Skip to main content

Advertisement

Log in

Molecular interactions between breast cancer cells and the bone microenvironment drive skeletal metastases

  • Published:
Cancer and Metastasis Reviews Aims and scope Submit manuscript

Abstract

Breast cancer cells preferentially spread to bone. Bone metastases are currently incurable and therefore better treatments need to be developed. Metastasis is an inefficient, multi-step process. Specific aspects of both breast cancer cells and the bone microenvironment contribute to the development of bone metastases. Breast cancers express chemokine receptors, integrins, cadherins, and bone-resorbing and bone-forming factors that contribute to the successful and preferential spread of tumor to bone. Bone is rich in growth factors and cell types that make it a hospitable environment for breast cancer growth. Once breast cancer cells enter the bone, a highly complex vicious cycle develops, in which breast cancer cells secrete factors that act on bone cells and other cells within the bone (stem cells, T cells, platelets, adipocytes, fibroblasts, and endothelial cells), causing them to secrete factors that act on adjacent cancer cells. The steps in the metastatic cascade and the vicious cycle within bone offer unique targets for adjuvant treatments to treat and cure bone metastases.

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.

Similar content being viewed by others

References

  1. Coleman, R. E. (1997). Skeletal complications of malignancy. Cancer, 80, 1588–1594.

    PubMed  CAS  Google Scholar 

  2. Kozlow, W., & Guise, T. A. (2005). Breast cancer metastasis to bone: Mechanisms of osteolysis and implications for therapy. Journal of Mammary Gland Biology and Neoplasia, 10, 169–180.

    PubMed  Google Scholar 

  3. Boyce, B. F., Yoneda, T., & Guise, T. A. (1999). Factors regulating the growth of metastatic cancer in bone. Endocrine Related Cancer, 6, 333–347.

    PubMed  CAS  Google Scholar 

  4. Clines, G. A., & Guise, T. A. (2005). Hypercalcaemia of malignancy and basic research on mechanisms responsible for osteolytic and osteoblastic metastasis to bone. Endocrine Related Cancer, 12, 549–583.

    PubMed  CAS  Google Scholar 

  5. Fidler, I. J. (2003). The pathogenesis of cancer metastasis: The ‘seed and soil’ hypothesis revisited. Nature Reviews. Cancer, 3, 453–458.

    PubMed  CAS  Google Scholar 

  6. Paget, S. (1989). The distribution of secondary growths in cancer of the breast. 1889. Cancer Metastasis Reviews, 8, 98–101.

    Google Scholar 

  7. Walther, H. E. (1948). Krebsmatastasen. Switzerland: Bens Schwabe Verlag.

    Google Scholar 

  8. Cifuentes, N., & Pickren, J. W. (1979). Metastases from carcinoma of mammary gland: An autopsy study. Journal of Surgical Oncology, 11, 193–205.

    PubMed  CAS  Google Scholar 

  9. Weiss, L. (1992). Comments on hematogenous metastatic patterns in humans as revealed by autopsy. Clinical & Experimental Metastasis, 10, 191–199.

    CAS  Google Scholar 

  10. Coleman, R. E., & Rubens, R. D. (1987). The clinical course of bone metastases from breast cancer. British Journal of Cancer, 55, 61–66.

    PubMed  CAS  Google Scholar 

  11. Kang, Y., Siegel, P. M., Shu, W., Drobnjak, M., Kakonen, S. M., Cordon-Cardo C., et al. (2003). A multigenic program mediating breast cancer metastasis to bone. Cancer Cell, 3, 537–549.

    PubMed  CAS  Google Scholar 

  12. van der Pluijm, G., Sijmons, B., Vloedgraven, H., Deckers, M., Papapoulos, S., & Lowik, C. (2001). Monitoring metastatic behavior of human tumor cells in mice with species-specific polymerase chain reaction: Elevated expression of angiogenesis and bone resorption stimulators by breast cancer in bone metastases. Journal of Bone and Mineral Research, 16, 1077–1091.

    PubMed  Google Scholar 

  13. Luker, K. E., & Luker, G. D. (2006). Functions of CXCL12 and CXCR4 ifsn breast cancer. Cancer Letter, 238, 30–41.

    CAS  Google Scholar 

  14. Shim, H., Lau, S. K., Devi, S., Yoon, Y., Cho, H. T., & Liang, Z. (2006). Lower expression of CXCR4 in lymph node metastases than in primary breast cancers: Potential regulation by ligand-dependent degradation and HIF-1alpha. Biochemical and Biophysical Research Communications, 346, 252–258.

    PubMed  CAS  Google Scholar 

  15. Salvucci, O., Bouchard, A., Baccarelli, A., Deschenes, J., Sauter, G., Simon, R., et al. (2006). The role of CXCR4 receptor expression in breast cancer: A large tissue microarray study. Breast Cancer Research and Treatment, 97, 275–283.

    PubMed  CAS  Google Scholar 

  16. Sloan, E. K., & Anderson, R. L. (2002). Genes involved in breast cancer metastasis to bone. Cellular and Molecular Life Sciences, 59, 1491–1502.

    PubMed  CAS  Google Scholar 

  17. Muller, A., Homey, B., Soto, H., Ge, N., Catron, D., Buchanan, M. E., et al. (2001). Involvement of chemokine receptors in breast cancer metastasis. Nature, 410, 50–56.

