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  • Review Article
  • Published:

Trophic macrophages in development and disease

Nature Reviews Immunology volume 9, pages 259–270 (2009)Cite this article

Key Points

  • Cells of the mononuclear phagocytic lineage differentiate into many different types of macrophage with a wide range of activities. These include specialized types of macrophage, such as Kupffer cells in the liver, microglial cells in the brain, dendritic cells and the highly specialized bone osteoclasts.

  • Macrophages have many functions, including roles in immunity, apoptotic-cell clearance, wound healing and, as discussed in this Review, development.

  • Analysis of macrophage-deficient mice has revealed many functions for these cells in development, and their loss perturbs the morphology and physiology of many tissues, such as the brain, mammary glands and bones.

  • Macrophages promote epithelial-cell outgrowth and branching morphogenesis in several tissues, including the pancreas and the mammary glands.

  • Macrophages regulate angiogenesis during development, wound repair and disease.

  • Macrophages have a role in adipogenesis and obesity.

  • Macrophages are strongly involved in many chronic diseases that are associated with ageing and provide trophic factors that are similar to those used during development; this has the effect of increasing disease pathology.

  • Cancers sequester the developmental roles of macrophages to enhance their growth, invasive capacity, intravasation, progression and metastatic capacity.

Abstract

Specialized phagocytes are found in the most primitive multicellular organisms. Their roles in homeostasis and in distinguishing self from non-self have evolved with the complexity of organisms and their immune systems. Equally important, but often overlooked, are the roles of macrophages in tissue development. As discussed in this Review, these include functions in branching morphogenesis, neuronal patterning, angiogenesis, bone morphogenesis and the generation of adipose tissue. In each case, macrophage depletion impairs the formation of the tissue and compromises its function. I argue that in several diseases, the unrestrained acquisition of these developmental macrophage functions exacerbates pathology. For example, macrophages enhance tumour progression and metastasis by affecting tumour-cell migration and invasion, as well as angiogenesis.

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Figure 1: The mononuclear phagocytic lineage and the control of its development by growth factors.
Figure 2: The trophic role of macrophages in bone morphogenesis.
Figure 3: The trophic role of macrophages in ductal branching.
Figure 4: The trophic role of macrophages in neuronal patterning.
Figure 5: The trophic role of macrophages in angiogenesis and vascular remodelling.

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References

  1. Tauber, A. I. Metchnikoff and the phagocytosis theory. Nature Rev. Mol. Cell Biol. 4, 897–901 (2003).

    Article  CAS  Google Scholar 

  2. Kawai, Y., Smedsrod, B., Elvevold, K. & Wake, K. Uptake of lithium carmine by sinusoidal endothelial and Kupffer cells of the rat liver: new insights into the classical vital staining and the reticulo-endothelial system. Cell Tissue Res. 292, 395–410 (1998).

    Article  CAS  PubMed  Google Scholar 

  3. van Furth, R. et al. The mononuclear phagocyte system: a new classification of macrophages, monocytes, and their precursor cells. Bull. World Health Organ. 46, 845–852 (1972). This article formalizes the concept of the MPS.

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Banchereau, J. et al. Immunobiology of dendritic cells. Annu. Rev. Immunol. 18, 767–811 (2000).

    Article  CAS  PubMed  Google Scholar 

  5. Hume, D. A. Macrophages as APC and the dendritic cell myth. J. Immunol. 181, 5829–5835 (2008).

    Article  CAS  PubMed  Google Scholar 

  6. Bailey, A. S. et al. Myeloid lineage progenitors give rise to vascular endothelium. Proc. Natl Acad. Sci. USA 103, 13156–13161 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Hume, D. A. The mononuclear phagocyte system. Curr. Opin. Immunol. 18, 49–53 (2006).

    Article  CAS  PubMed  Google Scholar 

  8. Bertrand, J. Y. et al. Three pathways to mature macrophages in the early mouse yolk sac. Blood 106, 3004–3011 (2005).

    Article  CAS  PubMed  Google Scholar 

  9. Rae, F. et al. Characterisation and trophic functions of murine embryonic macrophages based upon the use of a Csf1r–EGFP transgene reporter. Dev. Biol. 308, 232–246 (2007). This study examines the transcriptional profile of embryonic macrophages and suggests theirtrophic functions.

