Cytokine Networks That Mediate Epithelial Cell-Macrophage Crosstalk in the Mammary Gland: Implications for Development and Cancer

Article

Abstract

Dynamic interactions between the hormone responsive mammary gland epithelium and surrounding stromal macrophage populations are critical for normal development and function of the mammary gland. Macrophages are versatile cells capable of diverse roles in mammary gland development and maintenance of homeostasis, and their function is highly dependent on signals within the local cytokine microenvironment. The mammary epithelium secretes a number of cytokines, including colony stimulating factor 1 (CSF1), transforming growth factor beta 1 (TGFB1), and chemokine ligand 2 (CCL2) that affect the abundance, phenotype and function of macrophages. However, aberrations in these interactions have been found to increase the risk of tumour formation, and utilisation of stromal macrophage support by tumours can increase the invasive and metastatic potential of the cancer. Studies utilising genetically modified mouse models have shed light on the significance of epithelial cell-macrophage crosstalk, and the cytokines that mediate this communication, in mammary gland development and tumourigenesis. This article reviews the current status of our understanding of the roles of epithelial cell-derived cytokines in mammary gland development and cancer, with a focus on the crosstalk between epithelial cells and the local macrophage population.

Keywords

Macrophage Cytokines TGFB CSF1 CCL2 

Abbreviations

ArgI

Arginase I

CCL2

Chemokine ligand 2

CCR2

C-C chemokine receptor type 2

COX2

Cyclooxygenase 2

CSF1

Clony stimulating factor 1

CSF1R

Clony stimulating factor 1 receptor

DMBA

7,12-Dimethylbenz (a) anthracene

IFNG

Interferon gamma

IL4

Interleukin 4

IL5

Interleukin 5

IL12

Interleukin 12

IL13

Interleukin 13

iNOS

Inducible nitric oxide synthase

LAP

Latency-associated peptide

LTBP

Latent TGFB binding protein

LTGFB1

Latent transforming growth factor 1

MMTV

Mouse mammary tumour virus

NO

Nitric oxide

PyMT

Polyoma middle T antigen

SOCSI

Suppressor of cytokine signalling 1

TGFB1

Transforming growth factor beta 1

TGFBRI

Transforming growth factor beta type I receptor

TGFBRII

Transforming growth factor beta type II receptor

TNFA

Tumour necrosis factor alpha

WAP

Whey acidic protein

References

  1. 1.
    Hovey RC, Trott JF, Vonderhaar BK. Establishing a framework for the functional mammary gland: from endocrinology to morphology. J Mammary Gland Biol Neoplasia. 2002;7(1):17–38.PubMedCrossRefGoogle Scholar
  2. 2.
    Hennighausen L, Robinson GW. Information networks in the mammary gland. Nat Rev Mol Cell Biol. 2005;6(9):715–25.PubMedCrossRefGoogle Scholar
  3. 3.
    Fata JE, Chaudhary V, Khokha R. Cellular turnover in the mammary gland is correlated with systemic levels of progesterone and not 17beta-estradiol during the estrous cycle. Biol Reprod. 2001;65(3):680–8.PubMedCrossRefGoogle Scholar
  4. 4.
    Pollard JW, Hennighausen L. Colony stimulating factor 1 is required for mammary gland development during pregnancy. Proc Natl Acad Sci U S A. 1994;91(20):9312–6.PubMedCentralPubMedCrossRefGoogle Scholar
  5. 5.
    Sun X, Robertson SA, Ingman WV. Regulation of epithelial cell turnover and macrophage phenotype by epithelial cell-derived transforming growth factor beta1 in the mammary gland. Cytokine. 2013;61(2):377–88.PubMedCrossRefGoogle Scholar
  6. 6.