    PubMed  CAS  Google Scholar 

  18. Sun, Y. X., Schneider, A., Jung, Y., Wang, J., Dai, J., Wang, J., et al. (2005). Skeletal localization and neutralization of the SDF-1(CXCL12)/CXCR4 axis blocks prostate cancer metastasis and growth in osseous sites in vivo. Journal of Bone and Mineral Research, 20, 318–329.

    PubMed  CAS  Google Scholar 

  19. Liang, Z., Wu, T., Lou, H., Yu, X., Taichman, R. S., Lau, S. K., et al. (2004). Inhibition of breast cancer metastasis by selective synthetic polypeptide against CXCR4. Cancer Research, 64, 4302–4308.

    PubMed  CAS  Google Scholar 

  20. Liang, Z., Yoon, Y., Votaw, J., Goodman, M. M., Williams, L., & Shim, H. (2005). Silencing of CXCR4 blocks breast cancer metastasis. Cancer Research, 65, 967–971.

    PubMed  CAS  Google Scholar 

  21. Leonard, J. T., & Roy, K. (2006). The HIV entry inhibitors revisited. Current Medicinal Chemistry, 13, 911–934.

    PubMed  CAS  Google Scholar 

  22. Harms, J. F., Welch, D. R., Samant, R. S., Shevde, L. A., Miele, M. E., Babu, G. R., et al. (2004). A small molecule antagonist of the alpha(v)beta3 integrin suppresses MDA-MB-435 skeletal metastasis. Clinical & Experimental Metastasis, 21, 119–128.

    CAS  Google Scholar 

  23. Cacciari, B., & Spalluto, G. (2005). Non peptidic alphavbeta3 antagonists: Recent developments. Current Medicinal Chemistry, 12, 51–70.

    PubMed  CAS  Google Scholar 

  24. Liapis, H., Flath, A., & Kitazawa, S. (1996). Integrin alpha V beta 3 expression by bone-residing breast cancer metastases. Diagnostic Molecular Pathology, 5, 127–135.

    PubMed  CAS  Google Scholar 

  25. Felding-Habermann, B., O’Toole, T. E., Smith, J. W., Fransvea, E., Ruggeri, Z. M., Ginsberg, M. H., et al. (2001). Integrin activation controls metastasis in human breast cancer. Proceedings of the National Academy of Sciences of the United States of America, 98, 1853–1858.

    PubMed  CAS  Google Scholar 

  26. Sloan, E. K., Pouliot, N., Stanley, K. L., Chia, J., Moseley, J. M., Hards, D. K., et al. (2006). Tumor-specific expression of alphavbeta3 integrin promotes spontaneous metastasis of breast cancer to bone. Breast Cancer Research, 8, R20.

    PubMed  Google Scholar 

  27. Beekman, K. W., Colevas, A. D., Cooney, K., Dipaola, R., Dunn, R. L., Gross, M., et al. (2006). Phase II evaluations of cilengitide in asymptomatic patients with androgen-independent prostate cancer: Scientific rationale and study design. Clinical Genitourinary Cancer, 4, 299–302.

    PubMed  CAS  Google Scholar 

  28. Yoneda, T., & Hiraga, T. (2005). Crosstalk between cancer cells and bone microenvironment in bone metastasis. Biochemical and Biophysical Research Communications, 328, 679–687.

    PubMed  CAS  Google Scholar 

  29. Mbalaviele, G., Dunstan, C. R., Sasaki, A., Williams, P. J., Mundy, G. R., & Yoneda, T. (1996). E-cadherin expression in human breast cancer cells suppresses the development of osteolytic bone metastases in an experimental metastasis model. Cancer Research, 56, 4063–4070.

    PubMed  CAS  Google Scholar 

  30. Hazan, R. B., Phillips, G. R., Qiao, R. F., Norton, L., & Aaronson, S. A. (2000). Exogenous expression of N-cadherin in breast cancer cells induces cell migration, invasion, and metastasis. Journal of Cell Biology, 148, 779–790.

    PubMed  CAS  Google Scholar 

  31. Bachmeier, B. E., Nerlich, A. G., Lichtinghagen, R., & Sommerhoff, C. P. (2001). Matrix metalloproteinases (MMPs) in breast cancer cell lines of different tumorigenicity. Anticancer Research, 21, 3821–3828.

    PubMed  CAS  Google Scholar 

  32. Nakopoulou, L., Tsirmpa, I., Alexandrou, P., Louvrou, A., Ampela, C., Markaki, S., et al. (2003). MMP-2 protein in invasive breast cancer and the impact of MMP-2/TIMP-2 phenotype on overall survival. Breast Cancer Research and Treatment, 77, 145–155.

    PubMed  CAS  Google Scholar 

  33. Zhao, W., Byrne, M. H., Boyce., B. F., & Krane, S. M. (1999). Bone resorption induced by parathyroid hormone is strikingly diminished in collagenase-resistant mutant mice. Journal of Clinical Investigation, 103, 517–524.

    PubMed  CAS  Google Scholar 

  34. Coussens, L. M., Fingleton, B., & Matrisian, L. M. (2002). Matrix metalloproteinase inhibitors and cancer: Trials and tribulations. Science, 295, 2387–2392.

    PubMed  CAS  Google Scholar 

  35. Overall, C. M., & Lopez-Otin, C. (2002). Strategies for MMP inhibition in cancer: Innovations for the post-trial era. Nature Reviews. Cancer, 2, 657–672.

