The role of tumor-associated macrophages in breast cancer progression (Review)

  • Authors:
    • Elias Obeid
    • Rita Nanda
    • Yang-Xin Fu
    • Olufunmilayo I. Olopade
  • View Affiliations

  • Published online on: May 14, 2013     https://doi.org/10.3892/ijo.2013.1938
  • Pages: 5-12
Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )


Abstract

It is well established that the tumor microenvironment plays a major role in the aggressive behavior of malignant solid tumors. Among cell types associated with tumor microenvironment, tumor-associated macrophages (TAMs) are the most influential for tumor progression. Breast cancer is characterized by having a large population of TAMs, and experimental models have exposed multiple mechanisms by which TAMs interact with and influence the surrounding tumor cells. The process of metastasis involves tumor cells gaining access to the tissue outside the immediate tumor environment and invading the confining extracellular matrix (ECM). Supporting this process, TAMs secrete proangiogenic factors such as VEGF to build a network of vessels that provide nutrition for tumor cells, but also function as channels of transport into the ECM. Additionally, TAMs release factors to decrease the local pro-inflammatory antitumor response, suppressing it and providing a means of escape of the tumor cells. Similarly, hypoxia in the tumor microenvironment stimulates macrophages to further produce VEGF and suppress the T-cell immune responses, thus, enhancing the evasion of tumor cells and ultimately metastasis. Given the multiple roles of TAMS in breast cancer progression and metastasis, therapies targeting these cells are in development and demonstrate promising results.

References

1. 

Balkwill F and Mantovani A: Inflammation and cancer: back to Virchow? Lancet. 357:539–545. 2001. View Article : Google Scholar : PubMed/NCBI

2. 

Coussens LM and Werb Z: Inflammation and cancer. Nature. 420:860–867. 2002. View Article : Google Scholar : PubMed/NCBI

3. 

Lewis CE, Leek R, Harris A and McGee JO: Cytokine regulation of angiogenesis in breast cancer: the role of tumor-associated macrophages. J Leukoc Biol. 57:747–751. 1995.PubMed/NCBI

4. 

Bingle L, Brown NJ and Lewis CE: The role of tumour-associated macrophages in tumour progression: implications for new anticancer therapies. J Pathol. 196:254–265. 2002. View Article : Google Scholar : PubMed/NCBI

5. 

Leek RD and Harris AL: Tumor-associated macrophages in breast cancer. J Mammary Gland Biol Neoplasia. 7:177–189. 2002. View Article : Google Scholar : PubMed/NCBI

6. 

Gordon S and Taylor PR: Monocyte and macrophage heterogeneity. Nat Rev Immunol. 5:953–964. 2005. View Article : Google Scholar : PubMed/NCBI

7. 

Winston BW, Krein PM, Mowat C and Huang Y: Cytokine-induced macrophage differentiation: a tale of 2 genes. Clin Invest Med. 22:236–255. 1999.PubMed/NCBI

8. 

Fujimoto H, Sangai T, Ishii G, et al: Stromal MCP-1 in mammary tumors induces tumor-associated macrophage infiltration and contributes to tumor progression. Int J Cancer. 125:1276–1284. 2009. View Article : Google Scholar : PubMed/NCBI

9. 

Bernhagen J, Krohn R, Lue H, et al: MIF is a noncognate ligand of CXC chemokine receptors in inflammatory and atherogenic cell recruitment. Nat Med. 13:587–596. 2007. View Article : Google Scholar : PubMed/NCBI

10. 

Bando H, Matsumoto G, Bando M, et al: Expression of macrophage migration inhibitory factor in human breast cancer: association with nodal spread. Jpn J Cancer Res. 93:389–396. 2002. View Article : Google Scholar : PubMed/NCBI

11. 

Hagemann T, Wilson J, Kulbe H, et al: Macrophages induce invasiveness of epithelial cancer cells via NF-kappa B and JNK. J Immunol. 175:1197–1205. 2005. View Article : Google Scholar : PubMed/NCBI

12. 

