Skip to main content
Log in

Tumor-Associated Macrophages in Breast Cancer

  • Published:
Journal of Mammary Gland Biology and Neoplasia Aims and scope Submit manuscript

Abstract

Neoplastic cells form only one part of a complex network of cell types that make up a breast tumor. The normal cell types that make up the nonneoplastic components of tumors include fibroblasts, endothelium, and inflammatory cells, such as tumor associated macrophages (TAMs). TAMs have the potential to carry out both anti- and protumor activities. In their antitumor role TAMs can present tumor antigens to cytotoxic T-cells and are capable of being directly cytotoxic to neoplastic cells. Conversely, TAMs are also able to promote tumor growth directly by secreting breast tumor mitogens, such as epidermal growth factor, and indirectly by stimulating tumor angiogenesis and metastasis. Recent studies have indicated that in breast cancers the protumor role of TAMs is dominant, and that TAMs may be executing a “wound healing” type of process in response to stimuli found in the tumor microenvironment, such as hypoxia. As such, TAMs may provide opportunities for future therapeutic interventions.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

REFERENCES

  1. R. D. Leek, A. L. Harris, and C. E. Lewis (1994). Cytokine networks in solid human tumors: Regulation of angiogenesis. J.Leukoc.Biol. 56: 423–435.

    Google Scholar 

  2. R. D. Leek, C. E. Lewis, and A. L. Hariss (1997). The role of macrophages in tumor angiogenesis. In R. Bicknell and C. E. Lewis (eds.), Tumor Angiogenesis, Oxford University Press, Oxford.

    Google Scholar 

  3. M.Crowther, N. J. Brown, E. T. Bishop, and C. E. Lewis (2001). Microenvironmental influence on macrophage regulation of angiogenesis in wounds and malignant tumors. J.Leukoc.Biol. 70: 478–490.

    Google Scholar 

  4. B. Bottazzi, N. Polentarutti, R. Acero, A. Balsari, D. Boraschi, P. Ghezzi, M. Salmona, and A. Mantovani (1983). Regulation of the macrophage content of neoplasms by chemoattractants. Science 220: 210–212.

    Google Scholar 

  5. D. T. Graves and A. J. Valente (1991). Monocyte chemotac-tic proteins from human tumor cells. Biochem.Pharmacol. 41: 333–337.

    Google Scholar 

  6. R. D. Leek, C. E. Lewis, R. Whitehouse, M. Greenall, J. Clarke, and A. L. Harris (1996). Association of macrophage infiltra-tion with angiogenesis and prognosis in invasive breast carci-noma. Cancer Res. 56: 4625–4629.

    Google Scholar 

  7. M. J. Auger and J. A. Ross (1992). The biology of the macrophage. In C. E. Lewis and J. O. D. McGee (eds.), TheMacrophage, Oxford University Press, Oxford.

    Google Scholar 

  8. C. E. Lewis and J. O. D. McGee (1992). The Macrophage, Oxford University Press, Oxford.

    Google Scholar 

  9. B. W. Winston, P. M. Krein, C. Mowat, and Y. Huang (1999). Cytokine-induced macrophage differentiation: A tale of 2 genes. Clin.Invest.Med. 22: 236–255.

    Google Scholar 

  10. A. Mantovani (1994). Tumor-associated macrophages in neo-plastic progression: A paradigm for the in vivo function of chemokines. Lab.Invest. 71: 5–16.

    Google Scholar 

  11. E. Neumark, R. Anavi, I. P. Witz, and A. Ben-Baruch (1999). MCP-1 expression as a potential contributor to the high malig-nancy phenotype of murine mammary adenocarcinoma cells. Immunol.Lett. 68: 141–146.

    Google Scholar 

  12. T. Ueno, M. Toi, H. Saji, M. Muta, H. Bando, K. Kuroi, M. Koike, H. Inadera, and K. Matsushima (2000). Significance of macrophage chemoattractant protein-1 in macrophage re-cruitment, angiogenesis, and survival in human breast cancer. Clin.Cancer Res. 6: 3282–3289.

    Google Scholar 

  13. V. Goede, L. Brogelli, M. Ziche, and H. G. Augustin (1999). In-duction of inflammatory angiogenesis by monocyte chemoat-tractant protein-1. Int.J.Cancer 82: 765–770.

    Google Scholar 

  14. Y. X. Fu, J. P. Cai, Y. H. Chin, G. A. Watson, and D. M. Lopez (1992). Regulation of leukocyte binding to endothelial tissues by tumor-derived GM-CSF. Int.J.Cancer 50: 585–588.

