochoa JB, Ochoa AC (2003) L-arginine consumption by macrophages modulates the expression of CD3 zeta chain in T lymphocytes. J Immunol 171(3):1232–1239PubMedCrossRefGoogle Scholar
  171. Rodriguez PC, Quiceno DG, Ochoa AC (2007) L-arginine availability regulates T-lymphocyte cell-cycle progression. Blood 109(4):1568–1573. Scholar
  172. Rohde E, Malischnik C, Thaler D, Maierhofer T, Linkesch W, Lanzer G, Guelly C, Strunk D (2006) Blood monocytes mimic endothelial progenitor cells. Stem Cells 24(2):357–367. Scholar
  173. Romagnani P, Annunziato F, Liotta F, Lazzeri E, Mazzinghi B, Frosali F, Cosmi L, Maggi L, Lasagni L, Scheffold A, Kruger M, Dimmeler S, Marra F, Gensini G, Maggi E, Romagnani S (2005) CD14+CD34low cells with stem cell phenotypic and functional features are the major source of circulating endothelial progenitors. Circ Res 97(4):314–322. Scholar
  174. Roodhart JM, He H, Daenen LG, Monvoisin A, Barber CL, van Amersfoort M, Hofmann JJ, Radtke F, Lane TF, Voest EE, Iruela-Arispe ML (2013) Notch1 regulates angio-supportive bone marrow-derived cells in mice: relevance to chemoresistance. Blood 122(1):143–153. Scholar
  175. Roxburgh CS, McMillan DC (2014) Cancer and systemic inflammation: treat the tumour and treat the host. Br J Cancer 110(6):1409–1412. Scholar
  176. Ryder M, Ghossein RA, Ricarte-Filho JC, Knauf JA, Fagin JA (2008) Increased density of tumor-associated macrophages is associated with decreased survival in advanced thyroid cancer. Endocr Relat Cancer 15(4):1069–1074. Scholar
  177. Sakamori Y, Masago K, Ohmori K, Togashi Y, Nagai H, Okuda C, Kim YH, Ichiyama S, Mishima M (2012) Increase in circulating endothelial progenitor cells predicts response in patients with advanced non-small-cell lung cancer. Cancer Sci 103(6):1065–1070. Scholar
  178. Salvesen HB, Akslen LA (1999) Significance of tumour-associated macrophages, vascular endothelial growth factor and thrombospondin-1 expression for tumour angiogenesis and prognosis in endometrial carcinomas. Int J Cancer 84(5):538–543.<538::AID-IJC17>3.0.CO;2-BPubMedCrossRefPubMedCentralGoogle Scholar
  179. Sawano A, Iwai S, Sakurai Y, Ito M, Shitara K, Nakahata T, Shibuya M (2001) Flt-1, vascular endothelial growth factor receptor 1, is a novel cell surface marker for the lineage of monocyte-macrophages in humans. Blood 97(3):785–791PubMedCrossRefGoogle Scholar
  180. Schmeisser A, Garlichs CD, Zhang H, Eskafi S, Graffy C, Ludwig J, Strasser RH, Daniel WG (2001) Monocytes coexpress endothelial and macrophagocytic lineage markers and form cord-like structures in Matrigel under angiogenic conditions. Cardiovasc Res 49(3):671–680. Scholar
  181. Schmidt-Lucke C, Fichtlscherer S, Aicher A, Tschope C, Schultheiss HP, Zeiher AM, Dimmeler S (2010) Quantification of circulating endothelial progenitor cells using the modified ISHAGE protocol. PLoS One 5(11):e13790. Scholar
  182. Semenza GL (2003) Angiogenesis in ischemic and neoplastic disorders. Annu Rev Med 54:17–28. Scholar
  183. Shaked Y, Bertolini F, Man S, Rogers MS, Cervi D, Foutz T, Rawn K, Voskas D, Dumont DJ, Ben-David Y, Lawler J, Henkin J, Huber J, Hicklin DJ, D’Amato RJ, Kerbel RS (2005) Genetic heterogeneity of the vasculogenic phenotype parallels angiogenesis; Implications for cellular surrogate marker analysis of antiangiogenesis. Cancer Cell 7(1):101–111. Scholar
