Annals of Surgical Oncology

, Volume 19, Issue 12, pp 3979–3986 | Cite as

Elevated Levels of Proliferating and Recently Migrated Tumor-associated Macrophages Confer Increased Aggressiveness and Worse Outcomes in Breast Cancer

  • Rita A. Mukhtar
  • Amy P. Moore
  • Vickram J. Tandon
  • Onouwem Nseyo
  • Patrick Twomey
  • Charles Adeyinka Adisa
  • Ndukauba Eleweke
  • Alfred Au
  • Frederick L. Baehner
  • Dan H. Moore
  • Michael S. McGrath
  • Olofunmilayo I. Olopade
  • Joe W. Gray
  • Michael J. Campbell
  • Laura J. Esserman
Translational Research and Biomarkers

Abstract

Purpose

Macrophages play a major role in inflammatory processes and have been associated with poor prognosis in a variety of cancers, including breast cancer. Previously, we investigated the relationship of a subset of tumor-associated macrophages (PCNA+ TAMs) with clinicopathologic characteristics of breast cancer. We reported that high PCNA+ TAM counts were associated with hormone receptor (HR)-negative, high-grade tumors and early recurrence. To further understand the significance of elevated PCNA+ TAMs and the functionality of TAMs, we examined the expression of S100A8/S100A9 with the antibody Mac387. The heterodimeric S100A8/S100A9 complex plays a role in inflammation and is increased in several cancer types.

Methods

We performed immunohistochemistry using the Mac387 antibody on 367 invasive human breast cancer cases. Results were compared to previous PCNA+ TAM counts and were correlated with patient outcomes adjusting for HR status and histologic grade.

Results

Like PCNA+ TAMs, high Mac387 counts were associated with HR negativity, high tumor grade, younger age, and decreased recurrence-free survival. Mac387, however, appears to identify both a subset of macrophages and a subset of tumor cells. The concordance between Mac387 and PCNA+ TAM counts was low and cases that had both high Mac387 and high PCNA+ TAMs counts had a stronger association with early recurrence.

Conclusions

The presence of high numbers of PCNA+ TAMs and Mac387-positive cells in breast cancers with poor outcomes may implicate a subset of TAMs in breast cancer pathogenesis, and may ultimately serve to develop potential cellular targets for therapeutic interventions.