    Article  CAS  PubMed  Google Scholar 

  10. Lichanska, A. M. et al. Differentiation of the mononuclear phagocyte system during mouse embryogenesis: the role of transcription factor PU.1. Blood 94, 127–138 (1999). This paper examines the development of macrophages during embryogenesis.

    CAS  PubMed  Google Scholar 

  11. Dzierzak, E., Medvinsky, A. & de Bruijn, M. Qualitative and quantitative aspects of haematopoietic cell development in the mammalian embryo. Immunol. Today 19, 228–236 (1998).

    Article  CAS  PubMed  Google Scholar 

  12. Perry, V. H., Hume, D. A. & Gordon, S. Immunohistochemical localization of macrophages and microglia in the adult and developing mouse brain. Neuroscience 15, 313–326 (1985).

    Article  CAS  PubMed  Google Scholar 

  13. Sasmono, R. T. et al. A macrophage colony-stimulating factor receptor–green fluorescent protein transgene is expressed throughout the mononuclear phagocyte system of the mouse. Blood 101, 1155–1163 (2003). This study uses a valuable reporter mouse strain for studying the mononuclear phagocytic system in development and disease.

    Article  CAS  PubMed  Google Scholar 

  14. Cecchini, M. G. et al. Role of colony stimulating factor-1 in the establishment and regulation of tissue macrophages during postnatal development of the mouse. Development 120, 1357–1372 (1994). This paper provides a detailed characterization of macrophage deficiencies in Csf1op/op mice.

    CAS  PubMed  Google Scholar 

  15. Merad, M., Ginhoux, F. & Collin, M. Origin, homeostasis and function of Langerhans cells and other langerin-expressing dendritic cells. Nature Rev. Immunol. 8, 935–947 (2008).

    Article  CAS  Google Scholar 

  16. Ovchinnikov, D. A. et al. Expression of Gal4-dependent transgenes in cells of the mononuclear phagocyte system labeled with enhanced cyan fluorescent protein using Csf1r–Gal4VP16/UAS–ECFP double-transgenic mice. J. Leukoc. Biol. 83, 430–433 (2008).

    Article  CAS  PubMed  Google Scholar 

  17. Sasmono, R. T. et al. Mouse neutrophilic granulocytes express mRNA encoding the macrophage colony-stimulating factor receptor (CSF-1R) as well as many other macrophage-specific transcripts and can transdifferentiate into macrophages in vitro in response to CSF-1. J. Leukoc. Biol. 82, 111–123 (2007).

    Article  CAS  PubMed  Google Scholar 

  18. Gordon, S. Alternative activation of macrophages. Nature Rev. Immunol. 3, 23–35 (2003). This is a seminal review on the differences in macrophage phenotypes during immune responses.

    Article  CAS  Google Scholar 

  19. 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. 23, 549–555 (2002). The paper suggests that the M1- and M2-type classification for macrophages is applicable to those found in tumours.

    Article  CAS  PubMed  Google Scholar 

  20. Ricardo, S. D., van Goor, H. & Eddy, A. A. Macrophage diversity in renal injury and repair. J. Clin. Invest. 118, 3522–3530 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Hamilton, J. A. Colony-stimulating factors in inflammation and autoimmunity. Nature Rev. Immunol. 8, 533–544 (2008).

    Article  CAS  Google Scholar 

  22. Mosser, D. M. & Edwards, J. P. Exploring the full spectrum of macrophage activation. Nature Rev. Immunol. 8, 958–969 (2008). This is a recent review emphasizing multiple and plastic phenotypes of macrophages, with an emphasis on wound-healing macrophages.

    Article  CAS  Google Scholar 

  23. Chitu, V. & Stanley, E. R. Colony-stimulating factor-1 in immunity and inflammation. Curr. Opin. Immunol. 18, 39–48 (2006). An important review of the action of CSF1-regulated macrophages in disease.

    Article  CAS  PubMed  Google Scholar 

  24. Fortier, A. H. & Falk, L. A. Isolation of murine macrophages. Curr. Protoc Immunol. Chapter 14, Unit 14 1 (2001).

  25. Stanley, E. et al. Granulocyte/macrophage colony-stimulating factor-deficient mice show no major perturbation of hematopoiesis but develop a characteristic pulmonary pathology. Proc. Natl Acad. Sci. USA 91, 5592–5596 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Dranoff, G. et al. Involvement of granulocyte-macrophage colony-stimulating factor in pulmonary homeostasis. Science 264, 713–716 (1994). In this study and in reference 25, the generation of a mouse lacking GM-CSF indicates that this growth factor does not have a role in the regulation of the myeloid lineage in normal physiological conditions.