    Gouon-Evans V, Lin EY, Pollard JW. Requirement of macrophages and eosinophils and their cytokines/chemokines for mammary gland development. Breast Cancer Res. 2002;4(4):155–64.PubMedCentralPubMedCrossRefGoogle Scholar
  7. 7.
    Qian BZ et al. CCL2 recruits inflammatory monocytes to facilitate breast-tumour metastasis. Nature. 2011;475(7355):222–5.PubMedCentralPubMedCrossRefGoogle Scholar
  8. 8.
    Hodson LJ et al. Macrophage phenotype in the mammary gland fluctuates over the course of the estrous cycle and is regulated by ovarian steroid hormones. Biol Reprod. 2013;89(3):65.PubMedCrossRefGoogle Scholar
  9. 9.
    Li MO et al. Transforming growth factor-beta regulation of immune responses. Annu Rev Immunol. 2006;24:99–146.PubMedCrossRefGoogle Scholar
  10. 10.
    Tsunawaki S et al. Deactivation of macrophages by transforming growth factor-beta. Nature. 1988;334(6179):260–2.PubMedCrossRefGoogle Scholar
  11. 11.
    Nandan D, Reiner NE. TGF-beta attenuates the class II transactivator and reveals an accessory pathway of IFN-gamma action. J Immunol. 1997;158(3):1095–101.PubMedGoogle Scholar
  12. 12.
    Soria G, Ben-Baruch A. The inflammatory chemokines CCL2 and CCL5 in breast cancer. Cancer Lett. 2008;267(2):271–85.PubMedCrossRefGoogle Scholar
  13. 13.
    Lin EY et al. The macrophage growth factor CSF-1 in mammary gland development and tumor progression. J Mammary Gland Biol Neoplasia. 2002;7(2):147–62.PubMedCrossRefGoogle Scholar
  14. 14.
    Mantovani A et al. Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol. 2002;23(11):549–55.PubMedCrossRefGoogle Scholar
  15. 15.
    Wu Y, Zheng L. Dynamic education of macrophages in different areas of human tumors. Cancer Microenviron. 2012;5(3):195–201.PubMedCentralPubMedCrossRefGoogle Scholar
  16. 16.
    Cook J, Hagemann T. Tumour-associated macrophages and cancer. Curr Opin Pharmacol. 2013;13(4):595–601.PubMedCrossRefGoogle Scholar
  17. 17.
    Sica A et al. Tumour-associated macrophages are a distinct M2 polarised population promoting tumour progression: potential targets of anti-cancer therapy. Eur J Cancer. 2006;42(6):717–27.PubMedCrossRefGoogle Scholar
  18. 18.
    Gouon-Evans V, Rothenberg ME, Pollard JW. Postnatal mammary gland development requires macrophages and eosinophils. Development. 2000;127(11):2269–82.PubMedGoogle Scholar
  19. 19.
    Van Nguyen A, Pollard JW. Colony stimulating factor-1 is required to recruit macrophages into the mammary gland to facilitate mammary ductal outgrowth. Dev Biol. 2002;247(1):11–25.PubMedCrossRefGoogle Scholar
  20. 20.
    Ingman WV et al. Macrophages promote collagen fibrillogenesis around terminal end buds of the developing mammary gland. Dev Dyn. 2006;235(12):3222–9.PubMedCrossRefGoogle Scholar
  21. 21.
    Chua CL, H.L., Robertson SA, Ingman WV, Dual roles of macrophages in ovarian cycle-associated development and remodeling of the mammary gland epithelium. Development, 2010. In press.Google Scholar
  22. 22.
    Schwertfeger KL, Rosen JM, Cohen DA. Mammary gland macrophages: pleiotropic functions in mammary development. J Mammary Gland Biol Neoplasia. 2006;11(3–4):229–38.PubMedCrossRefGoogle Scholar
  23. 23.
    Stein WD et al. A serial analysis of gene expression (SAGE) database analysis of chemo sensitivity: comparing solid tumors with cell lines and comparing solid tumors from different tissue origins. Cancer Res. 2004;64(8):2805–16.PubMedCrossRefGoogle Scholar
  24. 24.
    Gyorki DE et al. Resident macrophages influence stem cell activity in the mammary gland. Breast Cancer Res. 2009;11(4):R62.PubMedCentralPubMedCrossRefGoogle Scholar
