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Reviews in Endocrine and Metabolic Disorders

, Volume 8, Issue 3, pp 279–287 | Cite as

Stromal induction of breast cancer: Inflammation and invasion

  • Evette S. Radisky
  • Derek C. RadiskyEmail author
Article

Abstract

 Many investigations of cancer development have pursued the mechanisms by which genetic mutations stimulate tumor development through activation of oncogenes or loss of tumor suppressor genes. However, there is an increasing awareness that signals provided by the stroma can induce the genetic alterations that underlie tumor formation, can stimulate tumor growth and progression, and can dictate both therapeutic response and ultimate clinical outcome. This principle is particularly clear in breast cancer, where recent investigations using sophisticated three-dimensional cell culture models and transgenic animals have been used to define how altered signals from the microenvironment contribute to breakdown of tissue structure, increased cellular proliferation, and transition to the malignant phenotype. We review here recent studies identifying new roles for cancer-associated fibroblasts in promoting tumor progression, through stimulation of inflammatory pathways and induction of extracellular matrix-remodelling proteases. These studies identify mechanisms by which development of a reactive tumor stroma causes mammary hyperproliferation, progression to fibrosis, development of neoplasia, increasing invasiveness, and eventual metastasis, and how intervention in these processes may provide new avenues for therapy.

Keywords

Basement membrane Breast cancer Extracellular matrix Stromal-epithelial interactions Cancer microenvironment Fibroblasts Matrix metalloproteinases Branching morphogenesis 