    Article  CAS  PubMed  Google Scholar 

  27. Nicola, N. A. et al. Functional inactivation in mice of the gene for the interleukin-3 (IL-3)-specific receptor beta-chain: implications for IL-3 function and the mechanism of receptor transmodulation in hematopoietic cells. Blood 87, 2665–2674 (1996).

    CAS  PubMed  Google Scholar 

  28. Anderson, K. L. et al. Myeloid development is selectively disrupted in PU.1 null mice. Blood 91, 3702–3710 (1998).

    CAS  PubMed  Google Scholar 

  29. Tondravi, M. M. et al. Osteopetrosis in mice lacking haematopoietic transcription factor PU.1. Nature 386, 81–84 (1997). References 28 and 29 show that the transcription factor PU.1 is important for myeloid-cell development and its absence results in osteopetrosis.

    Article  CAS  PubMed  Google Scholar 

  30. Simon, M. C. PU.1 and hematopoiesis: lessons learned from gene targeting experiments. Semin. Immunol. 10, 111–118 (1998).

    Article  CAS  PubMed  Google Scholar 

  31. Kohyama, M. et al. Role for Spi-C in the development of red pulp macrophages and splenic iron homeostasis. Nature 457, 318–321 (2009).

    Article  CAS  PubMed  Google Scholar 

  32. Pollard, J. W. & Stanley, E. R. Pleiotropic roles for CSF-1 in development defined by the mouse mutation osteopetrotic (op). Adv. Develop. Bioch. 4, 153–193 (1996).

    Article  CAS  Google Scholar 

  33. Dai, X. et al. Targeted disruption of the mouse CSF-1 receptor gene results in osteopetrosis, mononuclear phagocyte deficiency, increased primititive progenitor cell frequencies and reproductive defects. Blood 99, 111–120 (2002). In this paper, the phenotype of mice lacking Csf1r indicates the importance of CSF1R in regulating cells of the MPS.

    Article  CAS  PubMed  Google Scholar 

  34. Cohen, P. E., Zhu, L., Nishimura, K. & Pollard, J. W. Colony-stimulating factor 1 regulation of neuroendocrine pathways that control gonadal function in mice. Endocrinology 143, 1413–1422 (2002).

    Article  CAS  PubMed  Google Scholar 

  35. Lin, H. et al. Discovery of a cytokine and its receptor by functional screening of the extracellular proteome. Science 320, 807–811 (2008).

    Article  CAS  PubMed  Google Scholar 

  36. Guleria, I. & Pollard, J. W. Aberrant macrophage and neutrophil population dynamics and impaired Th1 response to Listeria monocytogenes in colony-stimulating factor 1- deficient mice. Infect. Immun. 69, 1795–1807 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Teitelbaum, R. et al. The M cell as a portal of entry to the lung for the bacterial pathogen for Mycobacterium tuberculosis. Immunity 10, 641–650 (1999).

    Article  CAS  PubMed  Google Scholar 

  38. Wiktor-Jedrzejczak, W. et al. Total absence of colony-stimulating factor 1 in the macrophage-deficient osteopetrotic (op/op) mouse. Proc. Natl Acad. Sci. USA 87, 4828–4832 (1990). This is the original characterization of mice lacking CSF1 because of an inactivating mutation in the Csf1 gene.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Van Wesenbeeck, L. et al. The osteopetrotic mutation toothless (tl) is a loss-of-function frameshift mutation in the rat Csf1 gene: evidence of a crucial role for CSF-1 in osteoclastogenesis and endochondral ossification. Proc. Natl Acad. Sci. USA 99, 14303–14308 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Dougall, W. et al. RANK is essential for osteoclast and lymph node development. Genes Develop. 13, 2412–2424 (1999). Discovery of the identity and function of the growth factor RANKL for the osteoclastic lineage.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Grey, A., Chen, Y., Paliwal, I., Carlberg, K. & Insogna, K. Evidence for a functional association between phosphatidylinositol 3- kinase and c-src in the spreading response of osteoclasts to colony- stimulating factor-1. Endocrinology 141, 2129–2138 (2000).