References

  1. 1.
    Eubank TD, Galloway M, Montague CM, Waldman WJ, Marsh CB. M-CSF induces vascular endothelial growth factor production and angiogenic activity from human monocytes. J Immunol. 2003;171:2637–43.PubMedGoogle Scholar
  2. 2.
    Lewis CE, Leek R, Harris A, McGee JO. Cytokine regulation of angiogenesis in breast cancer: the role of tumor-associated macrophages. J Leukoc Biol. 1995;57:747–51.PubMedGoogle Scholar
  3. 3.
    Lin EY, Pollard JW. Tumor-associated macrophages press the angiogenic switch in breast cancer. Cancer Res. 2007;67:5064–6.PubMedCrossRefGoogle Scholar
  4. 4.
    Lin EY, Li JF, Gnatovskiy L, et al. Macrophages regulate the angiogenic switch in a mouse model of breast cancer. Cancer Res. 2006;66:11238–46.PubMedCrossRefGoogle Scholar
  5. 5.
    Talmadge JE, Donkor M, Scholar E. Inflammatory cell infiltration of tumors: Jekyll or Hyde. Cancer Metastasis Rev. 2007;26:373–400.PubMedCrossRefGoogle Scholar
  6. 6.
    Chang YC, Chen TC, Lee CT, et al. Epigenetic control of MHC class II expression in tumor-associated macrophages by decoy receptor 3. Blood. 2008;111:5054–63.PubMedCrossRefGoogle Scholar
  7. 7.
    Van Ginderachter JA, Movahedi K, Hassanzadeh Ghassabeh G, et al. Classical and alternative activation of mononuclear phagocytes: picking the best of both worlds for tumor promotion. Immunobiology. 2006;211:487–501.PubMedCrossRefGoogle Scholar
  8. 8.
    Mosser DM. The many faces of macrophage activation. J Leukoc Biol. 2003;73:209–12.PubMedCrossRefGoogle Scholar
  9. 9.
    Mosser DM, Edwards JP. Exploring the full spectrum of macrophage activation. Nat Rev Immunol. 2008;8:958–69.PubMedCrossRefGoogle Scholar
  10. 10.
    Evans R, Cullen RT. In situ proliferation of intratumor macrophages. J Leukoc Biol. 1984;35:561–72.PubMedGoogle Scholar
  11. 11.
    Stewart CC. Local proliferation of mononuclear phagocytes in tumors. J Reticuloendothel Soc. 1983;34:23–7.PubMedGoogle Scholar
  12. 12.
    Stewart CC, Beetham KL. Cytocidal activity and proliferative ability of macrophages infiltrating the EMT6 tumor. Int J Cancer. 1978;22:152–9.PubMedCrossRefGoogle Scholar
  13. 13.
    Gottfried E, Kunz-Schughart LA, Weber A, et al. Expression of CD68 in non-myeloid cell types. Scand J Immunol. 2008;67:453–63.PubMedCrossRefGoogle Scholar
  14. 14.
    Leonardi E, Girlando S, Serio G, et al. PCNA and Ki67 expression in breast carcinoma: correlations with clinical and biological variables. J Clin Pathol. 1992;45:416–9.PubMedCrossRefGoogle Scholar
  15. 15.
    Campbell MJ, Tonlaar NY, Garwood ER, et al. Proliferating macrophages associated with high grade, hormone receptor negative breast cancer and poor clinical outcome. Breast Cancer Res Treat. 2011;128:703–11.PubMedCrossRefGoogle Scholar
  16. 16.
    Isbel NM, Nikolic-Paterson DJ, Hill PA, Dowling J, Atkins RC. Local macrophage proliferation correlates with increased renal M-CSF expression in human glomerulonephritis. Nephrol Dial Transplant. 2001;16:1638–47.PubMedCrossRefGoogle Scholar
  17. 17.
    Shiomi M, Yamada S, Ito T. Atheroma stabilizing effects of simvastatin due to depression of macrophages or lipid accumulation in the atheromatous plaques of coronary plaque-prone WHHL rabbits. Atherosclerosis. 2005;178:287–94.PubMedCrossRefGoogle Scholar
  18. 18.
    Fischer-Smith T, Croul S, Adeniyi A, et al. Macrophage/microglial accumulation and proliferating cell nuclear antigen expression in the central nervous system in human immunodeficiency virus encephalopathy. Am J Pathol. 2004;164:2089–99.PubMedCrossRefGoogle Scholar
  19. 19.
    Zenger E, Abbey NW, Weinstein MD, et al. Injection of human primary effusion lymphoma cells or associated macrophages into severe combined immunodeficient mice causes murine lymphomas. Cancer Res. 2002;62:5536.PubMedGoogle Scholar
  20. 20.
    Liu J, Li Z, Cui J, Xu G, Cui G. Cellular changes in the tumor microenvironment of human esophageal squamous cell carcinomas. Tumour Biol. 2012;33:495–505.PubMedCrossRefGoogle Scholar
  21. 21.
    Arai K, Takano S, Teratani T, Ito Y, Yamada T, Nozawa R. S100A8 and S100A9 overexpression is associated with poor pathological parameters in invasive ductal carcinoma of the breast. Curr Cancer Drug Targets. 2008;8:243–52.PubMedCrossRefGoogle Scholar
  22. 22.
    Subimerb C, Pinlaor S, Lulitanond V, et al. Circulating CD14(+) CD16(+) monocyte levels predict tissue invasive character of cholangiocarcinoma. Clin Exp Immunol. 2010;161:471–9.PubMedCrossRefGoogle Scholar
  23. 23.
    Gebhardt C, Breitenbach U, Tuckermann JP, Dittrich BT, Richter KH, Angel P. Calgranulins S100A8 and S100A9 are negatively regulated by glucocorticoids in a c-Fos-dependent manner and overexpressed throughout skin carcinogenesis. Oncogene. 2002;21:4266–76.PubMedCrossRefGoogle Scholar
  24. 24.
    Kim HJ, Kang HJ, Lee H, et al. Identification of S100A8 and S100A9 as serological markers for colorectal cancer. J Proteome Res. 2009;8:1368–79.PubMedCrossRefGoogle Scholar
  25. 25.
    Hermani A, Hess J, De Servi B, et al. Calcium-binding proteins S100A8 and S100A9 as novel diagnostic markers in human prostate cancer. Clin Cancer Res. 2005;11:5146–52.PubMedCrossRefGoogle Scholar
  26. 26.
    Chin K, DeVries S, Fridlyand J, et al. Genomic and transcriptional aberrations linked to breast cancer pathophysiologies. Cancer Cell. 2006;10:529–41.PubMedCrossRefGoogle Scholar
  27. 27.
    Mukhtar R, Moore A, Nseyo O, et al. Evaluation of levels of proliferating macrophages in patients at a county hospital and those with early recurrences. J Clin Oncol. 2010;28(15 Suppl):1110.Google Scholar
  28. 28.
    Huo D, Ikpatt F, Khramtsov A, et al. Population differences in breast cancer: survey in indigenous African women reveals over-representation of triple-negative breast cancer. J Clin Oncol. 2009;27:4515–21.PubMedCrossRefGoogle Scholar