  25. 25.
    O'Brien J et al. Macrophages are crucial for epithelial cell death and adipocyte repopulation during mammary gland involution. Development. 2012;139(2):269–75.PubMedCrossRefGoogle Scholar
  26. 26.
    Lindeman GJ et al. SOCS1 deficiency results in accelerated mammary gland development and rescues lactation in prolactin receptor-deficient mice. Genes Dev. 2001;15(13):1631–6.PubMedCentralPubMedCrossRefGoogle Scholar
  27. 27.
    Motta M, A.P., Baratta M., Leptin and prolactin modulate the expression of SOCS-1 in association with interleukin-6 and tumor necrosis factor-alpha in mammary cells: a role in differentiated secretory epithelium. Regul Pept, 2004. 121(1–3): p. 163–70.Google Scholar
  28. 28.
    Clarkson RW BM, Kritikou EA, Lee JM, Freeman TC, Tiffen PG, Watson CJ. The genes induced by signal transducer and activators of transcription (STAT)3 and STAT5 in mammary epithelial cells define the roles of these STATs in mammary development. Mol Endocrinol. 2006;20(3):675–85.PubMedCrossRefGoogle Scholar
  29. 29.
    Gordon S. The macrophage: past, present and future. Eur J Immunol. 2007;37(1):S9–17.PubMedCrossRefGoogle Scholar
  30. 30.
    Gordon S, Taylor PR. Monocyte and macrophage heterogeneity. Nat Rev Immunol. 2005;5(12):953–64.PubMedCrossRefGoogle Scholar
  31. 31.
    Hume DA et al. The mononuclear phagocyte system revisited. J Leukoc Biol. 2002;72(4):621–7.PubMedGoogle Scholar
  32. 32.
    Qian BZ, Pollard JW. Macrophage diversity enhances tumor progression and metastasis. Cell. 2010;141(1):39–51.PubMedCrossRefGoogle Scholar
  33. 33.
    Martinez FO, Helming L, Gordon S. Alternative activation of macrophages: an immunologic functional perspective. Annu Rev Immunol. 2009;27:451–83.PubMedCrossRefGoogle Scholar
  34. 34.
    Guo X et al. Microenvironmental control of the breast cancer cell cycle. Anat Rec (Hoboken). 2012;295(4):553–62.CrossRefGoogle Scholar
  35. 35.
    Mahmoud SM et al. Tumour-infiltrating macrophages and clinical outcome in breast cancer. J Clin Pathol. 2012;65(2):159–63.PubMedCrossRefGoogle Scholar
  36. 36.
    Wiktor-Jedrzejczak W et al. Total absence of colony-stimulating factor 1 in the macrophage-deficient osteopetrotic (op/op) mouse. Proc Natl Acad Sci U S A. 1990;87(12):4828–32.PubMedCentralPubMedCrossRefGoogle Scholar
  37. 37.
    Hamilton JA. CSF-1 signal transduction. J Leukoc Biol. 1997;62(2):145–55.PubMedGoogle Scholar
  38. 38.
    Rohrschneider LR et al. Growth and differentiation signals regulated by the M-CSF receptor. Mol Reprod Dev. 1997;46(1):96–103.PubMedCrossRefGoogle Scholar
  39. 39.
    Ryan GR et al. Rescue of the colony-stimulating factor 1 (CSF-1)-nullizygous mouse (Csf1(op)/Csf1(op)) phenotype with a CSF-1 transgene and identification of sites of local CSF-1 synthesis. Blood. 2001;98(1):74–84.PubMedCrossRefGoogle Scholar
  40. 40.
    Cecchini MG et al. Role of colony stimulating factor-1 in the establishment and regulation of tissue macrophages during postnatal development of the mouse. Development. 1994;120(6):1357–72.PubMedGoogle Scholar
  41. 41.
    Pollard JW et al. Apparent role of the macrophage growth factor, CSF-1, in placental development. Nature. 1987;330(6147):484–6.PubMedCrossRefGoogle Scholar
  42. 42.
    Byrne PV, Guilbert LJ, Stanley ER. Distribution of cells bearing receptors for a colony-stimulating factor (CSF-1) in murine tissues. J Cell Biol. 1981;91(3):848–53.PubMedCrossRefGoogle Scholar
  43. 43.