    Google Scholar 

  15. C. Pyke, N. Graem, E. Ralfkiaer, E. Ronne, G. Hoyer-Hansen, N. Brunner, and K. Dano (1993). Receptor for urokinase is present in tumor-associated macrophages in ductal breast car-cinoma. Cancer Res. 53: 1911–1915.

    Google Scholar 

  16. M. Dorsch, H. Hock, U. Kunzendorf, T. Diamantstein, and T. Blankenstein (1993). Macrophage colony-stimulating fac-tor gene transfer into tumor cells induces macrophage infiltra-tion but not tumor suppression. Eur.J.Immunol. 23: 186–190.

    Google Scholar 

  17. Y. Heike, S. Sone, S. Yano, H. Seimiya, T. Tsuruo, and T. Ogura (1993). M-CSF gene transduction in multidrug-resistant hu-man cancer cells to enhance anti-P-glycoprotein antibody-dependent macrophage-mediated cytotoxicity. Int.J.Cancer 54: 851–857.

    Google Scholar 

  18. S. M. Scholl, R. Lidereau, A. de la Rochefordiere, C. C. Le-Nir, V. Mosseri, C. Nogues, P. Pouillart, and F. R. Stanley (1996). Circulating levels of the macrophage colony stimulating factor CSF-1 in primary and metastatic breast cancer patients. Apilot study. Breast Cancer Res.Treat. 39: 275–283.

    Google Scholar 

  19. E. Y. Lin, A. V. Nguyen, R. G. Russell, and J. W. Pollard (2001). Colony-stimulating factor 1 promotes progression of mammary tumors to malignancy. J.Exp.Med. 193: 727–740.

    Google Scholar 

  20. E. R. Stanley, L. J. Guilbert, R. J. Tushinski, and S. H. Bartelmez (1983). CSF-1--a mononuclear phagocyte lineage-specific hemopoietic growth factor. J.Cell.Biochem. 21: 151–159.

    Google Scholar 

  21. B. M. Kacinski (1995). CSF-1 and its receptor in ovarian, en-dometrial and breast cancer. Ann.Med. 27: 79–85.

    Google Scholar 

  22. M. Relf, S. Lejeune, P. A. E. Scott, S. Fox, K. Smith, R. Leek, A. Moghaddam, R. Whitehouse, R. Bicknell, and A. L. Harris (1997). Expression of the angiogenic factors vascu-lar endothelial-cell growth-factor, acidic and basic fibroblast growth-factor, tumor-growth factor-beta-1, platelet-derived endothelial-cell growth-factor, placenta growth-factor, and pleiotrophin in human primary breast-cancer and its relation to angiogenesis. Cancer Res. 57: 963–969.

    Google Scholar 

  23. M. Clauss, M. Gerlach, H. Gerlach, J. Brett, F. Wang, P. C. Familletti, Y. C. Pan, J. V. Olander, D. T. Connolly, and D. Stern (1990). Vascular permeability factor: A tumor-derived polypeptide that induces endothelial cell and monocyte pro-coagulant activity, and promotes monocyte migration. J.Exp. Med. 172: 1535–1545.

    Google Scholar 

  24. R. D. Leek, N. C. Hunt, R. J. Landers, C. E. Lewis, J. A. Royds, and A. L. Harris (2000). Macrophage infiltration is associated with VEGF and EGFR expression in breast cancer. J.Pathol. 190: 430–436.

    Google Scholar 

  25. R. D. Leek, R. J. Landers, A. L. Harris, and C. E. Lewis (1999). Necrosis correlates with high vascular density and fo-cal macrophage infiltration in invasive carcinoma of the breast. Br.J.Cancer 79: 991–995.

    Google Scholar 

  26. A. C. Koong, N. C. Denko, K. M. Hudson, C. Schindler, L. Swiersz, C. Koch, S. Evans, H. Ibrahim, Q. T. Le, D. J. Terris, and A. J. Giaccia (2000). Candidate genes for the hypoxic tumor phenotype. Cancer Res. 60: 883–887.

    Google Scholar 

  27. A. Lal, H. Peters, B. St Croix, Z. A. Haroon, M. W. Dewhirst, R. L. Strausberg, J. H. Kaanders, A. J. van der Kogel, and G. J. Riggins (2001). Transcriptional response to hypoxia in human tumors. J.Natl.Cancer Inst. 93: 1337–1343.

    Google Scholar 

  28. M. J. Grimshaw and F. R. Balkwill (2001). Inhibition of monocyte and macrophage chemotaxis by hypoxia and inflammation--a potential mechanism. Eur.J.Immunol. 31: 480–489.