    Article  CAS  PubMed  Google Scholar 

  42. Begg, S. K. et al. Delayed hemopoietic development in osteopetrotic (op/op) mice. J. Exp. Med. 177, 237–242 (1993).

    Article  CAS  PubMed  Google Scholar 

  43. Wiktor-Jedrzejczak, W. et al. Correction by CSF-1 of defects in the osteopetrotic op/op mouse suggests local, developmental, and humoral requirements for this growth factor. Exp. Hematol. 19, 1049–1054 (1991).

    CAS  PubMed  Google Scholar 

  44. Marks, S. C. Jr et al. Administration of colony stimulating factor-1 corrects some macrophage, dental, and skeletal defects in an osteopetrotic mutation (toothless, tl) in the rat. Bone 13, 89–93 (1992).

    Article  PubMed  Google Scholar 

  45. Gouon-Evans, V., Rothenberg, M. E. & Pollard, J. W. Postnatal mammary gland development requires macrophages and eosinophils. Development 127, 2269–2282 (2000).

    CAS  PubMed  Google Scholar 

  46. Ingman, W. V., Wyckoff, J., Gouon-Evans, V., Condeelis, J. & Pollard, J. W. Macrophages promote collagen fibrillogenesis around terminal end buds of the developing mammary gland. Dev. Dyn. 235, 3222–3229 (2006).

    Article  CAS  PubMed  Google Scholar 

  47. Pollard, J. W. & Hennighausen, L. Colony stimulating factor 1 is required for mammary gland development during pregnancy. Proc. Natl Acad. Sci. USA 91, 9312–9316 (1994). References 45 and 47 show that macrophages regulate branching morphogenesis in the mammary gland.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Nguyen, A. V. & Pollard, J. W. Colony stimulating factor-1 is required to recruit macrophages into the mammary gland to facilitate mammary ductal outgrowth. Dev. Biol. 247, 11–25 (2002).

    Article  CAS  PubMed  Google Scholar 

  49. Banaei-Bouchareb, L. et al. Insulin cell mass is altered in Csf1op/Csf1op macrophage-deficient mice. J. Leukoc. Biol. 76, 359–367 (2004).

    Article  CAS  PubMed  Google Scholar 

  50. Geutskens, S. B., Otonkoski, T., Pulkkinen, M. A., Drexhage, H. A. & Leenen, P. J. Macrophages in the murine pancreas and their involvement in fetal endocrine development in vitro. J. Leukoc. Biol. 78, 845–852 (2005).

    Article  CAS  PubMed  Google Scholar 

  51. Cohen, P. E., Nishimura, K., Zhu, L. & Pollard, J. W. Macrophages: important accessory cells for reproductive function. J. Leukoc. Biol. 66, 765–772 (1999).

    Article  CAS  PubMed  Google Scholar 

  52. Cohen, P. E., Chisholm, O., Arceci, R. J., Stanley, E. R. & Pollard, J. W. Absence of colony stimulating factor-1 in osteopetrotic (csfmop/csfmop) mice results in male fertility defects. Biol. Reprod. 55, 310–317 (1996).

    Article  CAS  PubMed  Google Scholar 

  53. Cohen, P. E., Zhu, L. & Pollard, J. W. The absence of CSF-1 in osteopetrotic (csfmop/csfmop) mice disrupts estrous cycles and ovulation. Biol. Reprod. 56, 110–118 (1997).

    Article  CAS  PubMed  Google Scholar 

  54. Brigham, D. E., Little, G., Lukyanenko, Y. O. & Hutson, J. C. Effects of clodronate-containing liposomes on testicular macrophages and Leydig cells in vitro. J. Endocrinol. 155, 87–92 (1997).

    Article  CAS  PubMed  Google Scholar 

  55. Wu, R., Van der Hoek, K. H., Ryan, N. K., Norman, R. J. & Robker, R. L. Macrophage contributions to ovarian function. Hum. Reprod. Update 10, 119–133 (2004).

    Article  PubMed  Google Scholar 

  56. Brännström, M. & Norman, R. J. Involvement of leukocytes and cytokines in the ovulatory process and corpus luteum function. Human Reprod. 8, 1762–1775 (1993).

    Article  Google Scholar 

  57. Cohen, P. E., Hardy, M. P. & Pollard, J. W. Colony-stimulating factor-1 plays a major role in the development of reproductive function in male mice. Mol. Endocrinol. 11, 1636–1650 (1997). This study shows that CSF1-regulated microglial cells help to establish the hypothalamic–pituitary–gonadal axis during development.