    PubMed  CAS  Google Scholar 

  36. Guise, T. A., Kozlow, W. M., Heras-Herzig, A., Padalecki, S. S., Yin, J. J., & Chirgwin, J. M. (2005). Molecular mechanisms of breast cancer metastases to bone. Clinical Breast Cancer, 5 (Suppl), S46–53.

    Article  PubMed  CAS  Google Scholar 

  37. Abou-Samra, A. B., Juppner, H., Force, T., Freeman, M. W., Kong, X. F., Schipani, E., et al. (1992). Expression cloning of a common receptor for parathyroid hormone and parathyroid hormone-related peptide from rat osteoblast-like cells: A single receptor stimulates intracellular accumulation of both cAMP and inositol trisphosphates and increases intracellular free calcium. Proceedings of the National Academy of Sciences of the United States of America, 89, 2732–2736.

    PubMed  CAS  Google Scholar 

  38. Pierroz, D. D., Bouxsein, M. L., Rizzoli, R., & Ferrari, S. L. (2006). Combined treatment with a beta-blocker and intermittent PTH improves bone mass and microarchitecture in ovariectomized mice. Bone, 39, 260–267.

    PubMed  CAS  Google Scholar 

  39. Guise, T. A., Yin, J. J., Taylor, S. D., Kumagai, Y., Dallas, M., Boyce, B. F., et al. (1996). Evidence for a causal role of parathyroid hormone-related protein in the pathogenesis of human breast cancer-mediated osteolysis. Journal of Clinical Investigation, 98, 1544–1549.

    PubMed  CAS  Google Scholar 

  40. Thomas, R. J., Guise, T. A., Yin, J. J., Elliott, J., Horwood, N. J., Martin, T. J., et al. (1999). Breast cancer cells interact with osteoblasts to support osteoclast formation. Endocrinology, 140, 4451–4458.

    PubMed  CAS  Google Scholar 

  41. Henderson, M., Danks, J., Moseley, J., Slavin, J., Harris, T., McKinlay, M., et al. (2001). Parathyroid hormone-related protein production by breast cancers, improved survival, and reduced bone metastases. Journal of the National Cancer Institute, 93, 234–237.

    PubMed  CAS  Google Scholar 

  42. de la Mata, J., Uy, H. L., Guise, T. A., Story, B., Boyce, B. F., Mundy, G. R., et al. (1995). Interleukin-6 enhances hypercalcemia and bone resorption mediated by parathyroid hormone-related protein in vivo. Journal of Clinical Investigation, 95, 2846–2852.

    PubMed  Google Scholar 

  43. Kakonen, S., Kang, Y., Carreon, M., Niewolna, M., Kakonen, R., Chirgwin, J., et al. (2002). Breast cancer cell lines selected from bone metastases have greater metastatic capacity and express increased vascular endothelial growth factor (VEGF), interleukin-11 (IL-11), and parathyroild hormone-related protein (PTHrP) “abstract”. Journal of Bone and Mineral Research, 17, M060.

    Google Scholar 

  44. Bendre, M. S., Margulies, A. G., Walser, B., Akel, N. S., Bhattacharrya, S., Skinner, R. A., et al. (2005). Tumor-derived interleukin-8 stimulates osteolysis independent of the receptor activator of nuclear factor-kappaB ligand pathway. Cancer Research, 65, 11001–11009.

    PubMed  CAS  Google Scholar 

  45. Yin, J. J., Mohammad, K. S., Kakonen, S. M., Harris, S., Wu-Wong, J. R., Wessale, J. L., et al. (2003). A causal role for endothelin-1 in the pathogenesis of osteoblastic bone metastases. Proceedings of the National Academy of Sciences of the United States of America, 100, 10954–10959.

    PubMed  CAS  Google Scholar 

  46. Chirgwin, J. M., Mohammad, K. S., & Guise, T. A. (2004). Tumor–bone cellular interactions in skeletal metastases. Journal of Musculoskeletal & Neuronal Interactions, 4, 308–318.

    CAS  Google Scholar 

  47. Semenza, G. L. (2003). Targeting HIF-1 for cancer therapy. Nature Reviews. Cancer, 3, 721–732.

    PubMed  CAS  Google Scholar 

  48. Yin, J. J., Selander, K., Chirgwin, J. M., Dallas, M., Grubbs, B. G., Wieser, R., et al. (1999). TGF-beta signaling blockade inhibits PTHrP secretion by breast cancer cells and bone metastases development. Journal of Clinical Investigation, 103, 197–206.

    PubMed  CAS  Google Scholar 

  49. van ’t Veer, L. J., Dai, H., van de Vijver, M. J., He, Y. D., Hart, A. A., Mao, M., et al. (2002). Gene expression profiling predicts clinical outcome of breast cancer. Nature, 415, 530–536, 2002.

    Google Scholar 

  50. Yoneda, T., Williams, P. J., Hiraga, T., Niewolna, M., & Nishimura, R. (2001). A bone-seeking clone exhibits different biological properties from the MDA-MB-231 parental human breast cancer cells and a brain-seeking clone in vivo and in vitro. Journal of Bone and Mineral Research, 16, 1486–1495.

    PubMed  CAS  Google Scholar 

  51. Myoui, A., Nishimura, R., Williams, P. J., Hiraga, T., Tamura, D., Michigami, T., et al. (2003). C-SRC tyrosine kinase activity is associated with tumor colonization in bone and lung in an animal model of human breast cancer metastasis. Cancer Research, 63, 5028–5033.