    Google Scholar 

  29. T. M. Nilsson, A. E. Woods, and A. M. Rofe (1996). In vivo studies of macrophages and intercellular adhesion molecule-1 following lipopolysaccharide treatment in tumor-bearing rats. Immunol.Cell Biol. 74: 408–412.

    Google Scholar 

  30. D. Nath, A. Hartnell, L. Happerfield, D. W. Miles, J. Burchell, J. Taylor-Papadimitriou, and P. R. Crocker (1999). Macrophage-tumor cell interactions: Identification of MUC1 on breast cancer cells as a potential counter-receptor for the macrophage-restricted receptor, sialoadhesin. Immunology 98: 213–219.

    Google Scholar 

  31. V. Shankaran, H. Ikeda, A. T. Bruce, J. M. White, P. E. Swanson, L. J. Old, and R. D. Schreiber (2001). IFNgammaand lymphocytes prevent primary tumor development and shape tumor immunogenicity. Nature 410: 1107–1111.

    Google Scholar 

  32. G. Beatty and Y. Paterson (2001). IFN-gamma-dependent in-hibition of tumor angiogenesis by tumor-infiltrating CD4 C T cells requires tumor responsiveness to IFN-gamma. J.Im-munol. 166: 2276–2282.

    Google Scholar 

  33. Y. X. Fu, G. A. Watson, M. Kasahara, and D. M. Lopez (1991). The role of tumor-derived cytokines on the immune system of mice bearing a mammary adenocarcinoma. I: Induction of regulatory macrophages in normal mice by the in vivo admin-istration of rGM-CSF. J.Immunol. 146: 783–789.

    Google Scholar 

  34. C. Menetrier-Caux, G. Montmain, M. C. Dieu, C. Bain, M. C. Favrot, C. Caux, and J. Y. Blay (1998). Inhibition of the differentiation of dendritic cells from CD34( C ) progenitors by tumor cells: Role of interleukin-6 and macrophage colony-stimulating factor. Blood 92: 4778–4791.

    Google Scholar 

  35. D. I. Gabrilovich, H. L. Chen, K. R. Girgis, H. T. Cunningham, G. M. Meny, S. Nadaf, D. Kavanaugh, and D. P. Carbone (1996). Production of vascular endothelial growth factor by human tumors inhibits the functional maturation of dendritic cells. Nat.Med. 2: 1096–1103.

    Google Scholar 

  36. K. A. Backman and P. M. Guyre (1994). Gamma-interferon inhibits Fc receptor II-mediated phagocytosis of tumor cells by human macrophages. Cancer Res. 54: 2456–2461.

    Google Scholar 

  37. U. Boehm, T. Klamp, M. Groot, and J. C. Howard (1997). Cellular responses to interferon-gamma. Annu.Rev.Im-munol. 15: 749–795.

    Google Scholar 

  38. H. Lei, D. W. Ju, Y. Yu, Q. Tao, G. Chen, S. Gu, H. Hamada, and X. Cao (2000). Induction of potent antitumor response by vaccination with tumor lysate-pulsed macrophages engi-neered to secrete macrophage colony-stimulating factor and interferon-gamma. Gene.Ther. 7: 707–713.

    Google Scholar 

  39. L. Kaklamanis, R. Leek, M. Koukourakis, K. C. Gatter, and A. L. Harris (1995). Loss of transporter in antigen processing 1 transport protein and major histocompatibility complex class I molecules in metastatic versus primary breast cancer. Cancer Res. 55: 5191–5194.

    Google Scholar 

  40. S. E. Webb, J. W. Pollard, and G. E. Jones (1996). Direct ob-servation and quantification of macrophage chemoattraction to the growth factor CSF-1. J.Cell Sci. 109: 793–803.

    Google Scholar 

  41. R. A. Clynes, T. L. Towers, L. G. Presta, and J. V. Ravetch (2000). Inhibitory Fc receptors modulate in vivo cytoxicity against tumor targets. Nat.Med. 6: 443–446.

    Google Scholar 

  42. M. Watanabe, P. K. Wallace, T. Keler, Y. M. Deo, C. Akewanlop, and D. F. Hayes (1999). Antibody dependent cel-lular phagocytosis (ADCP) and antibody dependent cellular cytotoxicity (ADCC) of breast cancer cells mediated by bis-pecific antibody, MDX-210. Breast Cancer Res.Treat. 53: 199–207.

    Google Scholar 

  43. V. Schirrmacher, L. Bai, V. Umansky, L. Yu, Y. Xing, and Z. Qian (2000). Newcastle disease virus activates macrophages for anti-tumor activity. Int.J.Oncol. 16: 363–373.