References

  1. 1.
    Bissell MJ, Radisky DC. Putting tumours in context. Nat Rev Cancer 2001;1:46–54.PubMedCrossRefGoogle Scholar
  2. 2.
    Ronnov-Jessen L, Petersen OW, Koteliansky VE, Bissell MJ. The origin of the myofibroblasts in breast cancer. Recapitulation of tumor environment in culture unravels diversity and implicates converted fibroblasts and recruited smooth muscle cells. J Clin Invest 1995;95(2):859–73.PubMedCrossRefGoogle Scholar
  3. 3.
    Sternlicht MD, Werb Z. How matrix metalloproteinases regulate cell behavior. Annu Rev Cell Dev Biol. 2001;17:463–516.PubMedCrossRefGoogle Scholar
  4. 4.
    de Visser KE, Eichten A, Coussens LM. Paradoxical roles of the immune system during cancer development. Nat Rev Cancer 2006;6(1):24–37.PubMedCrossRefGoogle Scholar
  5. 5.
    Petersen OW, Nielsen HL, Gudjonsson T, Villadsen R, Rank F, Niebuhr E, et al. Epithelial to mesenchymal transition in human breast cancer can provide a nonmalignant stroma. Am J Pathol 2003;162(2):391–402.PubMedGoogle Scholar
  6. 6.
    Balkwill F, Charles KA, Mantovani A. Smoldering and polarized inflammation in the initiation and promotion of malignant disease. Cancer Cell 2005;7(3):211–7.PubMedCrossRefGoogle Scholar
  7. 7.
    Wiseman BS, Werb Z. Stromal effects on mammary gland development and breast cancer. Science 2002;296(5570):1046–9.PubMedCrossRefGoogle Scholar
  8. 8.
    Fata JE, Werb Z, Bissell MJ. Regulation of mammary gland branching morphogenesis by the extracellular matrix and its remodeling enzymes. Breast Cancer Res 2004;6(1):1–11.PubMedGoogle Scholar
  9. 9.
    Wiseman BS, Sternlicht MD, Lund LR, Alexander CM, Mott J, Bissell MJ, et al. Site-specific inductive and inhibitory activities of MMP-2 and MMP-3 orchestrate mammary gland branching morphogenesis. J Cell Biol 2003;162(6):1123–33.PubMedCrossRefGoogle Scholar
  10. 10.
    Thomasset N, Lochter A, Sympson C, Lund LR, Williams DR, Behrendtsen O, et al. Expression of autoactivated stromelysin-1 in mammary glands of transgenic mice leads to a reactive stroma during early development. Am J Pathol 1998;153(2):457–67.PubMedGoogle Scholar
  11. 11.
    Sternlicht MD, Lochter A, Sympson CJ, Huey B, Rougier J-P, Gray JW, et al. The stromal proteinase MMP3/stromelysin-1 promotes mammary carcinogenesis. Cell 1999;98(2):137–46.CrossRefGoogle Scholar
  12. 12.
    Derynck R, Akhurst RJ, Balmain A. TGF-beta signaling in tumor suppression and cancer progression. Nat Genet 2001;29(2):117–29.PubMedCrossRefGoogle Scholar
  13. 13.
    Smalley MJ, Dale TC. Wnt signaling and mammary tumorigenesis. J Mammary Gland Biol Neoplasia 2001;6(1):37–52.PubMedCrossRefGoogle Scholar
  14. 14.
    Politi K, Feirt N, Kitajewski J. Notch in mammary gland development and breast cancer. Semin Cancer Biol 2004;14(5):341–7.PubMedCrossRefGoogle Scholar
  15. 15.
    Kubo M, Nakamura M, Tasaki A, Yamanaka N, Nakashima H, Nomura M, et al. Hedgehog signaling pathway is a new therapeutic target for patients with breast cancer. Cancer Res 2004;64(17):6071–4.PubMedCrossRefGoogle Scholar
  16. 16.
    Campbell SM, Taha MM, Medina D, Rosen J. A clonal derivative of mammary epithelial cell line COMMA-D retains stem cell characteristics of unique morphological and functional heterogeneity. Exp Cell Res 1988;177(1):109–21.PubMedCrossRefGoogle Scholar
  17. 17.
    Barcellos-Hoff MH, Ravani SA. Irradiated mammary gland stroma promotes the expression of tumorigenic potential by unirradiated epithelial cells. Cancer Res 2000;60(5):1254–60.PubMedGoogle Scholar
  18. 18.
    Maffini MV, Soto AM, Calabro JM, Ucci A, Sonnenschein C. The stroma as a crucial target in rat mammary gland carcinogenesis. J Cell Sci 2004;117(Pt 8):1495–502.PubMedCrossRefGoogle Scholar
  19. 19.
    McDaniel SM, Rumer KK, Biroc SL, Metz RP, Singh M, Porter W, et al. Remodeling of the mammary microenvironment after lactation promotes breast tumor cell metastasis. Am J Pathol 2006;168(2):608–20.PubMedCrossRefGoogle Scholar
  20. 20.