    PubMed  CAS  Google Scholar 

  52. Rucci, N., Recchia, I., Angelucci, A., Alamanou, M., Del Fattore, A., Fortunati, D., et al. (2006). Inhibition of protein kinase c-Src reduces the incidence of breast cancer metastases and increases survival in mice: Implications for therapy. Journal of Pharmacology and Experimental Therapeutics, 318, 161–172.

    PubMed  CAS  Google Scholar 

  53. Shakespeare, W. C., Metcalf, C. A., 3rd, Wang, Y., Sundaramoorthi, R., Keenan, T., Weigele, M., et al. (2003). Novel bone-targeted Src tyrosine kinase inhibitor drug discovery. Current Opinion in Drug Discovery and Development, 6, 729–741.

    CAS  Google Scholar 

  54. Alberts, B., Johnson, A., Lewis, J., Raff, M., Roberts, K., & Walter, P. (2002). Molecular Biology of THE CELL: (4th ed., pp. 1259–1312). New York: Garland Science.

    Google Scholar 

  55. Hauschka, P. V., Mavrakos, A. E., Iafrati, M. D., Doleman, S. E., & Klagsbrun, M. (1986). Growth factors in bone matrix. Isolation of multiple types by affinity chromatography on heparin-Sepharose. Journal of Biological Chemistry, 261, 12665–12674.

    PubMed  CAS  Google Scholar 

  56. Parisi, M. S., Gazzerro, E., Rydziel, S., & Canalis, E. (2006). Expression and regulation of CCN genes in murine osteoblasts. Bone, 38, 671–677.

    PubMed  CAS  Google Scholar 

  57. Simonet, W. S., Lacey, D. L., Dunstan, C. R., Kelley, M., Chang, M. S., Luthy, R., et al. (1997). Osteoprotegerin: A novel secreted protein involved in the regulation of bone density. Cell, 89, 309–319.

    PubMed  CAS  Google Scholar 

  58. Cornish, J., Naot, D., & Reid, I. R. (2003). Adrenomedullin—A regulator of bone formation. Regulatory Peptides, 112, 79–86.

    PubMed  CAS  Google Scholar 

  59. Rifas, L., Halstead, L. R., Peck, W. A., Avioli, L. V., & Welgus, H. G. (1989). Human osteoblasts in vitro secrete tissue inhibitor of metalloproteinases and gelatinase but not interstitial collagenase as major cellular products. Journal of Clinical Investigation, 84, 686–694.

    PubMed  CAS  Google Scholar 

  60. Harada, S., Nagy, J. A., Sullivan, K. A., Thomas, K. A., Endo, N., Rodan, G. A., et al. (1994). Induction of vascular endothelial growth factor expression by prostaglandin E2 and E1 in osteoblasts. Journal of Clinical Investigation, 93, 2490–2496.

    Article  PubMed  CAS  Google Scholar 

  61. Felix, R., Halasy-Nagy, J., Wetterwald, A., Cecchini, M. G., Fleisch, H., & Hofstetter, W. (1996). Synthesis of membrane- and matrix-bound colony-stimulating factor-1 by cultured osteoblasts. Journal of Cellular Physiology, 166, 311–322.

    PubMed  CAS  Google Scholar 

  62. Schmidt, C., Steinbach, G., Decking, R., Claes, L. E., Ignatius, A. A. (2003). IL-6 and PGE2 release by human osteoblasts on implant materials. Biomaterials, 24, 4191–4196.

    PubMed  CAS  Google Scholar 

  63. Taichman, R., Reilly, M., Verma, R., Ehrenman, K., & Emerson, S. (2001). Hepatocyte growth factor is secreted by osteoblasts and cooperatively permits the survival of haematopoietic progenitors. British Journal of Haematology, 112, 438–448.

    PubMed  CAS  Google Scholar 

  64. Kostenuik, P. J., & Shalhoub, V. (2001). Osteoprotegerin: A physiological and pharmacological inhibitor of bone resorption. Current Pharmaceutical Design, 7, 613–635.

    PubMed  CAS  Google Scholar 

  65. Yoshiko, Y., Son, A., Maeda, S., Igarashi, A., Takano, S., Hu, J., et al. (1999). Evidence for stanniocalcin gene expression in mammalian bone. Endocrinology, 140, 1869–1874.

    PubMed  CAS  Google Scholar 

  66. Dallas, S. L., Rosser, J. L., Mundy, G. R., & Bonewald, L. F. (2002). Proteolysis of latent transforming growth factor-beta (TGF-beta)-binding protein-1 by osteoclasts. A cellular mechanism for release of TGF-beta from bone matrix. Journal of Biological Chemistry, 277, 21352–21360.

    PubMed  CAS  Google Scholar 

  67. Wakefield, L. M., & Roberts, A. B. (2002). TGF-beta signaling: Positive and negative effects on tumorigenesis. Current Opinion in Genetics and Development, 12, 22–29.

    PubMed  CAS  Google Scholar 

  68. Kakonen, S. M., Selander, K. S., Chirgwin, J. M., Yin, J. J., Burns, S., Rankin, W. A., et al. (2002). Transforming growth factor-beta stimulates parathyroid hormone-related protein and osteolytic metastases via Smad and mitogen-activated protein kinase signaling pathways. Journal of Biological Chemistry, 277, 24571–24578.