    Google Scholar 

  44. J. M. Quinn, J. O. McGee, and N. A. Athanasou (1998). Human tumor-associated macrophages differentiate into osteoclastic bone-resorbing cells. J.Pathol. 184: 31–36.

    Google Scholar 

  45. C. O'sullivan, C. E. Lewis, A. L. Harris, and J. O. McGee (1993). Secretion of epidermal growth factor by macrophages associated with breast carcinoma. Lancet 342: 148–149.

    Google Scholar 

  46. C. Sunderkotter, K. Steinbrink, M. Goebeler, R. Bhardwaj, and C. Sorg (1994). Macrophages and angiogenesis. J.Leukoc. Biol. 55: 410–422.

    Google Scholar 

  47. J. R. Sainsbury, J. R. Farndon, G. K. Needham, A. J. Malcolm, and A. L. Harris (1987). Epidermal-growth-factor receptor status as predictor of early recurrence of and death from breast cancer. Lancet 1: 1398–1402.

    Google Scholar 

  48. R. J. Steele, O. Eremin, M. Brown, and R. A. Hawkins (1986). Oestrogen receptor concentration and macrophage infiltra-tion in human breast cancer. Eur.J.Surg.Oncol. 12: 273–276.

    Google Scholar 

  49. G. Mor, W. Yue, R. J. Santen, L. Gutierrez, M. Eliza, L. M. Berstein, N. Harada, J. Wang, J. Lysiak, S. Diano, and F. Naftolin (1998). Macrophages, estrogen and the microen-vironment of breast cancer. J.Steroid Biochem.Mol.Biol. 67: 403–411.

    Google Scholar 

  50. C. I. Chang, J. C. Liao, and L. Kuo (2001). Macrophage arginase promotes tumor cell growth and suppresses nitric oxide-mediated tumor cytotoxicity. Cancer Res. 61: 1100–1106.

    Google Scholar 

  51. J. MacMicking, Q. W. Xie, and C. Nathan (1997). Nitric oxide and macrophage function. Annu.Rev.Immunol. 15: 323–350.

    Google Scholar 

  52. D. A. Wink, Y. Vodovotz, J. Laval, F. Laval, M. W. Dewhirst, and J. B. Mitchell (1998). The multifaceted roles of nitric oxide in cancer. Carcinogenesis 19: 711–721.

    Google Scholar 

  53. J. K. Ruohola, T. P. Viitanen, E. M. Valve, J. A. Seppanen, N. T. Loponen, J. J. Keskitalo, P. T. Lakkakorpi, and P. L. Harkonen (2001). Enhanced invasion and tumor growth of fibroblast growth factor 8b-overexpressing MCF-7 human breast can-cer cells. Cancer Res. 61: 4229–4237.

    Google Scholar 

  54. D. G. Fernig, H. L. Chen, H. Rahmoune, S. Descamps, B. Boilly, and H. Hondermarck (2000). Differential regulation of FGF-1 and-2 mitogenic activity is related to their kinet-ics of binding to heparan sulfate in MDA-MB-231 human breast cancer cells. Biochem.Biophys.Res.Commun. 267: 770–776.

    Google Scholar 

  55. J. Nagy, G. W. Curry, K. J. Hillan, I. C. McKay, E. Mallon, A. D. Purushotham, and W. D. George (1996). Hepatocyte growth factor/scatter factor expression and c-met in primary breast cancer. Surg.Oncol. 5: 15–21.

    Google Scholar 

  56. J. A. Leal, B. K. Gangrade, J. L. Kiser, J. V. May, and B. A. Keel (1991). Human mammary tumor cell proliferation: Primary role of platelet-derived growth factor and possible synergism with human alpha-fetoprotein. Steroids 56: 247–251.

    Google Scholar 

  57. H. Nagaoka, Y. Iino, H. Takei, and Y. Morishita (1998). Platelet-derived endothelial cell growth factor/thymidine phosphorylase expression in macrophages correlates with tu-mor angiogenesis and prognosis in invasive breast cancer. Int. J.Oncol. 13: 449–454.

    Google Scholar 

  58. N. Jonjic, T. Valkovic, K. Lucin, Z. Iternicka, M. Krstulja, E. Mustac, R. Dobi-Babic, F. Sasso, and M. Melato (1998). Comparison of microvessel density with tumor associated macrophages in invasive breast carcinoma. Anticancer Res. 18: 3767–3770.

    Google Scholar 

  59. D. Toomey, J. Harmey, C. Condron, E. Kay, and D. Bouchier-Hayes (1999). Phenotyping of immune cell infiltrates in breast and colorectal tumors. Immunol.Invest. 28: 29–41.