  184. Sharifi BG, Zeng Z, Wang L, Song L, Chen H, Qin M, Sierra-Honigmann MR, Wachsmann-Hogiu S, Shah PK (2006) Pleiotrophin induces transdifferentiation of monocytes into functional endothelial cells. Arterioscler Thromb Vasc Biol 26(6):1273–1280. Scholar
  185. Sica A, Bronte V (2007) Altered macrophage differentiation and immune dysfunction in tumor development. J Clin Invest 117(5):1155–1166. Scholar
  186. Sica A, Saccani A, Bottazzi B, Polentarutti N, Vecchi A, van Damme J, Mantovani A (2000) Autocrine production of IL-10 mediates defective IL-12 production and NF-kappa B activation in tumor-associated macrophages. J Immunol 164(2):762–767. Scholar
  187. Sica A, Schioppa T, Mantovani A, Allavena P (2006) Tumour-associated macrophages are a distinct M2 polarised population promoting tumour progression: potential targets of anti-cancer therapy. Eur J Cancer 42(6):717–727. Scholar
  188. Sica A, Larghi P, Mancino A, Rubino L, Porta C, Totaro MG, Rimoldi M, Biswas SK, Allavena P, Mantovani A (2008a) Macrophage polarization in tumour progression. Semin Cancer Biol 18(5):349–355. Scholar
  189. Sica A, Allavena P, Mantovani A (2008b) Cancer related inflammation: the macrophage connection. Cancer Lett 267(2):204–215. Scholar
  190. Spinelli FM, Vitale DL, Icardi A, Caon I, Brandone A, Giannoni P, Saturno V, Passi A, Garcia M, Sevic I, Alaniz L (2019) Hyaluronan preconditioning of monocytes/macrophages affects their angiogenic behavior and regulation of TSG-6 expression in a tumor type-specific manner. FEBS J 286(17):3433–3449. Scholar
  191. Sporn MB (1996) The war on cancer. Lancet 347(9012):1377–1381PubMedCrossRefGoogle Scholar
  192. Steidl C, Lee T, Shah SP, Farinha P, Han G, Nayar T, Delaney A, Jones SJ, Iqbal J, Weisenburger DD, Bast MA, Rosenwald A, Muller-Hermelink HK, Rimsza LM, Campo E, Delabie J, Braziel RM, Cook JR, Tubbs RR, Jaffe ES, Lenz G, Connors JM, Staudt LM, Chan WC, Gascoyne RD (2010) Tumor-associated macrophages and survival in classic Hodgkin’s lymphoma. N Engl J Med 362(10):875–885. Scholar
  193. Stockmann C, Doedens A, Weidemann A, Zhang N, Takeda N, Greenberg JI, Cheresh DA, Johnson RS (2008) Deletion of vascular endothelial growth factor in myeloid cells accelerates tumorigenesis. Nature 456(7223):814–818. Scholar
  194. Sun T, Yang Y, Luo X, Cheng Y, Zhang M, Wang K, Ge C (2014) Inhibition of tumor angiogenesis by interferon-gamma by suppression of tumor-associated macrophage differentiation. Oncol Res 21(5):227–235. Scholar
  195. Takanami I, Takeuchi K, Kodaira S (1999) Tumor-associated macrophage infiltration in pulmonary adenocarcinoma: association with angiogenesis and poor prognosis. Oncology 57(2):138–142. Scholar
  196. Timmermans F, Plum J, Yoder MC, Ingram DA, Vandekerckhove B, Case J (2009) Endothelial progenitor cells: identity defined? J Cell Mol Med 13(1):87–102. Scholar
  197. Torisu H, Ono M, Kiryu H, Furue M, Ohmoto Y, Nakayama J, Nishioka Y, Sone S, Kuwano M (2000) Macrophage infiltration correlates with tumor stage and angiogenesis in human malignant melanoma: possible involvement of TNFalpha and IL-1alpha. Int J Cancer 85(2):182–188.<182::AID-IJC6>3.0.CO;2-MPubMedCrossRefPubMedCentralGoogle Scholar