    Kacinski BM et al. FMS (CSF-1 receptor) and CSF-1 transcripts and protein are expressed by human breast carcinomas in vivo and in vitro. Oncogene. 1991;6(6):941–52.PubMedGoogle Scholar
  44. 44.
    Sapi E. The role of CSF-1 in normal physiology of mammary gland and breast cancer: an update. Exp Biol Med (Maywood). 2004;229(1):1–11.Google Scholar
  45. 45.
    Sapi E et al. Expression of CSF-I and CSF-I receptor by normal lactating mammary epithelial cells. J Soc Gynecol Investig. 1998;5(2):94–101.PubMedCrossRefGoogle Scholar
  46. 46.
    Lin EY et al. Colony-stimulating factor 1 promotes progression of mammary tumors to malignancy. J Exp Med. 2001;193(6):727–40.PubMedCentralPubMedCrossRefGoogle Scholar
  47. 47.
    Beuvon F et al. CSF-1 (colony stimulating factors 1) and CSF-1 receptor. General review and expression in invasive breast tumors. Bull Cancer. 1993;80(1):29–35.PubMedGoogle Scholar
  48. 48.
    Aharinejad S et al. Elevated CSF1 serum concentration predicts poor overall survival in women with early breast cancer. Endocr Relat Cancer. 2013;20(6):777–83.PubMedCrossRefGoogle Scholar
  49. 49.
    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. 2004;64(15):5378–84.PubMedCrossRefGoogle Scholar
  50. 50.
    Wyckoff J et al. A paracrine loop between tumor cells and macrophages is required for tumor cell migration in mammary tumors. Cancer Res. 2004;64(19):7022–9.PubMedCrossRefGoogle Scholar
  51. 51.
    Tucker RF et al. Growth inhibitor from BSC-1 cells closely related to platelet type beta transforming growth factor. Science. 1984;226(4675):705–7.PubMedCrossRefGoogle Scholar
  52. 52.
    Lyons RM et al. Mechanism of activation of latent recombinant transforming growth factor beta 1 by plasmin. J Cell Biol. 1990;110(4):1361–7.PubMedCrossRefGoogle Scholar
  53. 53.
    Ingman WV, Robertson SA. The essential roles of TGFB1 in reproduction. Cytokine Growth Factor Rev. 2009;20(3):233–9.PubMedCrossRefGoogle Scholar
  54. 54.
    Jakowlew SB. Transforming growth factor-beta in cancer and metastasis. Cancer Metastasis Rev. 2006;25(3):435–57.PubMedCrossRefGoogle Scholar
  55. 55.
    Nakao A et al. TGF-beta receptor-mediated signalling through Smad2, Smad3 and Smad4. EMBO J. 1997;16(17):5353–62.PubMedCentralPubMedCrossRefGoogle Scholar
  56. 56.
    Brown CB et al. Requirement of type III TGF-beta receptor for endocardial cell transformation in the heart. Science. 1999;283(5410):2080–2.PubMedCrossRefGoogle Scholar
  57. 57.
    Fleisch MC, Maxwell CA, Barcellos-Hoff MH. The pleiotropic roles of transforming growth factor beta in homeostasis and carcinogenesis of endocrine organs. Endocr Relat Cancer. 2006;13(2):379–400.PubMedCrossRefGoogle Scholar
  58. 58.
    Chong H et al. Immunocytochemical localization of latent transforming growth factor-beta1 activation by stimulated macrophages. J Cell Physiol. 1999;178(3):275–83.PubMedCrossRefGoogle Scholar
  59. 59.
    Barcellos-Hoff MH. Latency and activation in the control of TGF-beta. J Mammary Gland Biol Neoplasia. 1996;1(4):353–63.CrossRefGoogle Scholar
  60. 60.
    Lawrence DA, Pircher R, Jullien P. Conversion of a high molecular weight latent beta-TGF from chicken embryo fibroblasts into a low molecular weight active beta-TGF under acidic conditions. Biochem Biophys Res Commun. 1985;133(3):1026–34.PubMedCrossRefGoogle Scholar
  61. 61.
    Nunes I et al. Latent transforming growth factor-beta binding protein domains involved in activation and transglutaminase-dependent cross-linking of latent transforming growth factor-beta. J Cell Biol. 1997;136(5):1151–63.PubMedCentralPubMedCrossRefGoogle Scholar