  29. 29.
    Mukhtar RA, Moore AP, Nseyo O, et al. Elevated PCNA+ tumor-associated macrophages in breast cancer are associated with early recurrence and non-Caucasian ethnicity. Breast Cancer Res Treat. 2011;130:635–44.PubMedCrossRefGoogle Scholar
  30. 30.
    Shabo I, Stal O, Olsson H, Dore S, Svanvik J. Breast cancer expression of CD163, a macrophage scavenger receptor, is related to early distant recurrence and reduced patient survival. Int J Cancer. 2008;123:780–6.PubMedCrossRefGoogle Scholar
  31. 31.
    Shabo I, Svanvik J. Expression of macrophage antigens by tumor cells. Adv Exp Med Biol. 2011;714:141–50.PubMedCrossRefGoogle Scholar
  32. 32.
    Allavena P, Sica A, Solinas G, Porta C, Mantovani A. The inflammatory micro-environment in tumor progression: the role of tumor-associated macrophages. Crit Rev Oncol Hematol. 2008;66:1–9.PubMedCrossRefGoogle Scholar
  33. 33.
    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. 2009;125:1276–84.PubMedCrossRefGoogle Scholar
  34. 34.
    Eubank TD, Roberts RD, Khan M, et al. Granulocyte macrophage colony-stimulating factor inhibits breast cancer growth and metastasis by invoking an anti-angiogenic program in tumor-educated macrophages. Cancer Res. 2009;69:2133–40.PubMedCrossRefGoogle Scholar
  35. 35.
    Lin EY, Pollard JW. Macrophages: modulators of breast cancer progression. Novartis Found Symp. 2004;256:158–68.PubMedCrossRefGoogle Scholar
  36. 36.
    Sinha P, Clements VK, Miller S, Ostrand-Rosenberg S. Tumor immunity: a balancing act between T cell activation, macrophage activation and tumor-induced immune suppression. Cancer Immunol Immunother. 2005;54:1137–42.PubMedCrossRefGoogle Scholar
  37. 37.
    Sinha P, Clements VK, Bunt SK, Albelda SM, Ostrand-Rosenberg S. Cross-talk between myeloid-derived suppressor cells and macrophages subverts tumor immunity toward a type 2 response. J Immunol. 2007;179:977–83.PubMedGoogle Scholar
  38. 38.
    Mantovani A, Sica A, Sozzani S, Allavena P, Vecchi A, Locati M. The chemokine system in diverse forms of macrophage activation and polarization. Trends Immunol. 2004;25:677–86.PubMedCrossRefGoogle Scholar
  39. 39.
    DeNardo DG, Barreto JB, Andreu P, et al. CD4(+) T cells regulate pulmonary metastasis of mammary carcinomas by enhancing protumor properties of macrophages. Cancer Cell. 2009;16:91–102.PubMedCrossRefGoogle Scholar
  40. 40.
    Laoui D, Movahedi K, Van Overmeire E, et al. Tumor-associated macrophages in breast cancer: distinct subsets, distinct functions. Int J Dev Biol. 2011;55:861–7.PubMedCrossRefGoogle Scholar
  41. 41.
    Volodko NRA, Rudas M, Jakesz R. Tumour-associated macrophages in breast cancer and their prognostic correlations. Breast. 1998;7:99–105.CrossRefGoogle Scholar
  42. 42.
    Leek RD, Landers RJ, Harris AL, Lewis CE. Necrosis correlates with high vascular density and focal macrophage infiltration in invasive carcinoma of the breast. Br J Cancer. 1999;79:991–5.PubMedCrossRefGoogle Scholar
  43. 43.
    Balkwill F, Mantovani A. Cancer and inflammation: implications for pharmacology and therapeutics. Clin Pharmacol Ther. 2010;87:401–6.PubMedCrossRefGoogle Scholar
  44. 44.
    Patsialou A, Wyckoff J, Wang Y, Goswami S, Stanley ER, Condeelis JS. Invasion of human breast cancer cells in vivo requires both paracrine and autocrine loops involving the colony-stimulating factor-1 receptor. Cancer Res. 2009;69:9498–506.PubMedCrossRefGoogle Scholar
  45. 45.
    Ehrchen JM, Sunderkotter C, Foell D, Vogl T, Roth J. The endogenous Toll-like receptor 4 agonist S100A8/S100A9 (calprotectin) as innate amplifier of infection, autoimmunity, and cancer. J Leukoc Biol. 2009;86:557–66.PubMedCrossRefGoogle Scholar
  46. 46.
    Manitz MP, Horst B, Seeliger S, et al. Loss of S100A9 (MRP14) results in reduced interleukin-8-induced CD11b surface expression, a polarized microfilament system, and diminished responsiveness to chemoattractants in vitro. Mol Cell Biol. 2003;23:1034–43.PubMedCrossRefGoogle Scholar
  47. 47.
    Vogl T, Ludwig S, Goebeler M, et al. MRP8 and MRP14 control microtubule reorganization during transendothelial migration of phagocytes. Blood. 2004;104:4260–8.PubMedCrossRefGoogle Scholar
  48. 48.
    Buckner CM, Calderon TM, Willams DW, Belbin TJ, Berman JW. Characterization of monocyte maturation/differentiation that facilitates their transmigration across the blood–brain barrier and infection by HIV: implications for NeuroAIDS. Cell Immunol. 2011;267:109–23.PubMedCrossRefGoogle Scholar
  49. 49.
    McKiernan E, McDermott EW, Evoy D, Crown J, Duffy MJ. The role of S100 genes in breast cancer progression. Tumour Biol. 2011;32:441–50.PubMedCrossRefGoogle Scholar
  50. 50.
    Gebhardt C, Nemeth J, Angel P, Hess J. S100A8 and S100A9 in inflammation and cancer. Biochem Pharmacol. 2006;72:1622–31.PubMedCrossRefGoogle Scholar
  51. 51.
    Marigo I, Dolcetti L, Serafini P, Zanovello P, Bronte V. Tumor-induced tolerance and immune suppression by myeloid derived suppressor cells. Immunol Rev. 2008;222:162–79.PubMedCrossRefGoogle Scholar
  52. 52.
    Sinha P, Okoro C, Foell D, Freeze HH, Ostrand-Rosenberg S, Srikrishna G. Proinflammatory S100 proteins regulate the accumulation of myeloid-derived suppressor cells. J Immunol. 2008;181:4666–75.PubMedGoogle Scholar
  53. 53.
    Pawelek JM. Cancer-cell fusion with migratory bone-marrow-derived cells as an explanation for metastasis: new therapeutic paradigms. Future Oncol. 2008;4:449–52.PubMedCrossRefGoogle Scholar
  54. 54.
    Pawelek JM. Tumour-cell fusion as a source of myeloid traits in cancer. Lancet Oncol. 2005;6:988–93.PubMedCrossRefGoogle Scholar
  55. 55.
    Pawelek JM, Chakraborty AK. Fusion of tumour cells with bone marrow–derived cells: a unifying explanation for metastasis. Nat Rev Cancer. 2008;8:377–86.PubMedCrossRefGoogle Scholar