    Parmar H, Young P, Emerman JT, Neve RM, Dairkee S, Cunha GR. A novel method for growing human breast epithelium in vivo using mouse and human mammary fibroblasts. Endocrinology 2002;143(12):4886–96.PubMedCrossRefGoogle Scholar
  21. 21.
    Kuperwasser C, Chavarria T, Wu M, Magrane G, Gray JW, Carey L, et al. Reconstruction of functionally normal and malignant human breast tissues in mice. Proc Natl Acad Sci U S A 2004;101(14):4966–71.PubMedCrossRefGoogle Scholar
  22. 22.
    Desmouliere A, Chaponnier C, Gabbiani G. Tissue repair, contraction, and the myofibroblast. Wound Repair Regen 2005;13(1):7–12.PubMedCrossRefGoogle Scholar
  23. 23.
    Kalluri R, Zeisberg M. Fibroblasts in cancer. Nat Rev Cancer 2006;6(5):392–401.PubMedCrossRefGoogle Scholar
  24. 24.
    Radisky DC, Kenny PA, Bissell MJ. Fibrosis and cancer: Do myofibroblasts come also from epithelial cells via EMT? J Cell Biochem 2007;DOI  10.1002/jcb.21186.
  25. 25.
    Paszek MJ, Zahir N, Johnson KR, Lakins JN, Rozenberg GI, Gefen A, et al. Tensional homeostasis and the malignant phenotype. Cancer Cell 2005;8(3):241–54.PubMedCrossRefGoogle Scholar
  26. 26.
    Desmouliere A, Guyot C, Gabbiani G. The stroma reaction myofibroblast: a key player in the control of tumor cell behavior. Int J Dev Biol 2004;48(5–6):509–17.PubMedCrossRefGoogle Scholar
  27. 27.
    Orimo A, Gupta PB, Sgroi DC, Arenzana-Seisdedos F, Delaunay T, Naeem R, et al. Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion. Cell 2005;121(3):335–48.PubMedCrossRefGoogle Scholar
  28. 28.
    Balkwill F. Cancer and the chemokine network. Nat Rev Cancer 2004;4(7):540–50.PubMedCrossRefGoogle Scholar
  29. 29.
    Muller A, Homey B, Soto H, Ge N, Catron D, Buchanan ME, et al. Involvement of chemokine receptors in breast cancer metastasis. Nature 2001;410(6824):50–6.PubMedCrossRefGoogle Scholar
  30. 30.
    Chen Y, Stamatoyannopoulos G, Song CZ. Down-regulation of CXCR4 by inducible small interfering RNA inhibits breast cancer cell invasion in vitro. Cancer Res 2003;63(16):4801–4.PubMedGoogle Scholar
  31. 31.
    Boire A, Covic L, Agarwal A, Jacques S, Sherifi S, Kuliopulos A. PAR1 is a matrix metalloprotease-1 receptor that promotes invasion and tumorigenesis of breast cancer cells. Cell 2005;120(3):303–13.PubMedCrossRefGoogle Scholar
  32. 32.
    Ossovskaya VS, Bunnett NW. Protease-activated receptors: contribution to physiology and disease. Physiol Rev 2004;84(2):579–621.PubMedCrossRefGoogle Scholar
  33. 33.
    Perbal B. CCN proteins: multifunctional signalling regulators. Lancet 2004;363(9402):62–4.PubMedCrossRefGoogle Scholar
  34. 34.
    Pendurthi UR, Allen KE, Ezban M, Rao LVM. Factor VIIa and thrombin induce the expression of Cyr61 and connective tissue growth factor, extracellular matrix signaling proteins that could act as possible downstream mediators in factor VIIa x tissue factor-induced signal transduction. J Biol Chem 2000;275(19):14632–41.PubMedCrossRefGoogle Scholar
  35. 35.
    Green KA, Lund LR. ECM degrading proteases and tissue remodelling in the mammary gland. BioEssays 2005;27(9):894–903.PubMedCrossRefGoogle Scholar
  36. 36.
    Reich R, Thompson EW, Iwamoto Y, Martin GR, Deason JR, Fuller GC, et al. Effects of inhibitors of plasminogen activator, serine proteinases, and collagenase IV on the invasion of basement membranes by metastatic cells. Cancer Res 1988;48(12):3307–12.PubMedGoogle Scholar
  37. 37.
    Overall CM, Kleifeld O. Tumour microenvironment—opinion: validating matrix metalloproteinases as drug targets and anti-targets for cancer therapy. Nat Rev Cancer 2006;6(3):227–39.PubMedCrossRefGoogle Scholar
  38. 38.
    Sameni M, Dosescu J, Moin K, Sloane BF. Functional imaging of proteolysis: stromal and inflammatory cells increase tumor proteolysis. Mol Imaging 2003;2(3):159–75.PubMedCrossRefGoogle Scholar
  39. 39.
    Almholt K, Green KA, Juncker-Jensen A, Schnack B, Lund LR Romer J. Extracellular Proteolysis in Transgenic Mouse Models of Breast Cancer. J Mammary Gland Biol Neoplasia 2007;12(1):83–97.PubMedCrossRefGoogle Scholar