  62. 62.
    Ehrhart EJ et al. Latent transforming growth factor beta1 activation in situ: quantitative and functional evidence after low-dose gamma-irradiation. FASEB J. 1997;11(12):991–1002.PubMedGoogle Scholar
  63. 63.
    Barcellos-Hoff MH et al. Transforming growth factor-beta activation in irradiated murine mammary gland. J Clin Invest. 1994;93(2):892–9.PubMedCentralPubMedCrossRefGoogle Scholar
  64. 64.
    Wakefield LM et al. Recombinant latent transforming growth factor beta 1 has a longer plasma half-life in rats than active transforming growth factor beta 1, and a different tissue distribution. J Clin Invest. 1990;86(6):1976–84.PubMedCentralPubMedCrossRefGoogle Scholar
  65. 65.
    Ewan KB et al. Latent transforming growth factor-beta activation in mammary gland: regulation by ovarian hormones affects ductal and alveolar proliferation. Am J Pathol. 2002;160(6):2081–93.PubMedCentralPubMedCrossRefGoogle Scholar
  66. 66.
    Robinson SD et al. Regulated expression and growth inhibitory effects of transforming growth factor-beta isoforms in mouse mammary gland development. Development. 1991;113(3):867–78.PubMedGoogle Scholar
  67. 67.
    Pollard JW. Tumour-stromal interactions. Transforming growth factor-beta isoforms and hepatocyte growth factor/scatter factor in mammary gland ductal morphogenesis. Breast Cancer Res. 2001;3(4):230–7.PubMedCentralPubMedCrossRefGoogle Scholar
  68. 68.
    Joseph H et al. Overexpression of a kinase-deficient transforming growth factor-beta type II receptor in mouse mammary stroma results in increased epithelial branching. Mol Biol Cell. 1999;10(4):1221–34.PubMedCentralPubMedCrossRefGoogle Scholar
  69. 69.
    Daniel CW et al. TGF-beta 1-induced inhibition of mouse mammary ductal growth: developmental specificity and characterization. Dev Biol. 1989;135(1):20–30.PubMedCrossRefGoogle Scholar
  70. 70.
    Silberstein GB et al. Regulation of mammary morphogenesis: evidence for extracellular matrix-mediated inhibition of ductal budding by transforming growth factor-beta 1. Dev Biol. 1992;152(2):354–62.PubMedCrossRefGoogle Scholar
  71. 71.
    Pierce Jr DF et al. Inhibition of mammary duct development but not alveolar outgrowth during pregnancy in transgenic mice expressing active TGF-beta 1. Genes Dev. 1993;7(12):2308–17.PubMedCrossRefGoogle Scholar
  72. 72.
    Jhappan C et al. Targeting expression of a transforming growth factor beta 1 transgene to the pregnant mammary gland inhibits alveolar development and lactation. EMBO J. 1993;12(5):1835–45.PubMedCentralPubMedGoogle Scholar
  73. 73.
    Gorska AE et al. Dominant-negative interference of the transforming growth factor beta type II receptor in mammary gland epithelium results in alveolar hyperplasia and differentiation in virgin mice. Cell Growth Differ. 1998;9(3):229–38.PubMedGoogle Scholar
  74. 74.
    Crowley MR, Bowtell D, Serra R. TGF-beta, c-Cbl, and PDGFR-alpha the in mammary stroma. Dev Biol. 2005;279(1):58–72.PubMedCrossRefGoogle Scholar
  75. 75.
    Shull MM et al. Targeted disruption of the mouse transforming growth factor-beta 1 gene results in multifocal inflammatory disease. Nature. 1992;359(6397):693–9.PubMedCentralPubMedCrossRefGoogle Scholar
  76. 76.
    Kulkarni AB et al. Transforming growth factor beta 1 null mutation in mice causes excessive inflammatory response and early death. Proc Natl Acad Sci U S A. 1993;90(2):770–4.PubMedCentralPubMedCrossRefGoogle Scholar
  77. 77.