  198. Toy EP, Azodi M, Folk NL, Zito CM, Zeiss CJ, Chambers SK (2009) Enhanced ovarian cancer tumorigenesis and metastasis by the macrophage colony-stimulating factor. Neoplasia 11(2):136–144PubMedCrossRefGoogle Scholar
  199. Ueno T, Toi M, Saji H, Muta M, Bando H, Kuroi K, Koike M, Inadera H, Matsushima K (2000) Significance of macrophage chemoattractant protein-1 in macrophage recruitment, angiogenesis, and survival in human breast cancer. Clin Cancer Res 6(8):3282–3289PubMedPubMedCentralGoogle Scholar
  200. Urbich C, Heeschen C, Aicher A, Dernbach E, Zeiher AM, Dimmeler S (2003) Relevance of monocytic features for neovascularization capacity of circulating endothelial progenitor cells. Circulation 108(20):2511–2516. Scholar
  201. Venneri MA, De Palma M, Ponzoni M, Pucci F, Scielzo C, Zonari E, Mazzieri R, Doglioni C, Naldini L (2007) Identification of proangiogenic TIE2-expressing monocytes (TEMs) in human peripheral blood and cancer. Blood 109(12):5276–5285. Scholar
  202. Verbridge SS, Choi NW, Zheng Y, Brooks DJ, Stroock AD, Fischbach C (2009) Oxygen-controlled three-dimensional cultures to analyze tumor angiogenesis. Tissue Eng Part A 16(7):2133–2141. Scholar
  203. Wang X, Zhao X, Wang K, Wu L, Duan T (2013) Interaction of monocytes/macrophages with ovarian cancer cells promotes angiogenesis in vitro. Cancer Sci 104(4):516–523. Scholar
  204. Wang X, Zhu Q, Lin Y, Wu L, Wu X, Wang K, He Q, Xu C, Wan X (2017) Crosstalk between TEMs and endothelial cells modulates angiogenesis and metastasis via IGF1-IGF1R signalling in epithelial ovarian cancer. Br J Cancer 117(9):1371–1382. Scholar
  205. Wang F, Li B, Wei Y, Zhao Y, Wang L, Zhang P, Yang J, He W, Chen H, Jiao Z, Li Y (2018) Tumor-derived exosomes induce PD1(+) macrophage population in human gastric cancer that promotes disease progression. Oncogene 7(5):41. Scholar
  206. Wei C, Yang C, Wang S, Shi D, Zhang C, Lin X, Liu Q, Dou R, Xiong B (2019) Crosstalk between cancer cells and tumor associated macrophages is required for mesenchymal circulating tumor cell-mediated colorectal cancer metastasis. Mol Cancer 18(1):64. Scholar
  207. Willenborg S, Lucas T, van Loo G, Knipper JA, Krieg T, Haase I, Brachvogel B, Hammerschmidt M, Nagy A, Ferrara N, Pasparakis M, Eming SA (2012) CCR2 recruits an inflammatory macrophage subpopulation critical for angiogenesis in tissue repair. Blood 120(3):613–625. Scholar
  208. Wu SY, Watabe K (2017) The roles of microglia/macrophages in tumor progression of brain cancer and metastatic disease. Front Biosci (Landmark Ed) 22:1805–1829. Scholar
  209. Wu H, Xu JB, He YL, Peng JJ, Zhang XH, Chen CQ, Li W, Cai SR (2012) Tumor-associated macrophages promote angiogenesis and lymphangiogenesis of gastric cancer. J Surg Oncol 106(4):462–468. Scholar
  210. Wyckoff J, Wang W, Lin EY, Wang Y, Pixley F, Stanley ER, Graf T, Pollard JW, Segall J, Condeelis J (2004) A paracrine loop between tumor cells and macrophages is required for tumor cell migration in mammary tumors. Cancer Res 64(19):7022–7029. Scholar
  211. Xu J, Escamilla J, Mok S, David J, Priceman S, West B, Bollag G, McBride W, Wu L (2013) CSF1R signaling blockade stanches tumor-infiltrating myeloid cells and improves the efficacy of radiotherapy in prostate cancer. Cancer Res 73(9):2782–2794. Scholar