Mosser DM: The many faces of macrophage activation. J Leukoc Biol. 73:209–212. 2003. View Article : Google Scholar : PubMed/NCBI

13. 

Verreck FA, de Boer T, Langenberg DM, et al: Human IL-23-producing type 1 macrophages promote but IL-10-producing type 2 macrophages subvert immunity to (myco)bacteria. Proc Natl Acad Sci USA. 101:4560–4565. 2004. View Article : Google Scholar : PubMed/NCBI

14. 

Solinas G, Germano G, Mantovani A and Allavena P: Tumor-associated macrophages (TAM) as major players of the cancer-related inflammation. J Leukoc Biol. 86:1065–1073. 2009. View Article : Google Scholar : PubMed/NCBI

15. 

Lamagna C, Aurrand-Lions M and Imhof BA: Dual role of macrophages in tumor growth and angiogenesis. J Leukoc Biol. 80:705–713. 2006. View Article : Google Scholar : PubMed/NCBI

16. 

Benoit M, Desnues B and Mege JL: Macrophage polarization in bacterial infections. J Immunol. 181:3733–3739. 2008. View Article : Google Scholar : PubMed/NCBI

17. 

Mantovani A, Sica A, Sozzani S, Allavena P, Vecchi A and Locati M: The chemokine system in diverse forms of macrophage activation and polarization. Trends Immunol. 25:677–686. 2004. View Article : Google Scholar : PubMed/NCBI

18. 

Pollard JW: Tumour-educated macrophages promote tumour progression and metastasis. Nat Rev Cancer. 4:71–78. 2004. View Article : Google Scholar : PubMed/NCBI

19. 

Mosser DM and Edwards JP: Exploring the full spectrum of macrophage activation. Nat Rev Immunol. 8:958–969. 2008. View Article : Google Scholar : PubMed/NCBI

20. 

Brown JM and Giaccia AJ: The unique physiology of solid tumors: opportunities (and problems) for cancer therapy. Cancer Res. 58:1408–1416. 1998.PubMed/NCBI

21. 

Vaupel P, Kelleher DK and Hockel M: Oxygen status of malignant tumors: pathogenesis of hypoxia and significance for tumor therapy. Semin Oncol. 28:29–35. 2001. View Article : Google Scholar : PubMed/NCBI

22. 

Murdoch C, Giannoudis A and Lewis CE: Mechanisms regulating the recruitment of macrophages into hypoxic areas of tumors and other ischemic tissues. Blood. 104:2224–2234. 2004. View Article : Google Scholar : PubMed/NCBI

23. 

Turner L, Scotton C, Negus R and Balkwill F: Hypoxia inhibits macrophage migration. Eur J Immunol. 29:2280–2287. 1999. View Article : Google Scholar : PubMed/NCBI

24. 

Grimshaw MJ and Balkwill FR: Inhibition of monocyte and macrophage chemotaxis by hypoxia and inflammation - a potential mechanism. Eur J Immunol. 31:480–489. 2001. View Article : Google Scholar : PubMed/NCBI

25. 

Wain JH, Kirby JA and Ali S: Leucocyte chemotaxis: examination of mitogen-activated protein kinase and phosphoinositide 3-kinase activation by monocyte chemoattractant proteins-1, -2, -3 and -4. Clin Exp Immunol. 127:436–444. 2002. View Article : Google Scholar : PubMed/NCBI

26. 

Leek RD, Lewis CE, Whitehouse R, Greenall M, Clarke J and Harris AL: Association of macrophage infiltration with angiogenesis and prognosis in invasive breast carcinoma. Cancer Res. 56:4625–4629. 1996.PubMed/NCBI

27. 

Burke B, Tang N, Corke KP, et al: Expression of HIF-1alpha by human macrophages: implications for the use of macrophages in hypoxia-regulated cancer gene therapy. J Pathol. 196:204–212. 2002. View Article : Google Scholar : PubMed/NCBI

28. 