    Diebold RJ et al. Early-onset multifocal inflammation in the transforming growth factor beta 1-null mouse is lymphocyte mediated. Proc Natl Acad Sci U S A. 1995;92(26):12215–9.PubMedCentralPubMedCrossRefGoogle Scholar
  78. 78.
    Ingman WV, Robertson SA. Mammary gland development in transforming growth factor beta1 null mutant mice: systemic and epithelial effects. Biol Reprod. 2008;79(4):711–7.PubMedCrossRefGoogle Scholar
  79. 79.
    McGrath LJ et al. Exogenous transforming growth factor beta1 replacement and fertility in male Tgfb1 null mutant mice. Reprod Fertil Dev. 2009;21(4):561–70.PubMedCrossRefGoogle Scholar
  80. 80.
    Bottalico LA et al. Transforming growth factor-beta 1 inhibits scavenger receptor activity in THP-1 human macrophages. J Biol Chem. 1991;266(34):22866–71.PubMedGoogle Scholar
  81. 81.
    Sherry B et al. Induction of the chemokine beta peptides, MIP-1 alpha and MIP-1 beta, by lipopolysaccharide is differentially regulated by immunomodulatory cytokines gamma-IFN, IL-10, IL-4, and TGF-beta. Mol Med. 1998;4(10):648–57.PubMedCentralPubMedGoogle Scholar
  82. 82.
    Gong D et al. TGFbeta signaling plays a critical role in promoting alternative macrophage activation. BMC Immunol. 2012;13:31.PubMedCentralPubMedCrossRefGoogle Scholar
  83. 83.
    Cox A et al. A common coding variant in CASP8 is associated with breast cancer risk. Nat Genet. 2007;39(3):352–8.PubMedCrossRefGoogle Scholar
  84. 84.
    Krippl P et al. The L10P polymorphism of the transforming growth factor-beta 1 gene is not associated with breast cancer risk. Cancer Lett. 2003;201(2):181–4.PubMedCrossRefGoogle Scholar
  85. 85.
    Yang L, Pang Y, Moses HL. TGF-beta and immune cells: an important regulatory axis in the tumor microenvironment and progression. Trends Immunol. 2010;31(6):220–7.PubMedCentralPubMedCrossRefGoogle Scholar
  86. 86.
    Dumont N, Arteaga CL. Transforming growth factor-beta and breast cancer: tumor promoting effects of transforming growth factor-beta. Breast Cancer Res. 2000;2(2):125–32.PubMedCentralPubMedCrossRefGoogle Scholar
  87. 87.
    Pardali K, Moustakas A. Actions of TGF-beta as tumor suppressor and pro-metastatic factor in human cancer. Biochim Biophys Acta. 2007;1775(1):21–62.PubMedGoogle Scholar
  88. 88.
    Moustakas A et al. Mechanisms of TGF-beta signaling in regulation of cell growth and differentiation. Immunol Lett. 2002;82(1–2):85–91.PubMedCrossRefGoogle Scholar
  89. 89.
    Pierce Jr DF et al. Mammary tumor suppression by transforming growth factor beta 1 transgene expression. Proc Natl Acad Sci U S A. 1995;92(10):4254–8.PubMedCentralPubMedCrossRefGoogle Scholar
  90. 90.
    Siegel PM et al. Transforming growth factor beta signaling impairs Neu-induced mammary tumorigenesis while promoting pulmonary metastasis. Proc Natl Acad Sci U S A. 2003;100(14):8430–5.PubMedCentralPubMedCrossRefGoogle Scholar
  91. 91.
    Gorska AE et al. Transgenic mice expressing a dominant-negative mutant type II transforming growth factor-beta receptor exhibit impaired mammary development and enhanced mammary tumor formation. Am J Pathol. 2003;163(4):1539–49.PubMedCentralPubMedCrossRefGoogle Scholar
  92. 92.
    Bottinger EP et al. Transgenic mice overexpressing a dominant-negative mutant type II transforming growth factor beta receptor show enhanced tumorigenesis in the mammary gland and lung in response to the carcinogen 7,12-dimethylbenz-[a]-anthracene. Cancer Res. 1997;57(24):5564–70.PubMedGoogle Scholar
  93. 93.