    PubMed  CAS  Google Scholar 

  69. Muraoka, R. S., Dumont, N., Ritter, C. A., Dugger, T. C., Brantley, D. M., Chen, J., et al. (2002). Blockade of TGF-beta inhibits mammary tumor cell viability, migration, and metastases. Journal of Clinical Investigation, 109, 1551–1559.

    PubMed  CAS  Google Scholar 

  70. Yang, Y. A., Dukhanina, O., Tang, B., Mamura, M., Letterio, J. J., MacGregor, J., et al. (2002). Lifetime exposure to a soluble TGF-beta antagonist protects mice against metastasis without adverse side effects. Journal of Clinical Investigation, 109, 1607–1615.

    PubMed  CAS  Google Scholar 

  71. Bandyopadhyay, A., Agyin, J. K., Wang, L., Tang, Y., Lei, X., Story, B. M., et al. (2006). Inhibition of pulmonary and skeletal metastasis by a transforming growth factor-beta type I receptor kinase inhibitor. Cancer Research, 66, 6714–6721.

    PubMed  CAS  Google Scholar 

  72. Ge, R., Rajeev, V., Ray, P., Lattime, E., Rittling, S., Medicherla, S., et al. (2006). Inhibition of growth and metastasis of mouse mammary carcinoma by selective inhibitor of transforming growth factor-beta type I receptor kinase in vivo. Clinical Cancer Research, 12, 4315–4330.

    PubMed  CAS  Google Scholar 

  73. Mitsiades, C. S., Mitsiades N. S., McMullan, C. J., Poulaki, V., Shringarpure, R., Akiyama, M., et al. (2004). Inhibition of the insulin-like growth factor receptor-1 tyrosine kinase activity as a therapeutic strategy for multiple myeloma, other hematologic malignancies, and solid tumors. Cancer Cell, 5, 221–230.

    PubMed  CAS  Google Scholar 

  74. Goya, M., Miyamoto, S., Nagai, K., Ohki, Y., Nakamura, K., Shitara, K., et al. (2004). Growth inhibition of human prostate cancer cells in human adult bone implanted into nonobese diabetic/severe combined immunodeficient mice by a ligand-specific antibody to human insulin-like growth factors. Cancer Research, 64, 6252–6258.

    PubMed  CAS  Google Scholar 

  75. van Golen, C. M., Schwab, T. S., Kim, B., Soules, M. E., Su Oh, S., Fung, K., et al. (2006). Insulin-like growth factor-I receptor expression regulates neuroblastoma metastasis to bone. Cancer Research, 66, 6570–6578.

    PubMed  Google Scholar 

  76. Rubin, J., Fan, X., Rahnert, J., Sen, B., Hsieh, C. L., Murphy, T. C., et al. (2006). IGF-I secretion by prostate carcinoma cells does not alter tumor-bone cell interactions in vitro or in vivo. Prostate, 66, 789–800.

    PubMed  CAS  Google Scholar 

  77. Wozney, J. M. (1992). The bone morphogenetic protein family and osteogenesis. Molecular Reproduction and Development, 32, 160–167.

    PubMed  CAS  Google Scholar 

  78. Arnold, S. F., Tims, E., & McGrath, B. E. (1999). Identification of bone morphogenetic proteins and their receptors in human breast cancer cell lines: Importance of BMP2. Cytokine, 11, 1031–1037.

    PubMed  CAS  Google Scholar 

  79. Pouliot, F., Blais, A., & Labrie, C. (2003). Overexpression of a dominant negative type II bone morphogenetic protein receptor inhibits the growth of human breast cancer cells. Cancer Research, 63, 277–281.

    PubMed  CAS  Google Scholar 

  80. Ghosh-Choudhury, N., Ghosh-Choudhury, G., Celeste, A., Ghosh, P. M., Moyer, M., Abboud, S. L., et al. (2000). Bone morphogenetic protein-2 induces cyclin kinase inhibitor p21 and hypophosphorylation of retinoblastoma protein in estradiol-treated MCF-7 human breast cancer cells. Biochimica et Biophysica Acta, 1497, 186–196.

    PubMed  CAS  Google Scholar 

  81. Helms, M. W., Packeisen, J., August, C., Schittek, B., Boecker, W., Brandt, B. H., et al. (2005). First evidence supporting a potential role for the BMP/SMAD pathway in the progression of oestrogen receptor-positive breast cancer. Journal of Pathology, 206, 366–376.

    PubMed  CAS  Google Scholar 

  82. Clement, J. H., Raida, M., Sanger, J., Bicknell, R., Liu, J., Naumann, A., et al. (2005). Bone morphogenetic protein 2 (BMP-2) induces in vitro invasion and in vivo hormone independent growth of breast carcinoma cells. International Journal of Oncology, 27, 401–407.

    PubMed  CAS  Google Scholar 

  83. Valta, M. P., Hentunen, T., Qu, Q., Valve, E. M., Harjula, A., Seppanen, J. A., et al. (2006). Regulation of osteoblast differentiation: A novel function for fibroblast growth factor 8. Endocrinology, 147, 2171–2182.

    PubMed  CAS  Google Scholar 

  84. Ornitz, D. M. (2005). FGF signaling in the developing endochondral skeleton. Cytokine & Growth Factor Reviews, 16, 205–213.