Copyright information

© Society of Surgical Oncology 2012

Authors and Affiliations

  • Rita A. Mukhtar
    • 1
  • Amy P. Moore
    • 2
  • Vickram J. Tandon
    • 1
  • Onouwem Nseyo
    • 1
  • Patrick Twomey
    • 1
  • Charles Adeyinka Adisa
    • 3
  • Ndukauba Eleweke
    • 3
  • Alfred Au
    • 1
  • Frederick L. Baehner
    • 4
  • Dan H. Moore
    • 5
  • Michael S. McGrath
    • 4
  • Olofunmilayo I. Olopade
    • 6
  • Joe W. Gray
    • 7
  • Michael J. Campbell
    • 1
  • Laura J. Esserman
    • 1
  1. 1.Department of SurgeryUniversity of CaliforniaSan FranciscoUSA
  2. 2.Department of Medicine, Division of Hematology and OncologyUniversity of CaliforniaSan FranciscoUSA
  3. 3.Department of SurgeryAbia State UniversityAbiaNigeria
  4. 4.Departments of Laboratory Medicine and PathologyUniversity of CaliforniaSan FranciscoUSA
  5. 5.Department of Epidemiology and BiostatisticsUniversity of CaliforniaSan FranciscoUSA
  6. 6.Department of Medicine, Division of Hematology and OncologyUniversity of ChicagoChicagoUSA
  7. 7.Department of Biomedical EngineeringOregon Health and Science UniversityPortlandUSA

Personalised recommendations