    Forrester E et al. Effect of conditional knockout of the type II TGF-beta receptor gene in mammary epithelia on mammary gland development and polyomavirus middle T antigen induced tumor formation and metastasis. Cancer Res. 2005;65(6):2296–302.PubMedCrossRefGoogle Scholar
  94. 94.
    Bierie B et al. Transforming growth factor-beta regulates mammary carcinoma cell survival and interaction with the adjacent microenvironment. Cancer Res. 2008;68(6):1809–19.PubMedCrossRefGoogle Scholar
  95. 95.
    Yang L et al. Abrogation of TGF beta signaling in mammary carcinomas recruits Gr-1 + CD11b + myeloid cells that promote metastasis. Cancer Cell. 2008;13(1):23–35.PubMedCentralPubMedCrossRefGoogle Scholar
  96. 96.
    Muraoka RS et al. Increased malignancy of Neu-induced mammary tumors overexpressing active transforming growth factor beta1. Mol Cell Biol. 2003;23(23):8691–703.PubMedCentralPubMedCrossRefGoogle Scholar
  97. 97.
    Yang YA et al. Lifetime exposure to a soluble TGF-beta antagonist protects mice against metastasis without adverse side effects. J Clin Invest. 2002;109(12):1607–15.PubMedCentralPubMedCrossRefGoogle Scholar
  98. 98.
    Tan AR, Alexe G, Reiss M. Transforming growth factor-beta signaling: emerging stem cell target in metastatic breast cancer? Breast Cancer Res Treat. 2009;115(3):453–95.PubMedCentralPubMedCrossRefGoogle Scholar
  99. 99.
    Bhowmick NA et al. TGF-beta signaling in fibroblasts modulates the oncogenic potential of adjacent epithelia. Science. 2004;303(5659):848–51.PubMedCrossRefGoogle Scholar
  100. 100.
    Yadav A, Saini V, Arora S. MCP-1: chemoattractant with a role beyond immunity: a review. Clin Chim Acta. 2010;411(21–22):1570–9.PubMedCrossRefGoogle Scholar
  101. 101.
    Deshmane SL et al. Monocyte chemoattractant protein-1 (MCP-1): an overview. J Interferon Cytokine Res. 2009;29(6):313–26.PubMedCentralPubMedCrossRefGoogle Scholar
  102. 102.
    Cushing SD et al. Minimally modified low density lipoprotein induces monocyte chemotactic protein 1 in human endothelial cells and smooth muscle cells. Proc Natl Acad Sci U S A. 1990;87(13):5134–8.PubMedCentralPubMedCrossRefGoogle Scholar
  103. 103.
    Standiford TJ et al. Alveolar macrophage-derived cytokines induce monocyte chemoattractant protein-1 expression from human pulmonary type II-like epithelial cells. J Biol Chem. 1991;266(15):9912–8.PubMedGoogle Scholar
  104. 104.
    Matsushima K et al. Purification and characterization of a novel monocyte chemotactic and activating factor produced by a human myelomonocytic cell line. J Exp Med. 1989;169(4):1485–90.PubMedCrossRefGoogle Scholar
  105. 105.
    Yoshimura T et al. Purification and amino acid analysis of two human glioma-derived monocyte chemoattractants. J Exp Med. 1989;169(4):1449–59.PubMedCrossRefGoogle Scholar
  106. 106.
    Carr MW et al. Monocyte chemoattractant protein 1 acts as a T-lymphocyte chemoattractant. Proc Natl Acad Sci U S A. 1994;91(9):3652–6.PubMedCentralPubMedCrossRefGoogle Scholar
  107. 107.
    Allavena P et al. Induction of natural killer cell migration by monocyte chemotactic protein-1, −2 and −3. Eur J Immunol. 1994;24(12):3233–6.PubMedCrossRefGoogle Scholar
  108. 108.
    Fuentes ME et al. Controlled recruitment of monocytes and macrophages to specific organs through transgenic expression of monocyte chemoattractant protein-1. J Immunol. 1995;155(12):5769–76.PubMedGoogle Scholar
  109. 109.
    Lu B et al. Abnormalities in monocyte recruitment and cytokine expression in monocyte chemoattractant protein 1-deficient mice. J Exp Med. 1998;187(4):601–8.PubMedCentralPubMedCrossRefGoogle Scholar
  110. 110.