    CAS  Google Scholar 

  85. Moursi, A. M., Winnard, P. L., Winnard, A. V., Rubenstrunk, J. M., & Mooney, M. P. (2002). Fibroblast growth factor 2 induces increased calvarial osteoblast proliferation and cranial suture fusion. Cleft Palate Craniofacial Journal, 39, 487–496.

    PubMed  Google Scholar 

  86. Chikazu, D., Katagiri, M., Ogasawara, T., Ogata, N., Shimoaka, T., Takato, T., et al. (2001). Regulation of osteoclast differentiation by fibroblast growth factor 2: Stimulation of receptor activator of nuclear factor kappaB ligand/osteoclast differentiation factor expression in osteoblasts and inhibition of macrophage colony-stimulating factor function in osteoclast precursors. Journal of Bone and Mineral Research, 16, 2074–2081.

    PubMed  CAS  Google Scholar 

  87. Yoshimura, N., Sano, H., Hashiramoto, A., Yamada, R., Nakajima, H., Kondo, M., et al. (1998). The expression and localization of fibroblast growth factor-1 (FGF-1) and FGF receptor-1 (FGFR-1) in human breast cancer. Clinical Immunology and Immunopathology, 89, 28–34.

    PubMed  CAS  Google Scholar 

  88. Okunieff, P., Fenton, B. M., Zhang, L., Kern, F. G., Wu, T., Greg, J. R., et al. (2003). Fibroblast growth factors (FGFS) increase breast tumor growth rate, metastases, blood flow, and oxygenation without significant change in vascular density. Advances in Experimental in Medicine and Biology, 530, 593–601.

    CAS  Google Scholar 

  89. Liu, J. F., Crepin, M., Liu, J. M., Barritault, D., & Ledoux, D.(2002). FGF-2 and TPA induce matrix metalloproteinase-9 secretion in MCF-7 cells through PKC activation of the Ras/ERK pathway. Biochemical and Biophysical Research Communications, 293, 1174–1182.

    PubMed  CAS  Google Scholar 

  90. Yi, B., Williams, P. J., Niewolna, M., Wang, Y., & Yoneda, T. (2002). Tumor-derived platelet-derived growth factor-BB plays a critical role in osteosclerotic bone metastasis in an animal model of human breast cancer. Cancer Research, 62, 917–923.

    PubMed  CAS  Google Scholar 

  91. Franchimont, N., & Canalis, E. (1995). Platelet-derived growth factor stimulates the synthesis of interleukin-6 in cells of the osteoblast lineage. Endocrinology, 136, 5469–5475.

    PubMed  CAS  Google Scholar 

  92. Seymour, L., Dajee, D., & Bezwoda, W. R. (1993). Tissue platelet derived-growth factor (PDGF) predicts for shortened survival and treatment failure in advanced breast cancer. Breast Cancer Research and Treatment, 26, 247–252.

    PubMed  CAS  Google Scholar 

  93. Seymour, L., & Bezwoda, W. R. (1994). Positive immunostaining for platelet derived growth factor (PDGF) is an adverse prognostic factor in patients with advanced breast cancer. Breast Cancer Research and Treatment, 32, 229–233.

    PubMed  CAS  Google Scholar 

  94. Lev, D. C., Kim, S. J., Onn, A., Stone, V., Nam, D. H., Yazici, S., et al. (2005). Inhibition of platelet-derived growth factor receptor signaling restricts the growth of human breast cancer in the bone of nude mice. Clinical Cancer Research, 11, 306–314.

    PubMed  CAS  Google Scholar 

  95. Silver, I. A., Murrills, R. J., & Etherington, D. J. (1988). Microelectrode studies on the acid microenvironment beneath adherent macrophages and osteoclasts. Experimental Cell Research, 175, 266–276.

    PubMed  CAS  Google Scholar 

  96. Sanders, J. L., Chattopadhyay, N., Kifor, O., Yamaguchi, T., Butters, R. R., & Brown, E. M. (2000). Extracellular calcium-sensing receptor expression and its potential role in regulating parathyroid hormone-related peptide secretion in human breast cancer cell lines. Endocrinology, 141, 4357–4364.

    PubMed  CAS  Google Scholar 

  97. Southby, J., Kissin, M. W., Danks, J. A., Hayman, J. A., Moseley, J. M., Henderson, M. A., et al. (1990). Immunohistochemical localization of parathyroid hormone-related protein in human breast cancer. Cancer Research, 50, 7710–7716.

    PubMed  CAS  Google Scholar 

  98. Powell, G. J., Southby, J., Danks, J. A., Stillwell, R. G., Hayman, J. A., Henderson, M. A., et al. (1991). Localization of parathyroid hormone-related protein in breast cancer metastases: Increased incidence in bone compared with other sites. Cancer Research, 51, 3059–3061.

    PubMed  CAS  Google Scholar 

  99. Vargas, S. J., Gillespie, M. T., Powell, G. J., Southby, J., Danks, J. A., Moseley, J. M., et al. (1992). Localization of parathyroid hormone-related protein mRNA expression in breast cancer and metastatic lesions by in situ hybridization. Journal of Bone and Mineral Research, 7, 971–979.

    Article  PubMed  CAS  Google Scholar 

  100. Nemeth, E. F. (2002). The search for calcium receptor antagonists (calcilytics). Journal of Molecular Endocrinology, 29, 15–21.