    Article  CAS  PubMed  Google Scholar 

  58. Michaelson, M. D. et al. CSF-1 deficiency in mice results in abnormal brain development. Development 122, 1–12 (1996). The first study to indicate that the lack of CSF1 signalling in microglial cells perturbs brain physiology.

    Google Scholar 

  59. Bulloch, K. et al. CD11c/EYFP transgene illuminates a discrete network of dendritic cells within the embryonic, neonatal, adult, and injured mouse brain. J. Comp. Neurol. 508, 687–710 (2008).

    Article  PubMed  Google Scholar 

  60. Kondo, Y., Lemere, C. A. & Seabrook, T. J. Osteopetrotic (op/op) mice have reduced microglia, no αβ deposition, and no changes in dopaminergic neurons. J. Neuroinflammation 4, 31 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Vilhardt, F. Microglia: phagocyte and glia cell. Int. J. Biochem. Cell Biol. 37, 17–21 (2005).

    Article  CAS  PubMed  Google Scholar 

  62. Rapalino, O. et al. Implantation of stimulated homologous macrophages results in partial recovery of paraplegic rats. Nature Med. 4, 814–821 (1998).

    Article  CAS  PubMed  Google Scholar 

  63. Lalancette-Hebert, M., Gowing, G., Simard, A., Weng, Y. C. & Kriz, J. Selective ablation of proliferating microglial cells exacerbates ischemic injury in the brain. J. Neurosci. 27, 2596–2605 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Berezovskaya, O., Maysinger, D. & Federoff, S. The hematopoietic cytokine, colony stimulating factor 1, is also a growth factor in the CNS: congenital absence of CSF-1 in mice results in abnormal microglial response and increased neuron vulnerability to injury. Int. J. Dev. Neurosci. 13, 285–299 (1995).

    Article  CAS  PubMed  Google Scholar 

  65. Gottfried-Blackmore, A., Sierra, A., Jellinck, P. H., McEwen, B. S. & Bulloch, K. Brain microglia express steroid-converting enzymes in the mouse. J. Steroid Biochem. Mol. Biol. 109, 96–107 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Lingen, M. W. Role of leukocytes and endothelial cells in the development of angiogenesis in inflammation and wound healing. Arch. Pathol. Lab. Med. 125, 67–71 (2001).

    CAS  PubMed  Google Scholar 

  67. Bergmann, C. E. et al. Arteriogenesis depends on circulating monocytes and macrophage accumulation and is severely depressed in op/op mice. J. Leukoc. Biol. 80, 59–65 (2006).

    Article  CAS  PubMed  Google Scholar 

  68. Diez-Roux, G., Argilla, M., Makarenkova, H., Ko, K. & Lang, R. A. Macrophages kill capillary cells in G1 phase of the cell cycle during programmed vascular regression. Development 126, 2141–2147 (1999).

    CAS  PubMed  Google Scholar 

  69. Lobov, I. B. et al. WNT7b mediates macrophage-induced programmed cell death in patterning of the vasculature. Nature 437, 417–421 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Rao, S. et al. Obligatory participation of macrophages in an angiopoietin 2-mediated cell death switch. Development 134, 4449–4458 (2007). References 69 and 70 show that macrophages are essential for vascular patterning in the eye.

    Article  CAS  PubMed  Google Scholar 

  71. Plaks V. et al. Uterine dendritic cells are crucial for decidua formation during embryo implantation J. Clin. Invest. 118, 3954–3965 (2008). This paper identifies new functions for DCs in angiogenesis during early embryo implantation.

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Grunewald, M. et al. VEGF-induced adult neovascularization: recruitment, retention, and role of accessory cells. Cell 124, 175–189 (2006).

    Article  CAS  PubMed  Google Scholar 

  73. Ceradini, D. J. et al. Progenitor cell trafficking is regulated by hypoxic gradients through HIF-1 induction of SDF-1. Nature Med. 10, 858–864 (2004).

    Article  CAS  PubMed  Google Scholar 

  74. Levine, J. A., Jensen, M. D., Eberhardt, N. L. & O'Brien, T. Adipocyte macrophage colony-stimulating factor is a mediator of adipose tissue growth. J. Clin. Invest. 101, 1557–1564 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Wei, S. et al. Modulation of CSF-1-regulated post-natal development with anti-CSF-1 antibody. Immunobiology 210, 109–119 (2005).