    Google Scholar 

  60. A. K. Madan, K. Yu, N. Dhurandhar, C. Cullinane, Y. Pang, and D. J. Beech (1999). Association of hyaluronidase and breast adenocarcinoma invasiveness. Oncol.Rep. 6: 607–609.

    Google Scholar 

  61. P. Bertrand, N. Girard, C. Duval, J. d'Anjou, C. Chauzy, J. F. Menard, and B. Delpech (1997). Increased hyaluronidase levels in breast tumor metastases. Int.J.Cancer 73: 327–331.

    Google Scholar 

  62. D. Liu, E. Pearlman, E. Diaconu, K. Guo, H. Mori, T. Haqqi, S. Markowitz, J. Willson, and M. S. Sy (1996). Expression of hyaluronidase by tumor cells induces angiogenesis in vivo. Proc.Natl.Acad.Sci.USA 93: 7832–7837.

    Google Scholar 

  63. J. Folkman (1990). What is the evidence that tumors are an-giogenesis dependent. J.Natl.Cancer Inst. 82: 4–6.

    Google Scholar 

  64. N. Weidner, J. P. Semple, W. R. Welch, and J. Folkman (1991). Tumor angiogenesis and metastasis--correlation in invasive breast carcinoma. N.Engl.J.Med. 324: 1–8.

    Google Scholar 

  65. A. H. Lee, L. C. Happerfield, L. G. Bobrow, and R. R. Millis (1997). Angiogenesis and inflammation in invasive carcinoma of the breast. J.Clin.Pathol. 50: 669–673.

    Google Scholar 

  66. A. H. Lee, L. C. Happerfield, R. R. Millis, and L. G. Bobrow (1996). Inflammatory infiltrate in invasive lobular and ductal carcinoma of the breast. Br.J.Cancer 74: 796–801.

    Google Scholar 

  67. S. M. Pupa, R. Bufalino, A. M. Invernizzi, S. Andreola, F. Rilke, L. Lombardi, M. I. Colnaghi, and S. Menard (1996). Macrophage infiltrate and prognosis in c-erbB-2-overexpressing breast carcinomas. J.Clin.Oncol. 14: 85–94.

    Google Scholar 

  68. J. S. Ross and J. A. Fletcher (1999). HER-2/neu (c-erb-B2) gene and protein in breast cancer. Am.J.Clin.Pathol. 112: S53–S67.

    Google Scholar 

  69. W. R. Bezwoda (2000). c-erb-B2 expression and response to treatment in metastatic breast cancer. Med.Oncol. 17: 22–28.

    Google Scholar 

  70. M. Cazin, D. Paluszezak, A. Bianchi, J. C. Cazin, C. Aerts, and C. Voisin (1990). Effects of anaerobiosis upon morphology and energy metabolism of alveolar macrophages cultured in gas phase. Eur.Respir.J. 3: 1015–1022.

    Google Scholar 

  71. J. S. Lewis, R. J. Landers, J. C. Underwood, A. L. Harris, and C. E. Lewis (2000). Expression of vascular endothelial growth factor by macrophages is up-regulated in poorly vascularized areas of breast carcinomas. J.Pathol. 192: 150–158.

    Google Scholar 

  72. J. H. Harmey, E. Dimitriadis, E. Kay, H. P. Redmond, and D. Bouchier-Hayes (1998). Regulation of macrophage pro-duction of vascular endothelial growth factor (VEGF) by hypoxia and transforming growth factor beta-1. Ann.Surg. Oncol. 5: 271–278.

    Google Scholar 

  73. N. S. Brown, A. Jones, C. Fujiyama, A. L. Harris, and R. Bicknell (2000). Thymidine phosphorylase induces carci-noma cell oxidative stress and promotes secretion of angio-genic factors. Cancer Res. 60: 6298–6302.

    Google Scholar 

  74. D. W. Miles, L. C. Happerfield, M. S. Naylor, L. G. Bobrow, R. D. Rubens, and F. R. Balkwill (1994). Expression of tumor necrosis factor (TNF alpha) and its receptors in benign and malignant breast tissue. Int.J.Cancer 56: 777–782.

    Google Scholar 

  75. H. Eda, K. Fujimoto, S. Watanabe, M. Ura, A. Hino, Y. Tanaka, K. Wada, and H. Ishitsuka (1993). Cytokines induce thymidine phosphorylase expression in tumor cells and make them more susceptible to 50-deoxy-5-fluorouridine. Cancer Chemother. Pharmacol. 32: 333–338.

    Google Scholar 

  76. R. D. Leek, R. Landers, S. B. Fox, F. Ng, A. L. Harris, and C. E. Lewis (1998). Association of tumor necrosis factor alpha and its receptors with thymidine phosphorylase expression in invasive breast carcinoma. Br.J.Cancer 77: 2246–2251.