    PubMed  CAS  Google Scholar 

  101. Strewler, G. J. (2006). The stem cell niche and bone metastasis. BoneKEy-Osteovision, 3, 19–29.

    Google Scholar 

  102. Sohara, Y., Shimada, H., Minkin, C., Erdreich-Epstein, A., Nolta, J. A., & DeClerck, Y. A. (2005). Bone marrow mesenchymal stem cells provide an alternate pathway of osteoclast activation and bone destruction by cancer cells. Cancer Research, 65, 1129–1135.

    PubMed  CAS  Google Scholar 

  103. Neiva, K., Sun, Y. X., & Taichman, R. S. (2005). The role of osteoblasts in regulating hematopoietic stem cell activity and tumor metastasis. Brazilian Journal of Medical and Biological Research, 38, 1449–1454.

    PubMed  CAS  Google Scholar 

  104. Calvi, L. M., Adams, G. B., Weibrecht, K. W., Weber, J. M., Olson, D. P., Knight, M. C., et al. (2003). Osteoblastic cells regulate the haematopoietic stem cell niche. Nature, 425, 841–846.

    PubMed  CAS  Google Scholar 

  105. Al-Hajj, M., Wicha, M. S., Benito-Hernandez, A., Morrison, S. J., & Clarke, M. F. (2003). Prospective identification of tumorigenic breast cancer cells. Proceedings of the National Academy of Sciences of the United States of America, 100, 3983–3988.

    PubMed  CAS  Google Scholar 

  106. Pantel, K., & Brakenhoff, R. H. (2004). Dissecting the metastatic cascade. Nature Reviews. Cancer, 4, 448–456.

    PubMed  CAS  Google Scholar 

  107. Muller, V., & Pantel, K. (2004). Bone marrow micrometastases and circulating tumor cells: Current aspects and future perspectives. Breast Cancer Research, 6, 258–261.

    PubMed  Google Scholar 

  108. Fournier, P. G., Chirgwin, J. M., & Guise, T. A. (2006). New insights into the role of T cells in the vicious cycle of bone metastases. Current Opinion in Rheumatology, 18, 396–404.

    PubMed  CAS  Google Scholar 

  109. Weitzmann, M. N., & Pacifici, R. (2005). The role of T lymphocytes in bone metabolism. Immunological Reviews, 208, 154–168.

    PubMed  CAS  Google Scholar 

  110. Stanley, K. T., VanDort, C., Motyl, C., Endres, J., & Fox, D. A. (2006). Immunocompetent properties of human osteoblasts: Interactions with T lymphocytes. Journal of Bone and Mineral Research, 21, 29–36.

    PubMed  CAS  Google Scholar 

  111. Roato, I., Grano, M., Brunetti, G., Colucci, S., Mussa, A., Bertetto, O., et al. (2005). Mechanisms of spontaneous osteoclastogenesis in cancer with bone involvement. FASEB Journal, 19, 228–230.

    PubMed  CAS  Google Scholar 

  112. Siegel, P. M., & Massague, J. (2003). Cytostatic and apoptotic actions of TGF-beta in homeostasis and cancer. Nature Reviews. Cancer, 3, 807–821.

    PubMed  CAS  Google Scholar 

  113. Bosma, G. C., Custer, R. P., & Bosma, M. J. (1983). A severe combined immunodeficiency mutation in the mouse. Nature, 301, 527–530.

    PubMed  CAS  Google Scholar 

  114. Morrison, J., Partridge, T., & Bou-Gharios, G. (2005). Nude mutation influences limb skeletal muscle development. Matrix Biology, 23, 535–542.

    PubMed  CAS  Google Scholar 

  115. Keuren, J. F., Magdeleyns, E. J., Govers-Riemslag, J. W., Lindhout, T., Curvers, J. (2006). Effects of storage-induced platelet microparticles on the initiation and propagation phase of blood coagulation. British Journal of Haematology, 134, 307–313.

    PubMed  CAS  Google Scholar 

  116. Palumbo, J. S., Talmage, K. E., Massari, J. V., La Jeunesse, C. M., Flick, M. J., Kombrinck, K. W., et al. (2005). Platelets and fibrin(ogen) increase metastatic potential by impeding natural killer cell-mediated elimination of tumor cells. Blood, 105, 178–185.

    PubMed  CAS  Google Scholar 

  117. Boucharaba, A., Serre, C. M., Gres, S., Saulnier-Blache, J. S., Bordet, J. C., Guglielmi, J., et al. (2004). Platelet-derived lysophosphatidic acid supports the progression of osteolytic bone metastases in breast cancer. Journal of Clinical Investigation, 114, 1714–1725.

    PubMed  CAS  Google Scholar 

  118. Boucharaba, A., Serre, C. M., Guglielmi, J., Bordet, J. C., Clezardin, P., & Peyruchaud, O. (2006). The type 1 lysophosphatidic acid receptor is a target for therapy in bone metastases. Proceedings of the National Academy of Sciences of the United States of America, 103, 9643–9648.

    PubMed  CAS  Google Scholar 

  119. Manabe, Y., Toda, S., Miyazaki, K., & Sugihara, H. (2003). Mature adipocytes, but not preadipocytes, promote the growth of breast carcinoma cells in collagen gel matrix culture through cancer–stromal cell interactions. Journal of Pathology, 201, 221–228.

    PubMed  Google Scholar 

  120. Calle, E. E., & Thun, M. J. (2004). Obesity and cancer. Oncogene, 23, 6365–6378.

    PubMed  CAS  Google Scholar 

  121. Elliott, B. E., Tam, S. P., Dexter, D., & Chen, Z. Q. (1992). Capacity of adipose tissue to promote growth and metastasis of a murine mammary carcinoma: Effect of estrogen and progesterone. International Journal Cancer, 51, 416–424.