  212. Yamaguchi Y, Okazaki Y, Seta N, Satoh T, Takahashi K, Ikezawa Z, Kuwana M (2010) Enhanced angiogenic potency of monocytic endothelial progenitor cells in patients with systemic sclerosis. Arthritis Res Ther 12(6):R205. Scholar
  213. Yan D, Wang HW, Bowman RL, Joyce JA (2016) STAT3 and STAT6 signaling pathways synergize to promote cathepsin secretion from macrophages via IRE1alpha activation. Cell Rep 16(11):2914–2927. Scholar
  214. Yang L, Pang Y, Moses HL (2010) TGF-beta and immune cells: an important regulatory axis in the tumor microenvironment and progression. Trends Immunol 31(6):220–227. Scholar
  215. Yang WJ, Hao YX, Yang X, Fu XL, Shi Y, Yue HL, Yin P, Dong HL, Yu PW (2018) Overexpression of Tie2 is associated with poor prognosis in patients with gastric cancer. Oncol Lett 15(5):8027–8033. Scholar
  216. Yoder MC (2012) Human endothelial progenitor cells. Cold Spring Harb Perspect Med 2(7):a006692. Scholar
  217. Yu D, Sun X, Qiu Y, Zhou J, Wu Y, Zhuang L, Chen J, Ding Y (2007) Identification and clinical significance of mobilized endothelial progenitor cells in tumor vasculogenesis of hepatocellular carcinoma. Clin Cancer Res 13(13):3814–3824. Scholar
  218. Zabuawala T, Taffany DA, Sharma SM, Merchant A, Adair B, Srinivasan R, Rosol TJ, Fernandez S, Huang K, Leone G, Ostrowski MC (2010) An ets2-driven transcriptional program in tumor-associated macrophages promotes tumor metastasis. Cancer Res 70(4):1323–1333. Scholar
  219. Zajac E, Schweighofer B, Kupriyanova TA, Juncker-Jensen A, Minder P, Quigley JP, Deryugina EI (2013) Angiogenic capacity of M1- and M2-polarized macrophages is determined by the levels of TIMP-1 complexed with their secreted proMMP-9. Blood 122(25):4054–4067. Scholar
  220. Zeisberger SM, Odermatt B, Marty C, Zehnder-Fjallman AH, Ballmer-Hofer K, Schwendener RA (2006) Clodronate-liposome-mediated depletion of tumour-associated macrophages: a new and highly effective antiangiogenic therapy approach. Br J Cancer 95(3):272–281. Scholar
  221. Zeng XY, Xie H, Yuan J, Jiang XY, Yong JH, Zeng D, Dou YY, Xiao SS (2019) M2-like tumor-associated macrophages-secreted EGF promotes epithelial ovarian cancer metastasis via activating EGFR-ERK signaling and suppressing lncRNA LIMT expression. Cancer Biol Ther 20(7):956–966. Scholar
  222. Zhang Z, Chen F, Shang L (2018) Advances in antitumor effects of NSAIDs. Cancer Manag Res 10:4631–4640. Scholar
  223. Zhu XD, Zhang JB, Zhuang PY, Zhu HG, Zhang W, Xiong YQ, Wu WZ, Wang L, Tang ZY, Sun HC (2008) 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 26(16):2707–2716. Scholar
  224. Zhu C, Chrifi I, Mustafa D, van der Weiden M, Leenen PJM, Duncker DJ, Kros JM, Cheng C (2017) CECR1-mediated cross talk between macrophages and vascular mural cells promotes neovascularization in malignant glioma. Oncogene 36(38):5356–5368. Scholar

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© Springer Nature Switzerland AG 2020

Authors and Affiliations

  • Sofia Gouveia-Fernandes
    • 1
  1. 1.CEDOC, Chronic Diseases Research Centre, NOVA Medical School | Faculdade de Ciências MédicasUniversidade NOVA de LisboaLisbonPortugal

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