    Google Scholar 

  77. R. Hildenbrand, G. Wolf, B. Bohme, U. Bleyl, and A. Steinborn (1999). Urokinase plasminogen activator receptor (CD87) expression of tumor-associated macrophages in ductal car-cinoma in situ, breast cancer, and resident macrophages of normal breast tissue. J.Leukoc.Biol. 66: 40–49.

    Google Scholar 

  78. R. Hildenbrand, I. Dilger, A. Horlin, and H. J. Stutte (1995). Urokinase and macrophages in tumor angiogenesis. Br.J.Can-cer 72: 818–823.

    Google Scholar 

  79. R. Hildenbrand, C. Jansen, G. Wolf, B. Bohme, S. Berger, G. von Minckwitz, A. Horlin, M. Kaufmann, and H. J. Stutte (1998). Transforming growth factor-beta stimulates urokinase expression in tumor-associated macrophages of the breast. Lab.Invest. 78: 59–71.

    Google Scholar 

  80. R. A. Walker, S. J. Dearing, and B. Gallacher (1994). Rela-tionship of transforming growth factor beta 1 to extracellular matrix and stromal infiltrates in invasive breast carcinoma. Br. J.Cancer 69: 1160–1165.

    Google Scholar 

  81. D. Toomey, C. Condron, Q. D. Wu, E. Kay, J. Harmey, P. Broe, C. Kelly, and D. Bouchier-Hayes (2001). TGF-beta1 is ele-vated in breast cancer tissue and regulates nitric oxide pro-duction from a number of cellular sources during hypoxia re-oxygenation injury. Br.J.Biomed.Sci. 58: 177–183.

    Google Scholar 

  82. J. P. Van Netten, B. J. Ashmead, R. L. Parker, I. G. Thornton, C. Fletcher, D. Cavers, P. Coy, and M. L. Brigden (1993). Macrophage-tumor cell associations: A factor in metastasis of breast cancer? J.Leukoc.Biol. 54: 360–362.

    Google Scholar 

  83. P. R. Crocker, S. Mucklow, V. Bouckson, A. McWilliam, A. C. Willis, S. Gordon, G. Milon, S. Kelm, and P. Bradfield (1994). Sialoadhesin, a macrophage sialic acid binding recep-tor for haemopoietic cells with 17 immunoglobulin-like do-mains. EMBO J. 13: 4490–4503.

    Google Scholar 

  84. C. W. Pugh, J. Gleadle, and P. H. Maxwell (2001). Hypoxia and oxidative stress in breast cancer. Hypoxia signalling pathways. Breast Cancer Res. 3: 313–317.

    Google Scholar 

  85. M. Hampl, T. Tanaka, P. S. Albert, J. Lee, N. Ferrari, and H. A. Fine (2001). Therapeutic effects of viral vector-mediated antiangiogenic gene transfer in malignant ascites. Hum.Gene Ther. 12: 1713–1729.

    Google Scholar 

  86. S. A. Im, J. S. Kim, C. Gomez-Manzano, J. Fueyo, T. J. Liu, M. S. Cho, C. M. Seong, S. N. Lee, Y. K. Hong, and W. K. Yung (2001). Inhibition of breast cancer growth in vivo by antian-giogenesis gene therapy with adenovirus-mediated antisense-VEGF. Br.J.Cancer 84: 1252–1257.

    Google Scholar 

  87. M. Kampa, A. Hatzoglou, G. Notas, M. Niniraki, E. Kouroumalis, and E. Castanas (2001). Opioids are non-competitive inhibitors of nitric oxide synthase in T47D human breast cancer cells. Cell Death Differ. 8: 943–952.

    Google Scholar 

  88. S. Pervin, R. Singh, C. L. Gau, H. Edamatsu, F. Tamanoi, and G. Chaudhuri (2001). Potentiation of nitric oxide-induced apoptosis of MDA-MB-468 cells by farnesyltransferase in-hibitor: Implications in breast cancer. Cancer Res. 61: 4701–4706.

    Google Scholar 

  89. L. C. Jadeski and P. K. Lala (1999). Nitric oxide synthase inhi-bition by N(G)-nitro-L-arginine methyl ester inhibits tumor-induced angiogenesis in mammary tumors. Am.J.Pathol. 155: 1381–1390.

    Google Scholar 

  90. L. L. Thomsen and D. W. Miles (1998). Role of nitric oxide in tumor progression: Lessons from human tumors. Cancer Metastasis Rev. 17: 107–118.