    Article  CAS  PubMed  Google Scholar 

  76. Wiktor-Jedrzejczak, W. et al. CSF-1 defeciency in the op/op mouse has differntial effects on macrophage populations and differentiation stages. Exp. Hematol. 20, 1004–1010 (1992).

    CAS  PubMed  Google Scholar 

  77. Gouon-Evans, V. & Pollard, J. W. Unexpected deposition of brown fat in mammary gland during postnatal development. Mol. Endocrinol. 16, 2618–2627 (2002).

    Article  CAS  PubMed  Google Scholar 

  78. Sonnet, C. et al. Human macrophages rescue myoblasts and myotubes from apoptosis through a set of adhesion molecular systems. J. Cell Sci. 119, 2497–2507 (2006).

    Article  CAS  PubMed  Google Scholar 

  79. Chazaud, B. et al. Satellite cells attract monocytes and use macrophages as a support to escape apoptosis and enhance muscle growth. J. Cell Biol. 163, 1133–1143 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Bryer, S. C., Fantuzzi, G., Van Rooijen, N. & Koh, T. J. Urokinase-type plasminogen activator plays essential roles in macrophage chemotaxis and skeletal muscle regeneration. J. Immunol. 180, 1179–1188 (2008).

    Article  CAS  PubMed  Google Scholar 

  81. Kawane, K. et al. Requirement of DNase II for definitive erythropoiesis in the mouse fetal liver. Science 292, 1546–1549 (2001). This study identifies a new function for macrophages in erythropoiesis.

    Article  CAS  PubMed  Google Scholar 

  82. Dupasquier, M., Stoitzner, P., van Oudenaren, A., Romani, N. & Leenen, P. J. Macrophages and dendritic cells constitute a major subpopulation of cells in the mouse dermis. J. Invest. Dermatol. 123, 876–879 (2004).

    Article  CAS  PubMed  Google Scholar 

  83. Smith, S. J., Kotecha, S., Towers, N. & Mohun, T. J. Targeted cell-ablation in Xenopus embryos using the conditional, toxic viral protein M2(H37A). Dev. Dyn. 236, 2159–2171 (2007).

    Article  CAS  PubMed  Google Scholar 

  84. Martinez, F. O., 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. 177, 7303–7311 (2006).

    Article  CAS  PubMed  Google Scholar 

  85. Klimp, A. H., de Vries, E. G., Scherphof, G. L. & Daemen, T. A potential role of macrophage activation in the treatment of cancer. Crit. Rev. Oncol. Hematol. 44, 143–161 (2002).

    Article  CAS  PubMed  Google Scholar 

  86. Mantovani, A., Bottazzi, B., Colotta, F., Sozzani, S. & Ruco, L. The origin and function of tumor-associated macrophages. Immunol. Today 13, 463–464 (1993). This is a ground-breaking review that suggests that TAMs help tumour growth.

    Google Scholar 

  87. Condeelis, J. & Pollard, J. W. Macrophages: obligate partners for tumor cell migration, invasion, and metastasis. Cell 124, 263–266 (2006).

    Article  CAS  PubMed  Google Scholar 

  88. Mantovani, A., Schioppa, T., Porta, C., Allavena, P. & Sica, A. Role of tumor-associated macrophages in tumor progression and invasion. Cancer Metastasis Rev. 25, 315–322 (2006).

    Article  PubMed  Google Scholar 

  89. Bingle, L., Brown, N. J. & Lewis, C. E. The role of tumour-associated macrophages in tumour progression: implications for new anticancer therapies. J. Pathol. 196, 254–265 (2002).

    Article  CAS  PubMed  Google Scholar 

  90. Lin, E. Y., Gouon-Evans, V., Nguyen, A. V. & Pollard, J. W. The macrophage growth factor, CSF-1, in mammary gland development and tumor progression. J. Mammary Gland Biol. Neoplasia 7, 147–162 (2002).

    Article  PubMed  Google Scholar 

  91. Scholl, S. M. et al. Anti-colony-stimulating factor-1 antibody staining in primary breast adenocarcinomas correlates with marked inflammatory cell infiltrates and prognosis. J. Natl Cancer Inst. 86, 120–126 (1994).