Kimbro KS and Simons JW: Hypoxia-inducible factor-1 in human breast and prostate cancer. Endocr Relat Cancer. 13:739–749. 2006. View Article : Google Scholar : PubMed/NCBI

29. 

Giaccia A, Siim BG and Johnson RS: HIF-1 as a target for drug development. Nat Rev Drug Discov. 2:803–811. 2003. View Article : Google Scholar : PubMed/NCBI

30. 

Lewis JS, Landers RJ, Underwood JC, Harris AL and Lewis CE: Expression of vascular endothelial growth factor by macrophages is upregulated in poorly vascularized areas of breast carcinomas. J Pathol. 192:150–158. 2000. View Article : Google Scholar : PubMed/NCBI

31. 

Leek RD, Talks KL, Pezzella F, et al: Relation of hypoxia-inducible factor-2 alpha (HIF-2 alpha) expression in tumor-infiltrative macrophages to tumor angiogenesis and the oxidative thymidine phosphorylase pathway in Human breast cancer. Cancer Res. 62:1326–1329. 2002.

32. 

Murata Y, Ohteki T, Koyasu S and Hamuro J: IFN-gamma and pro-inflammatory cytokine production by antigen-presenting cells is dictated by intracellular thiol redox status regulated by oxygen tension. Eur J Immunol. 32:2866–2873. 2002. View Article : Google Scholar : PubMed/NCBI

33. 

Doedens AL, Stockmann C, Rubinstein MP, et al: Macrophage expression of hypoxia-inducible factor-1 alpha suppresses T-cell function and promotes tumor progression. Cancer Res. 70:7465–7475. 2010. View Article : Google Scholar : PubMed/NCBI

34. 

Schmeisser A, Marquetant R, Illmer T, et al: The expression of macrophage migration inhibitory factor 1alpha (MIF 1alpha) in human atherosclerotic plaques is induced by different proatherogenic stimuli and associated with plaque instability. Atherosclerosis. 178:83–94. 2005. View Article : Google Scholar

35. 

Oda S, Oda T, Nishi K, et al: Macrophage migration inhibitory factor activates hypoxia-inducible factor in a p53-dependent manner. PLoS One. 3:e22152008. View Article : Google Scholar : PubMed/NCBI

36. 

Yu X, Lin SG, Huang XR, et al: Macrophage migration inhibitory factor induces MMP-9 expression in macrophages via the MEK-ERK MAP kinase pathway. J Interferon Cytokine Res. 27:103–109. 2007. View Article : Google Scholar : PubMed/NCBI

37. 

Leek RD, Hunt NC, Landers RJ, Lewis CE, Royds JA and Harris AL: Macrophage infiltration is associated with VEGF and EGFR expression in breast cancer. J Pathol. 190:430–436. 2000. View Article : Google Scholar : PubMed/NCBI

38. 

Bingle L, Lewis CE, Corke KP, Reed MW and Brown NJ: Macrophages promote angiogenesis in human breast tumour spheroids in vivo. Br J Cancer. 94:101–107. 2006. View Article : Google Scholar : PubMed/NCBI

39. 

Vicioso L, Gonzalez FJ, Alvarez M, et al: Elevated serum levels of vascular endothelial growth factor are associated with tumor-associated macrophages in primary breast cancer. Am J Clin Pathol. 125:111–118. 2006. View Article : Google Scholar : PubMed/NCBI

40. 

Lin EY, Li JF, Gnatovskiy L, et al: Macrophages regulate the angiogenic switch in a mouse model of breast cancer. Cancer Res. 66:11238–11246. 2006. View Article : Google Scholar : PubMed/NCBI

41. 

Lin EY, Li JF, Bricard G, et al: Vascular endothelial growth factor restores delayed tumor progression in tumors depleted of macrophages. Mol Oncol. 1:288–302. 2007. View Article : Google Scholar : PubMed/NCBI

42. 