    Rutledge BJ et al. High level monocyte chemoattractant protein-1 expression in transgenic mice increases their susceptibility to intracellular pathogens. J Immunol. 1995;155(10):4838–43.PubMedGoogle Scholar
  111. 111.
    Ueno T et al. Significance of macrophage chemoattractant protein-1 in macrophage recruitment, angiogenesis, and survival in human breast cancer. Clin Cancer Res. 2000;6(8):3282–9.PubMedGoogle Scholar
  112. 112.
    O'Brien J et al. Alternatively activated macrophages and collagen remodeling characterize the postpartum involuting mammary gland across species. Am J Pathol. 2010;176(3):1241–55.PubMedCentralPubMedCrossRefGoogle Scholar
  113. 113.
    Glynn DJ, Hutchinson MR, Ingman WV. Toll-like receptor 4 regulates lipopolysaccharide-induced inflammation and lactation insufficiency in a mouse model of mastitis. Biol Reprod. 2014;90(5):91.PubMedCrossRefGoogle Scholar
  114. 114.
    Fujimoto H et al. Stromal MCP-1 in mammary tumors induces tumor-associated macrophage infiltration and contributes to tumor progression. Int J Cancer. 2009;125(6):1276–84.PubMedCrossRefGoogle Scholar
  115. 115.
    Arendt LM et al. Obesity promotes breast cancer by CCL2-mediated macrophage recruitment and angiogenesis. Cancer Res. 2013;73(19):6080–93.PubMedCrossRefGoogle Scholar
  116. 116.
    Ghilardi G et al. Breast cancer progression and host polymorphisms in the chemokine system: role of the macrophage chemoattractant protein-1 (MCP-1) -2518 G allele. Clin Chem. 2005;51(2):452–5.PubMedCrossRefGoogle Scholar
  117. 117.
    Rovin BH, Lu L, Saxena R. A novel polymorphism in the MCP-1 gene regulatory region that influences MCP-1 expression. Biochem Biophys Res Commun. 1999;259(2):344–8.PubMedCrossRefGoogle Scholar
  118. 118.
    Zafiropoulos A et al. Significant involvement of CCR2-64I and CXCL12-3a in the development of sporadic breast cancer. J Med Genet. 2004;41(5):e59.PubMedCentralPubMedCrossRefGoogle Scholar
  119. 119.
    Lu X, Kang Y. Chemokine (C-C motif) ligand 2 engages CCR2+ stromal cells of monocytic origin to promote breast cancer metastasis to lung and bone. J Biol Chem. 2009;284(42):29087–96.PubMedCentralPubMedCrossRefGoogle Scholar
  120. 120.
    Yoshimura T et al. Monocyte chemoattractant protein-1/CCL2 produced by stromal cells promotes lung metastasis of 4 T1 murine breast cancer cells. PLoS One. 2013;8(3):e58791.PubMedCentralPubMedCrossRefGoogle Scholar
  121. 121.
    Takahashi M et al. Chemokine CCL2/MCP-1 negatively regulates metastasis in a highly bone marrow-metastatic mouse breast cancer model. Clin Exp Metastasis. 2009;26(7):817–28.PubMedCrossRefGoogle Scholar
  122. 122.
    Granot Z et al. Tumor entrained neutrophils inhibit seeding in the premetastatic lung. Cancer Cell. 2011;20(3):300–14.PubMedCentralPubMedCrossRefGoogle Scholar
  123. 123.
    Li M et al. A role for CCL2 in both tumor progression and immunosurveillance. Oncoimmunology. 2013;2(7):e25474.PubMedCentralPubMedCrossRefGoogle Scholar
  124. 124.
    Khaled WT et al. The IL-4/IL-13/Stat6 signalling pathway promotes luminal mammary epithelial cell development. Development. 2007;134(15):2739–50.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  1. 1.School of Paediatrics and Reproductive HealthUniversity of AdelaideAdelaideAustralia
  2. 2.Robinson Research InstituteUniversity of AdelaideAdelaideAustralia
  3. 3.Discipline of Surgery, School of Medicine, The Queen Elizabeth HospitalUniversity of AdelaideWoodvilleAustralia

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