    Article  CAS  PubMed  Google Scholar 

  92. Murdoch, C., Muthana, M., Coffelt, S. B. & Lewis, C. E. The role of myeloid cells in the promotion of tumour angiogenesis. Nature Rev. Cancer 8, 618–631 (2008).

    Article  CAS  Google Scholar 

  93. Lin, E. Y., Nguyen, A. V., Russell, R. G. & Pollard, J. W. Colony-stimulating factor 1 promotes progression of mammary tumors to malignancy. J. Exp. Med. 193, 727–740 (2001). This paper shows that macrophages have an important role in promoting tumour progression and metastasis.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Oguma, K. et al. Activated macrophages promote Wnt signalling through tumour necrosis factor-α in gastric tumour cells. Embo J. 27, 1671–1681 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Kimura, Y. N. et al. Inflammatory stimuli from macrophages and cancer cells synergistically promote tumor growth and angiogenesis. Cancer Sci. 98, 2009–2018 (2007).

    Article  CAS  PubMed  Google Scholar 

  96. Gazzaniga, S. et al. Targeting tumor-associated macrophages and inhibition of MCP-1 reduce angiogenesis and tumor growth in a human melanoma xenograft. J. Invest. Dermatol. 127, 2031–2041 (2007).

    Article  CAS  PubMed  Google Scholar 

  97. Aharinejad, S. et al. Colony-stimulating factor-1 blockade by antisense oligonucleotides and small interfering RNAs suppresses growth of human mammary tumor xenografts in mice. Cancer Res. 64, 5378–5384 (2004).

    Article  CAS  PubMed  Google Scholar 

  98. Paulus, P., Stanley, E. R., Schafer, R., Abraham, D. & Aharinejad, S. Colony-stimulating factor-1 antibody reverses chemoresistance in human MCF-7 breast cancer xenografts. Cancer Res. 66, 4349–4356 (2006).

    Article  CAS  PubMed  Google Scholar 

  99. Hanahan, D. & Folkman, J. Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell 86, 353–364 (1996).

    Article  CAS  PubMed  Google Scholar 

  100. Folkman, J. Role of angiogenesis in tumor growth and metastasis. Semin. Oncol. 29, 15–18 (2002).

    Article  CAS  PubMed  Google Scholar 

  101. Lin, E. Y. & Pollard, J. W. Tumor-associated macrophages press the angiogenic switch in breast cancer. Cancer Res. 67, 5064–5066 (2007).

    Article  CAS  PubMed  Google Scholar 

  102. Leek, R. D. & Harris, A. L. Tumor-associated macrophages in breast cancer. J. Mammary Gland. Biol. Neoplasia 7, 177–189 (2002).

    Article  PubMed  Google Scholar 

  103. Lin, E. Y. et al. Macrophages regulate the angiogenic switch in a mouse model of breast cancer. Cancer Res. 66, 11238–11246 (2006).

    Article  CAS  PubMed  Google Scholar 

  104. Lin, E. Y. et al. Vascular endothelial growth factor restores delayed tumor progression in tumors depleted of macrophages. Mol. Oncol. 1, 288–302 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  105. Stockmann, C. et al. Deletion of vascular endothelial growth factor in myeloid cells accelerates tumorigenesis. Nature 456, 814–818 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. De Palma, M., Murdoch, C., Venneri, M. A., Naldini, L. & Lewis, C. E. Tie2-expressing monocytes: regulation of tumor angiogenesis and therapeutic implications. Trends Immunol. 28, 519–524 (2007).

    Article  CAS  PubMed  Google Scholar 

  107. Wyckoff, J. B. et al. Direct visualization of macrophage-assisted tumor cell intravasation in mammary tumors. Cancer Res. 67, 2649–2656 (2007).

    Article  CAS  PubMed  Google Scholar 

  108. Wyckoff, J. et al. A paracrine loop between tumor cells and macrophages is required for tumor cell migration in mammary tumors. Cancer Res. 64, 7022–7029 (2004).

    Article  CAS  PubMed  Google Scholar 

  109. Pukrop, T. et al. Wnt 5a signaling is critical for macrophage-induced invasion of breast cancer cell lines. Proc. Natl Acad. Sci. USA 103, 5454–5459 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Hagemann, T. et al. Macrophages induce invasiveness of epithelial cancer cells via NF-κB and JNK. J. Immunol. 175, 1197–1205 (2005).