Ojalvo LS, King W, Cox D and Pollard JW: High-density gene expression analysis of tumor-associated macrophages from mouse mammary tumors. Am J Pathol. 174:1048–1064. 2009. View Article : Google Scholar : PubMed/NCBI

43. 

Tang X, Mo C, Wang Y, Wei D and Xiao H: Anti-tumour strategies aiming to target tumour-associated macrophages. Immunology. 138:93–104. 2013. View Article : Google Scholar : PubMed/NCBI

44. 

Nagakawa Y, Aoki T, Kasuya K, Tsuchida A and Koyanagi Y: Histologic features of venous invasion, expression of vascular endothelial growth factor and matrix metalloproteinase-2 and matrix metalloproteinase-9, and the relation with liver metastasis in pancreatic cancer. Pancreas. 24:169–178. 2002. View Article : Google Scholar

45. 

Duffy MJ, O'Grady P, Devaney D, O'Siorain L, Fennelly JJ and Lijnen HJ: Urokinase-plasminogen activator, a marker for aggressive breast carcinomas. Preliminary report. Cancer. 62:531–533. 1988. View Article : Google Scholar : PubMed/NCBI

46. 

Ulisse S, Baldini E, Sorrenti S and D'Armiento M: The urokinase plasminogen activator system: a target for anti-cancer therapy. Curr Cancer Drug Targets. 9:32–71. 2009. View Article : Google Scholar : PubMed/NCBI

47. 

Kantelhardt EJ, Vetter M, Schmidt M, et al: Prospective evaluation of prognostic factors uPA/PAI-1 in node-negative breast cancer: phase III NNBC3-Europe trial (AGO, GBG, EORTCPBG) comparing 6xFEC versus 3xFEC/3xDocetaxel. BMC Cancer. 11:1402011. View Article : Google Scholar : PubMed/NCBI

48. 

Wyckoff JB, Wang Y, Lin EY, et al: Direct visualization of macrophage-assisted tumor cell intravasation in mammary tumors. Cancer Res. 67:2649–2656. 2007. View Article : Google Scholar : PubMed/NCBI

49. 

Ingman WV, Wyckoff J, Gouon-Evans V, Condeelis J and Pollard JW: Macrophages promote collagen fibrillogenesis around terminal end buds of the developing mammary gland. Dev Dyn. 235:3222–3229. 2006. View Article : Google Scholar : PubMed/NCBI

50. 

Rakoff-Nahoum S and Medzhitov R: Toll-like receptors and cancer. Nat Rev Cancer. 9:57–63. 2009. View Article : Google Scholar

51. 

Gonzalez-Reyes S, Marin L, Gonzalez L, et al: Study of TLR3, TLR4 and TLR9 in breast carcinomas and their association with metastasis. BMC Cancer. 10:6652010. View Article : Google Scholar : PubMed/NCBI

52. 

Siednienko J and Miggin SM: Expression analysis of the Toll-like receptors in human peripheral blood mononuclear cells. Methods Mol Biol. 517:3–14. 2009. View Article : Google Scholar : PubMed/NCBI

53. 

Kim S, Takahashi H, Lin WW, et al: Carcinoma-produced factors activate myeloid cells through TLR2 to stimulate metastasis. Nature. 457:102–106. 2009. View Article : Google Scholar : PubMed/NCBI

54. 

Naugler WE, Sakurai T, Kim S, et al: Gender disparity in liver cancer due to sex differences in MyD88-dependent IL-6 production. Science. 317:121–124. 2007. View Article : Google Scholar

55. 

Sandholm J, Kauppila JH, Pressey C, et al: Estrogen receptor-alpha and sex steroid hormones regulate Toll-like receptor-9 expression and invasive function in human breast cancer cells. Breast Cancer Res Treat. 132:411–419. 2012. View Article : Google Scholar

56. 