    Google Scholar 

  91. C. Denoyelle, M. Vasse, M. Korner, Z. Mishal, F. Ganne, J. P. Vannier, J. Soria, and C. Soria (2001). Cerivastatin, an inhibitor of HMG-CoA reductase, inhibits the signaling pathways involved in the invasiveness and metastatic prop-erties of highly invasive breast cancer cell lines: An in vitro study. Carcinogenesis 22: 1139–1148.

    Google Scholar 

  92. D. M. Evans and K. Sloan-Stakleff (2000). Suppression of the invasive capacity of human breast cancer cells by inhibition of urokinase plasminogen activator via amiloride and B428. Am.Surg. 66: 460–464.

    Google Scholar 

  93. A. Kruger, R. Soeltl, V. Lutz, O. G. Wilhelm, V. Magdolen, E. E. Rojo, P. A. Hantzopoulos, H. Graeff, B. Gansbacher, and M. Schmitt (2000). Reduction of breast carcinoma tumor growth and lung colonization by overexpression of the sol-uble urokinase-type plasminogen activator receptor (CD87). Cancer Gene Ther. 7: 292–299.

    Google Scholar 

  94. H. Li, H. Lu, F. Griscelli, P. Opolon, L. Q. Sun, T. Ragot, Y. Legrand, D. Belin, J. Soria, C. Soria, M. Perricaudet, and P. Yeh (1998). Adenovirus-mediated delivery of a uPA/uPAR antagonist suppresses angiogenesis-dependent tumor growth and dissemination in mice. Gene.Ther. 5: 1105–1113.

    Google Scholar 

  95. R. J. Tressler, P. A. Pitot, J. R. Stratton, L. D. Forrest, S. Zhuo, R. J. Drummond, S. Fong, M. V. Doyle, L. V. Doyle, H. Y. Min, and S. Rosenberg (1999). Urokinase receptor antago-nists: Discovery and application to in vivo models of tumor growth. APMIS 107: 168–173.

    Google Scholar 

  96. R. H. Xing, A. Mazar, J. Henkin, and S. A. Rabbani (1997). Prevention of breast cancer growth, invasion, and metasta-sis by antiestrogen tamoxifen alone or in combination with urokinase inhibitor B-428. Cancer Res. 57: 3585–3593.

    Google Scholar 

  97. C. Erlichman, A. A. Adjei, S. R. Alberts, J. A. Sloan, R. M. Goldberg, H. C. Pitot, J. Rubin, P. J. Atherton, G. G. Klee, and R. Humphrey (2001). Phase I study of the matrix metallopro-teinase inhibitor, BAY 12–9566. Ann.Oncol. 12: 389–395.

    Google Scholar 

  98. Y. Jiang, M. Wang, M. Y. Celiker, Y. E. Liu, Q. X. Sang, I. D. Goldberg, and Y. E. Shi (2001). Stimulation of mammary tumorigenesis by systemic tissue inhibitor of matrix metallo-proteinase 4 gene delivery. Cancer Res. 61: 2365–2370.

    Google Scholar 

  99. J. Lee, M. Weber, S. Mejia, E. Bone, P. Watson, and W. Orr (2001). A matrix metalloproteinase inhibitor, batimastat, re-tards the development of osteolytic bone metastases by MDA-MB-231 human breast cancer cells in Balb C nu/nu mice. Eur. J.Cancer 37: 106–113.

    Google Scholar 

  100. P. D. Brown (2000). Ongoing trials with matrix metallopro-teinase inhibitors. Expert Opin.Investig.Drugs 9: 2167–2177.

    Google Scholar 

  101. P. D. Brown (1998). Matrix metalloproteinase inhibitors. Breast Cancer Res.Treat. 52: 125–136.

    Google Scholar 

  102. H. S. Rasmussen and P. P. McCann (1997). Matrix metallo-proteinase inhibition as a novel anticancer strategy: A review with special focus on batimastat and marimastat. Pharmacol. Ther. 75: 69–75.

    Google Scholar 

  103. F. Ciardiello, R. Caputo, R. Bianco, V. Damiano, G. Fontanini, S. Cuccato, S. De Placido, A. R. Bianco, and G. Tortora (2001). Inhibition of growth factor production and angiogenesis in human cancer cells by ZD1839 (Iressa), a selective epidermal growth factor receptor tyrosine kinase inhibitor. Clin.Cancer Res. 7: 1459–1465.

    Google Scholar 

  104. D. Liu, L. Buluwela, S. Ali, S. Thomson, J. J. Gomm, and R. C. Coombes (2001). Retroviral infection of the FGF2 gene into MCF-7 cells induces branching morphogenesis, retards cell growth and suppresses tumorigenicity in nude mice. Eur. J.Cancer 37: 268–280.