  40. 40.
    Egeblad M, Werb Z. New functions for the matrix metalloproteinases in cancer progression. Nat Rev Cancer 2002;2(3):161–74.PubMedCrossRefGoogle Scholar
  41. 41.
    Duffy MJ. The urokinase plasminogen activator system: role in malignancy. Curr Pharm Des 2004;10(1):39–49.PubMedCrossRefGoogle Scholar
  42. 42.
    Sidenius N, Blasi F. The urokinase plasminogen activator system in cancer: recent advances and implication for prognosis and therapy. Cancer Metastasis Rev 2003;22(2–3):205–22.PubMedCrossRefGoogle Scholar
  43. 43.
    Han B, Nakamura M, Mori I, Nakamura Y, Kakudo K. Urokinase-type plasminogen activator system and breast cancer (Review). Oncol Rep 2005;14(1):105–12.PubMedGoogle Scholar
  44. 44.
    Almholt K, Lund LR, Rygaard J, Nielsen BS, Dano K, Romer J, et al. Reduced metastasis of transgenic mammary cancer in urokinase-deficient mice. Int J Cancer 2005;113(4):525–32.PubMedCrossRefGoogle Scholar
  45. 45.
    Pedersen TX, Pennington CJ, Almholt K, Christensen IJ, Nielsen BS, Edwards DR, et al. Extracellular protease mRNAs are predominantly expressed in the stromal areas of microdissected mouse breast carcinomas. Carcinogenesis 2005;26(7):1233–40.PubMedCrossRefGoogle Scholar
  46. 46.
    Toole BP. Emmprin (CD147), a cell surface regulator of matrix metalloproteinase production and function. Curr Top Dev Biol 2003;54:371–89.PubMedCrossRefGoogle Scholar
  47. 47.
    Quemener C, Gabison EE, Naïme B, Lescaille G, Bougatef F, Podgorniak MP, et al. Extracellular matrix metalloproteinase inducer up-regulates the urokinase-type plasminogen activator system promoting tumor cell invasion. Cancer Res 2007;67(1):9–15.PubMedCrossRefGoogle Scholar
  48. 48.
    de Mascarel I, Macgrogan G, Mathoulin-Pelissie S, Sowbeyran I, Picot V, Coindre J-M. Breast ductal carcinoma in situ with microinvasion: a definition supported by a long-term study of 1248 serially sectioned ductal carcinomas. Cancer 2002;94(8):2134–42.PubMedCrossRefGoogle Scholar
  49. 49.
    Nielsen BS, Rank F, Illemann M, Lund LR, Dano K. Stromal cells associated with early invasive foci in human mammary ductal carcinoma in situ coexpress urokinase and urokinase receptor. Int J Cancer 2007;120(10):2086–95.PubMedCrossRefGoogle Scholar
  50. 50.
    Nielsen BS, Rank F, Lopez JM, Balbin M, Vizoso F, Lund LR, et al. Collagenase-3 expression in breast myofibroblasts as a molecular marker of transition of ductal carcinoma in situ lesions to invasive ductal carcinomas. Cancer Res 2001;61(19):7091–100.PubMedGoogle Scholar
  51. 51.
    Friedl P, Wolf K. Tumour-cell invasion and migration: diversity and escape mechanisms. Nat Rev Cancer 2003;3(5):362–74.PubMedCrossRefGoogle Scholar
  52. 52.
    Wolf K, Mazo I, Leung H, Engelke K, von Andrian UH, Deryugina EI, et al. Compensation mechanism in tumor cell migration: mesenchymal-amoeboid transition after blocking of pericellular proteolysis. J Cell Biol 2003;160(2):267–77.PubMedCrossRefGoogle Scholar
  53. 53.
    Hotary K, Li X-Y, Allen E, Stevens SL, Weiss SJ. A cancer cell metalloprotease triad regulates the basement membrane transmigration program. Genes Dev 2006;20(19):2673–86.PubMedCrossRefGoogle Scholar
  54. 54.
    Jessani N, Liu Y, Humphrey M, Cravalt BF. Enzyme activity profiles of the secreted and membrane proteome that depict cancer cell invasiveness. Proc Natl Acad Sci U S A 2002;99(16):10335–40.PubMedCrossRefGoogle Scholar
  55. 55.
    Lafleur MA, Drew AF, de Sonsa EL, Blick T, Bills M, Walker EC, et al. Upregulation of matrix metalloproteinases (MMPs) in breast cancer xenografts: a major induction of stromal MMP-13. Int J Cancer 2005;114(4):544–54.PubMedCrossRefGoogle Scholar
  56. 56.
    Schmidt-Kittler O, Ragg T, Daskalakis A, Granzow M, Ahr A, Blankenstein TJF, et al. From latent disseminated cells to overt metastasis: genetic analysis of systemic breast cancer progression. Proc Natl Acad Sci U S A 2003;100(13):7737–42.PubMedCrossRefGoogle Scholar