    Article  CAS  PubMed  Google Scholar 

  111. Ojalvo, L. S., King, W., Cox, D. & Pollard, J. W. High density gene expression analysis of tumor associated macrophages from mouse mammary tumors. Am. J. Pathol. 174, 1048–1064 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Biswas, S. K. et al. A distinct and unique transcriptional program expressed by tumor-associated macrophages (defective NF-κB and enhanced IRF-3/STAT1 activation). Blood 107, 2112–2122 (2006).

    Article  CAS  PubMed  Google Scholar 

  113. Hagemann, T., Biswas, S. K., Lawrence, T., Sica, A. & Lewis, C. E. Regulation of macrophage function in tumors: the multifaceted role of NF-κB. Blood 26 Jan 2009 (doi:10.1182/blood-2008-12-172825).

    Article  CAS  PubMed  Google Scholar 

  114. Hagemann, T. et al. “Re-educating” tumor-associated macrophages by targeting NF-κB. J. Exp. Med. 205, 1261–1268 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Balkwill, F., Charles, K. A. & Mantovani, A. Smoldering and polarized inflammation in the initiation and promotion of malignant disease. Cancer Cell 7, 211–217 (2005).

    Article  CAS  PubMed  Google Scholar 

  116. Coussens, L. M. & Werb, Z. Inflammation and cancer. Nature 420, 860–867 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Gouon-Evans, V., Lin, E. Y. & Pollard, J. W. Requirement of macrophages and eosinophils and their cytokines/chemokines for mammary gland development. Breast Cancer Res. 4, 155–164 (2002).

    Article  PubMed  PubMed Central  Google Scholar 

  118. Campbell, I. K., Rich, M. J., Bischof, R. J. & Hamilton, J. A. The colony-stimulating factors and collagen-induced arthritis: exacerbation of disease by M-CSF and G-CSF and requirement for endogenous M-CSF. J. Leukoc. Biol. 68, 144–150 (2000).

    CAS  PubMed  Google Scholar 

  119. Babamusta, F. et al. Angiotensin II infusion induces site-specific intra-laminar hemorrhage in macrophage colony-stimulating factor-deficient mice. Atherosclerosis 186, 282–290 (2006).

    Article  CAS  PubMed  Google Scholar 

  120. Motoyoshi, K. Biological activities and clinical application of M-CSF. Int. J. Hematol. 67, 109–122 (1998).

    Article  CAS  PubMed  Google Scholar 

  121. Weisberg, S. P. et al. Obesity is associated with macrophage accumulation in adipose tissue. J. Clin. Invest. 112, 1796–1808 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Pang, C. et al. Macrophage infiltration into adipose tissue may promote angiogenesis for adipose tissue remodeling in obesity. Am. J. Physiol. Endocrinol. Metab. 295, E313–E322 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Xu, H. et al. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J. Clin. Invest. 112, 1821–1830 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Lang, P. et al. Monomeric tartrate resistant acid phosphatase induces insulin sensitive obesity. PLoS ONE 3, e1713 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Patsouris, D. et al. Ablation of CD11c-positive cells normalizes insulin sensitivity in obese insulin resistant animals. Cell. Metab. 8, 301–309 (2008). Reference 121 and 125 link macrophages with obesity and insulin insensitivity.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Varol, C., Yona, S. & Jung, S. Origins and tissue-context-dependent fates of blood monocytes. Immunol. Cell Biol. 87, 30–38 (2009).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

I apologize to all authors whose work I could not cite because of space restrictions. J.W.P. is the Louis Goldstein Swan Chair in Women's Cancer Research. His research discussed in this Review is supported by National Institutes of Health grants HD30820, CA131270, CA100324 and the Cancer Center (CA P30-13,330). I thank R. Hynes, Koch Integrative Cancer Center, Massachusetts Institute of Technology, Boston, and C. Stewart, Institute of Molecular Biology, Singapore, for their hospitality towards me during my sabbatical, a period during which this article was written.

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  1. Department of Developmental and Molecular Biology, Department of Obstetrics and Gynecology and Women's Health, Center for the Study of Reproductive Biology and Women's Health, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Chanin 607, Bronx, 10461, New York, USA

    Jeffrey W. Pollard

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Angiogenic switch

The marked increase in vascularization that is observed as benign tumours transition to malignancy.

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Pollard, J. Trophic macrophages in development and disease. Nat Rev Immunol 9, 259–270 (2009). https://doi.org/10.1038/nri2528

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