Apetoh L, Ghiringhelli F, Tesniere A, et al: Toll-like receptor 4-dependent contribution of the immune system to anticancer chemotherapy and radiotherapy. Nat Med. 13:1050–1059. 2007. View Article : Google Scholar

57. 

Apetoh L, Tesniere A, Ghiringhelli F, Kroemer G and Zitvogel L: Molecular interactions between dying tumor cells and the innate immune system determine the efficacy of conventional anti-cancer therapies. Cancer Res. 68:4026–4030. 2008. View Article : Google Scholar : PubMed/NCBI

58. 

Kim SY, Choi YJ, Joung SM, Lee BH, Jung YS and Lee JY: Hypoxic stress upregulates the expression of Toll-like receptor 4 in macrophages via hypoxia-inducible factor. Immunology. 129:516–524. 2010. View Article : Google Scholar : PubMed/NCBI

59. 

Tlsty TD and Coussens LM: Tumor stroma and regulation of cancer development. Annu Rev Pathol. 1:119–150. 2006. View Article : Google Scholar : PubMed/NCBI

60. 

Allavena P, Signorelli M, Chieppa M, et al: Anti-inflammatory properties of the novel antitumor agent yondelis (trabectedin): inhibition of macrophage differentiation and cytokine production. Cancer Res. 65:2964–2971. 2005. View Article : Google Scholar

61. 

Dineen SP, Lynn KD, Holloway SE, et al: Vascular endothelial growth factor receptor 2 mediates macrophage infiltration into orthotopic pancreatic tumors in mice. Cancer Res. 68:4340–4346. 2008. View Article : Google Scholar : PubMed/NCBI

62. 

Miller K, Wang M, Gralow J, et al: Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med. 357:2666–2676. 2007. View Article : Google Scholar : PubMed/NCBI

63. 

Miles DW, Chan A, Dirix LY, et al: Phase III study of bevacizumab plus docetaxel compared with placebo plus docetaxel for the first-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol. 28:3239–3247. 2010. View Article : Google Scholar : PubMed/NCBI

64. 

Gnant M, Mlineritsch B, Schippinger W, et al: Endocrine therapy plus zoledronic acid in premenopausal breast cancer. N Engl J Med. 360:679–691. 2009. View Article : Google Scholar : PubMed/NCBI

65. 

Green JR and Guenther A: The backbone of progress - preclinical studies and innovations with zoledronic acid. Crit Rev Oncol Hematol. 77(Suppl 1): S3–S12. 2011. View Article : Google Scholar : PubMed/NCBI

66. 

Giraudo E, Inoue M and Hanahan D: An amino-bisphosphonate targets MMP-9-expressing macrophages and angiogenesis to impair cervical carcinogenesis. J Clin Invest. 114:623–633. 2004. View Article : Google Scholar : PubMed/NCBI

67. 

Guiducci C, Vicari AP, Sangaletti S, Trinchieri G and Colombo MP: Redirecting in vivo elicited tumor infiltrating macrophages and dendritic cells towards tumor rejection. Cancer Res. 65:3437–3446. 2005.PubMed/NCBI

Related Articles

Journal Cover

July 2013
Volume 43 Issue 1

Print ISSN: 1019-6439
Online ISSN:1791-2423

Sign up for eToc alerts

Recommend to Library

Copy and paste a formatted citation
APA
Obeid, E., Nanda, R., Fu, Y., & Olopade, O.I. (2013). The role of tumor-associated macrophages in breast cancer progression (Review). International Journal of Oncology, 43, 5-12. https://doi.org/10.3892/ijo.2013.1938
MLA
Obeid, E., Nanda, R., Fu, Y., Olopade, O. I."The role of tumor-associated macrophages in breast cancer progression (Review)". International Journal of Oncology 43.1 (2013): 5-12.
Chicago
Obeid, E., Nanda, R., Fu, Y., Olopade, O. I."The role of tumor-associated macrophages in breast cancer progression (Review)". International Journal of Oncology 43, no. 1 (2013): 5-12. https://doi.org/10.3892/ijo.2013.1938