  57. 57.
    Itoh Y, Seiki M. MT1-MMP: a potent modifier of pericellular microenvironment. J Cell Physiol 2006;206(1):1–8.PubMedCrossRefGoogle Scholar
  58. 58.
    Artym VV, Zhang Y, Seillier-Moiseiwitsch F, Yamada KM, Mueller S. Dynamic interactions of cortactin and membrane type 1 matrix metalloproteinase at invadopodia: defining the stages of invadopodia formation and function. Cancer Res 2006;66(6):3034–43.PubMedCrossRefGoogle Scholar
  59. 59.
    Nakahara H, Howard L, Thompson EW, Sato H, Seiki M, Yen Y, et al. Transmembrane/cytoplasmic domain-mediated membrane type 1-matrix metalloprotease docking to invadopodia is required for cell invasion. Proc Natl Acad Sci U S A 1997;94(15):7959–64.PubMedCrossRefGoogle Scholar
  60. 60.
    Mylona E, Nomikos A, Magkou C, Kamberou M, Papassideri I, Keramopoulos A, et al. The clinicopathological and prognostic significance of membrane type 1 matrix metalloproteinase (MT1-MMP) and MMP-9 according to their localization in invasive breast carcinoma. Histopathology 2007;50(3):338–47.PubMedCrossRefGoogle Scholar
  61. 61.
    Okada A, Bellocq JP, Rouyer N, Chenard MP, Rio MC, Chambon P, et al. Membrane-type matrix metalloproteinase (MT-MMP) gene is expressed in stromal cells of human colon, breast, and head and neck carcinomas. Proc Natl Acad Sci U S A 1995;92(7):2730–4.PubMedCrossRefGoogle Scholar
  62. 62.
    Szabova L, Yamada S, Birkedal-Hansen H, Holmbeck K. Expression pattern of four membrane-type matrix metalloproteinases in the normal and diseased mouse mammary gland. J Cell Physiol 2005;205(1):123–32.PubMedCrossRefGoogle Scholar
  63. 63.
    Bisson C, Blacher S, Polette M, Blanc J-F, Kebers F, Desreux J, et al. Restricted expression of membrane type 1-matrix metalloproteinase by myofibroblasts adjacent to human breast cancer cells. Int J Cancer 2003;105(1):7–13.PubMedCrossRefGoogle Scholar
  64. 64.
    Golubkov VS, Strongin AY. Proteolysis-driven oncogenesis. Cell Cycle 2007;6(2):147–50.PubMedGoogle Scholar
  65. 65.
    Lengauer C, Kinzler KW, Vogelstein B. Genetic instabilities in human cancers. Nature 1998;396(6712):643–9.PubMedCrossRefGoogle Scholar
  66. 66.
    Radisky DC, Bissell MJ. Matrix metalloproteinase-induced genomic instability. Curr Opin Genet Dev 2006;16(1):45–50.PubMedCrossRefGoogle Scholar
  67. 67.
    Radisky DC, Levy DD, Littlepage LE, Liu H, Nelson CM, Fata JE, et al. Rac1b and reactive oxygen species mediate MMP-3-induced EMT and genomic instability. Nature 2005;436(7047):123–7.PubMedCrossRefGoogle Scholar
  68. 68.
    Golubkov VS, Chekanov AV, Doxsey SJ, Strongin AY. Centrosomal pericentrin is a direct cleavage target of membrane type-1 matrix metalloproteinase in humans but not in mice: potential implications for tumorigenesis. J Biol Chem 2005;280(51):42237–41.PubMedCrossRefGoogle Scholar
  69. 69.
    Golubkov VS, Chekanov AV, Savinov AY, Rozanov DV, Golubkova NV, Strongin AY. Membrane type-1 matrix metalloproteinase confers aneuploidy and tumorigenicity on mammary epithelial cells. Cancer Res 2006;66(21):10460–5.PubMedCrossRefGoogle Scholar
  70. 70.
    Fujiwara T, Bandi M, Nitta M, Ivanova EV, Bronson RT, Pellman D. Cytokinesis failure generating tetraploids promotes tumorigenesis in p53-null cells. Nature 2005;437(7061):1043–7.PubMedCrossRefGoogle Scholar
  71. 71.
    Ellsworth DL, Liebman MN, Hooke JA, Shriver CD. Genomic instability in histologically normal breast tissues: implications for carcinogenesis. Lancet Oncol 2004;5(12):753–8.PubMedCrossRefGoogle Scholar
  72. 72.
    Albini A, Sporn MB. The tumour microenvironment as a target for chemoprevention. Nat Rev Cancer 2007;7(2):139–47.PubMedCrossRefGoogle Scholar
  73. 73.
    Joyce JA. Therapeutic targeting of the tumor microenvironment. Cancer Cell 2005;7(6):513–20.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  1. 1.Mayo Clinic Cancer CenterJacksonvilleUSA

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