    Google Scholar 

  105. M. K. Yunmbam and A. Wellstein (2001). The bacterial polysaccharide tecogalan blocks growth of breast cancer cells in vivo. Oncol.Rep. 8: 161–164.

    Google Scholar 

  106. R. Bagheri-Yarmand, Y. Kourbali, C. Mabilat, J. F. Morere, A. Martin, H. Lu, C. Soria, J. Jozefonvicz, and M. Crepin (1998). The suppression of fibroblast growth factor 2/fi-broblast growth factor 4-dependent tumor angiogenesis and growth by the anti-growth factor activity of dextran derivative (CMDB7). Br.J.Cancer 78: 111–118.

    Google Scholar 

  107. N. S. Chang (1998). Transforming growth factor-beta protec-tion of cancer cells against tumor necrosis factor cytotoxicity is counteracted by hyaluronidase (review). Int.J.Mol.Med. 2: 653–659.

    Google Scholar 

  108. G. Baumgartner, C. Gomar-Hoss, L. Sakr, E. Ulsperger, and C. Wogritsch (1998). The impact of extracellular matrix on the chemoresistance of solid tumors--experimental and clinical results of hyaluronidase as additive to cytostatic chemother-apy. Cancer Lett. 131: 85–99.

    Google Scholar 

  109. B. S. Croix, J. W. Rak, S. Kapitain, C. Sheehan, C. H. Graham, and R. S. Kerbel (1996). Reversal by hyaluronidase of adhesion-dependent multicellular drug resistance in mam-mary carcinoma cells. J.Natl.Cancer Inst. 88: 1285–1296.

    Google Scholar 

  110. M.Jaffar, K. J. Williams, and I. J. Stratford (2001). Bioreductive and gene therapy approaches to hypoxic diseases. Adv.Drug. Deliv.Rev. 53: 217–228.

    Google Scholar 

  111. G. Perletti, P. Concari, R. Giardini, E. Marras, F. Piccinini, J. Folkman, and L. Chen (2000). Antitumor activity of endo-statin against carcinogen-induced rat primary mammary tu-mors. Cancer Res. 60: 1793–1796.

    Google Scholar 

  112. M. S. O'Reilly, T. Boehm, Y. Shing, N. Fukai, G. Vasios, W. S. Lane, E. Flynn, J. R. Birkhead, B. R. Olsen, and J. Folkman (1997). Endostatin: An endogenous inhibitor of angiogenesis and tumor growth. Cell 88: 277–285.

    Google Scholar 

  113. J. Vukanovic and J. T. Isaacs (1995). Linomide inhibits angiogenesis, growth, metastasis, and macrophage infiltra-tion within rat prostatic cancers. Cancer Res. 55: 1499–1504.

    Google Scholar 

  114. L. Griffiths, K. Binley, S. Iqball, O. Kan, P. Maxwell, P. Ratcliffe, C. Lewis, A. Harris, S. Kingsman, and S. Naylor (2000). The macrophage--a novel system to deliver gene ther-apy to pathological hypoxia. Gene.Ther. 7: 255–262.

    Google Scholar 

  115. M. Adachi, M. F. Roussel, K. Havenith, and C. J. Sherr (1997). Features of macrophage differentiation induced by p19INK4d, a specific inhibitor of cyclin D-dependent kinases. Blood 90: 126–137.

    Google Scholar 

  116. K. L. Talks, H. Turley, K. C. Gatter, P. H. Maxwell, C. W. Pugh, P. J. Ratcliffe, and A. L. Harris (2000). The expression and distribution of the hypoxia-inducible factors HIF-1alpha and HIF-2alpha in normal human tissues, cancers, and tumor-associated macrophages. Am.J.Pathol. 157: 411–421.

    Google Scholar 

  117. H. M. Ogmundsdottir (2001). Immune reaction to breast can-cer: For better or for worse? Arch.Immunol.ther.Exp.(Warsz) 49(Suppl. 2): S75–S81.

    Google Scholar 

  118. L. A. DiPietro (1995). Wound healing: The role of the macrophage and other immune cells. Shock 4: 233–240.

    Google Scholar 

  119. D. R. Knighton and V. D. Fiegel (1989). Macrophage-derived growth factors in wound healing: Regulation of growth factor production by the oxygen microenvironment. Am.Rev.Respir. Dis. 140: 1108–1111.

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Russell D. Leek.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Leek, R.D., Harris, A.L. Tumor-Associated Macrophages in Breast Cancer. J Mammary Gland Biol Neoplasia 7, 177–189 (2002). https://doi.org/10.1023/A:1020304003704

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1020304003704

Navigation