    CAS  Google Scholar 

  122. Iyengar, P., Combs, T. P., Shah, S. J., Gouon-Evans, V., Pollard, J. W, Albanese C., et al. (2003). Adipocyte-secreted factors synergistically promote mammary tumorigenesis through induction of anti-apoptotic transcriptional programs and proto-oncogene stabilization. Oncogene, 22, 6408–6423.

    PubMed  CAS  Google Scholar 

  123. Somasundar, P., McFadden, D. W., Hileman, S. M., & Vona-Davis, L. (2004). Leptin is a growth factor in cancer. Journal of Surgical Research, 116, 337–349.

    PubMed  CAS  Google Scholar 

  124. Maurin, A. C., Chavassieux, P. M., Frappart, L., Delmas, P. D., Serre, C. M., & Meunier, P. J. (2000). Influence of mature adipocytes on osteoblast proliferation in human primary cocultures. Bone, 26, 485–489.

    PubMed  CAS  Google Scholar 

  125. Thomas, T., Gori, F., Khosla, S., Jensen, M. D., Burguera, B., & Riggs, B. L. (1999). Leptin acts on human marrow stromal cells to enhance differentiation to osteoblasts and to inhibit differentiation to adipocytes. Endocrinology, 140, 1630–1638.

    PubMed  CAS  Google Scholar 

  126. Parr, C., & Jiang, W. G., (2006). Hepatocyte growth factor activation inhibitors (HAI-1 and HAI-2) regulate HGF-induced invasion of human breast cancer cells. International Journal of Cancer, 119, 1176–1183.

    CAS  Google Scholar 

  127. Maeda, T., Alexander, C. M., & Friedl, A. (2004). Induction of syndecan-1 expression in stromal fibroblasts promotes proliferation of human breast cancer cells. Cancer Research, 64, 612–621.

    PubMed  CAS  Google Scholar 

  128. Maeda, T., Desouky, J., & Friedl, A. (2006). Syndecan-1 expression by stromal fibroblasts promotes breast carcinoma growth in vivo and stimulates tumor angiogenesis. Oncogene, 25, 1408–1412.

    PubMed  CAS  Google Scholar 

  129. Saad, S., Gottlieb, D. J., Bradstock, K. F., Overall, C. M., & Bendall, L. J. (2002). Cancer cell-associated fibronectin induces release of matrix metalloproteinase-2 from normal fibroblasts. Cancer Research, 62, 283–289.

    PubMed  CAS  Google Scholar 

  130. Nguyen, N., Kuliopulos, A., Graham, R. A., & Covic, L. (2006). Tumor-derived Cyr61(CCN1) promotes stromal matrix metalloproteinase-1 production and protease-activated receptor 1-dependent migration of breast cancer cells. Cancer Research, 66, 2658–2665.

    PubMed  CAS  Google Scholar 

  131. Delany, A. M., & Canalis, E. (2001). The metastasis-associated metalloproteinase stromelysin-3 is induced by transforming growth factor-beta in osteoblasts and fibroblasts. Endocrinology, 142, 1561–1566.

    PubMed  CAS  Google Scholar 

  132. Lau, Y. S., Sabokbar, A., Giele, H., Cerundolo, V., Hofstetter, W., & Athanasou, N. A. (2006). Malignant melanoma and bone resorption. British Journal of Cancer, 94, 1496–1503.

    PubMed  CAS  Google Scholar 

  133. Chavez-Macgregor, M., Aviles-Salas, A., Green, D., Fuentes-Alburo, A., Gomez-Ruiz, C., & Aguayo, A. (2005). Angiogenesis in the bone marrow of patients with breast cancer. Clinical Cancer Research, 11, 5396–5400.

    PubMed  CAS  Google Scholar 

  134. Oehler, M. K., Hague, S., Rees, M. C., & Bicknell, R. (2002). Adrenomedullin promotes formation of xenografted endometrial tumors by stimulation of autocrine growth and angiogenesis. Oncogene, 21, 2815–2821.

    PubMed  CAS  Google Scholar 

  135. Menendez, J. A., Mehmi, I., Griggs, D. W., & Lupu, R. (2003). The angiogenic factor CYR61 in breast cancer: Molecular pathology and therapeutic perspectives. Endocrine Related Cancer, 10, 141–152.

    PubMed  CAS  Google Scholar 

  136. Wang, X. B., Yang, Q. X., & Pei, X. J. (2006). Expression of angiogenesis-related factors in invasive breast cancer and its clinical significance. Nan Fang Yi Ke Da Xue Xue Bao, 26, 860–863 (Article in Chinese).

    PubMed  CAS  Google Scholar 

  137. Li, Y., Tondravi, M., Liu, J., Smith, E., Haudenschild, C. C., Kaczmarek, M., et al. (2001). Cortactin potentiates bone metastasis of breast cancer cells. Cancer Research, 61, 6906–6911.

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to J.M. Chirgwin.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Siclari, V., Guise, T. & Chirgwin, J. Molecular interactions between breast cancer cells and the bone microenvironment drive skeletal metastases. Cancer Metastasis Rev 25, 621–633 (2006). https://doi.org/10.1007/s10555-006-9023-1

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10555-006-9023-1

Keywords

Navigation