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The bone microenvironment in metastasis; what is special about bone?

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Abstract

The skeleton is a common destination for many cancer metastases including breast and prostate cancer. There are many characteristics of bone that make it an ideal environment for cancer cell migration and colonization. Metaphyseal bone, found at the ends of long bone, in ribs, and in vertebrae, is comprised of trabecular bone interspersed with marrow and rich vasculature. The specialized microvasculature is adapted for the easy passage of cells in and out of the bone marrow. Moreover, the metasphyseal regions of bone are constantly undergoing remodeling, a process that releases growth factors from the matrix. Bone turnover also involves the production of numerous cytokines and chemokines that provide a means of communication between osteoblasts and osteoclasts, but co-incidentally can also attract and support metastatic cells. Once in the marrow, cancer cells can interact directly and indirectly with osteoblasts and osteclasts, as well as hematopoietic and stromal cells. Cancer cells secrete factors that affect the network of cells in the bone microenvironment as well as interact with other cytokines. Additionally, transient cells of the immune system may join the local mileau to ultimately support cancer cell growth. However, most metastasized cells that enter the bone marrow are transient; a few may remain in a dormant state for many years. Advances in understanding the bone cell-tumor cell interactions are key to controlling, if not preventing metastasis to bone.

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References

  1. Rubens, R. D., & Mundy, G. R. (2000). Cancer and the skeleton. London: Martin Dunitz.

    Google Scholar 

  2. Price, J. E. (2004). The breast comprehensive management of benign and malignant disorders pp. 537–557. St. Louis: Saunders.

    Google Scholar 

  3. Mundy, G. R. (2002). Metastasis to bone: Causes, consequences and therapeutic opportunities. Nature Reviews. Cancer, 2, 584–593.

    PubMed  CAS  Google Scholar 

  4. Chambers, A. F., Groom, A. C., & MacDonald, I. C. (2002). Dissemination and growth of cancer cells in metastatic sites. Nature Reviews. Cancer, 2, 563–572.

    PubMed  CAS  Google Scholar 

  5. Batson, O. V. (1942). Annals of Internal Medicine, 16, 38–45.

    Google Scholar 

  6. Marks, S. C., & Odgren, P. R. (2002). Structure and development of the skeleton. In J. P. Bilezikian, L. G. Raisz, & G. A. Rodan (Eds.) Principles of bone biology (vol. 1 (pp. 3–15). New York: Academic.

    Google Scholar 

  7. Hancox, N. M. (1972). Biology of bone. Cambridge: University Press.

    Google Scholar 

  8. Baron, R. (2003). General principles of bone biology. In M. J. Favus (Ed.) Primer on the metabolic bone diseases and disorders of mineral metabolism (pp. 1–8). Washington, D.C.: American Society for Bone and Mineral Research.

    Google Scholar 

  9. Alberts, B., Johnson, A., Lewis, J., Raff, M., Roberts, K., & Walter, P. (2002). Molecular biology of the cell p. 1308. New York: Garland Science.

    Google Scholar 

  10. Guise, T. A., & Mundy, G. R. (1998). Cancer and bone. Endocrine Reviews, 19, 18–54.

    PubMed  CAS  Google Scholar 

  11. Price, J. S., Oyajobi, B. O., & Russell, R. G. (1994). The cell biology of bone growth. European Journal of Clinical Nutrition, 48(Suppl 1), S131–S149.

    PubMed  Google Scholar 

  12. Minguell, J. J., Erices, A., & Conget, P. (2001). Mesenchymal stem cells. Experimental Biology and Medicine, 226, 507–520.

    PubMed  CAS  Google Scholar 

  13. Kanis, J. A., & McCloskey, E. V. (1997). Bone turnover and biochemical markers in malignancy. Cancer, 80, 1538–1545.

    PubMed  CAS  Google Scholar 

  14. Gartner, L. P., & Hiatt, J. L. (1997). Color textbook of histology. Philadelphia: Saunders.

    Google Scholar 

  15. Baron, R. (2003). General principles of bone biology. In J. B. Lian, & S. R. Goldring (Eds.) Primer on the metabolic bone diseases and disorders of mineral metabolism. Washington, D.C: American Society for Bone and Mineral Research.

    Google Scholar 

  16. Takahashi, N., Udagawa, N., Takami, M., & Suda, T. (2002). Cells of bone: Osteoclast generation. In J. P. Bilezikian, L. G. Raisz, & G. A. Rodan (Eds.) Principles of bone biology (vol. 1 (pp. 109–126). San Diego: Academic.

    Google Scholar 

  17. Michigami, T., Shimizu, N., Williams, P. J., Miewolna, M., Dallas, S. L., Mundy, G. R., et al. (2000). Cell–cell contact between marrow stromal cells and myeloma cells via VCAM-1 and α4B1 integrin enhances production of osteoclast-stimulating activity. Blood, 96, 1953–1960.

    PubMed  CAS  Google Scholar 

  18. 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 

  19. Maurin, A. C., Chavassieux, P. M., Frappart, L., Delmas, P., 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 

  20. 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 

  21. 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 

  22. 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 

  23. 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 

  24. Eberhardt, C., Gray, P. W., & Tjoelker, L. W. (1997). Human lysophosphatidic acid acyltransferase: cDNA cloning, expression, and localization to chromosome 9q34.3. Journal of Biological Chemistry, 272, 20299–20305.

    PubMed  CAS  Google Scholar 

  25. 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 

  26. Lapumbo, J. S., Talmage, K. E., Massari, J. B., 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.

    Google Scholar 

  27. Walsh, M. C., Kim, N., Kadono, Y., Rho, J., Lee, S. Y., Lorenzo, J., et al. (2006). Osteoimmunology: Interplay between the immune system and bone metabolism. In W. E. Paul, C. G. Fathman, & L. H. Glimcher (Eds.) Annual review of immunology (vol. 24 (pp. 33–63). Palo Alto: Annual Reviews.

    Google Scholar 

  28. Sroato, I., Grano, N., Brunetti, G., Colucci, S., Mussa, A., & Bertetto, O. (2005). Mechanisms of spontaneous osteoclastogenesis in cancer with bone involvement. FASEB Journal, 19, 228–230.

    Google Scholar 

  29. 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 

  30. Coussens, L. M., & Werb, Z. (2002). Inflammation and cancer. Nature, 420, 860–867.

    PubMed  CAS  Google Scholar 

  31. Brigati, C., Noonan, D. N., Albini, A., & Benelli, R. (2002). Tumors and inflammatory infiltrates: Friends or foes? Clinical & Experimental Metastasis, 19, 247–258.

    CAS  Google Scholar 

  32. Schoppmann, S. F., Birner, P., Stockl, J., Kalt, R., Ullrich, R., Caucig, C., et al. (2002). Tumor-associated macrophages express lymphatic endothelial growth factors and are related to peritumoral lymphangiogenesis. American Journal of Pathology, 161, 947–956.

    PubMed  CAS  Google Scholar 

  33. Torisu, H., Ono, M., Kiryu, H., Furue, M., Ohmoto, Y., Nakayama, J., et al. (2000). Macrophage infiltration correlates with tumor stage and angiogenesis in human malignant melanoma: Possible involvement of TNF-α and IL-1α. International Journal of Cancer, 85, 182–188.

    CAS  Google Scholar 

  34. Jonjic, N., Peri, G., Bernasconi, S., Sciacca, F. L., Colotta, F., Pelicci, P., et al. (1992). Expression of adhesion molecules and chemotactic cytokines in cultured human mesothelial cells. Journal of Experimental Medicine, 176, 1165–1174.

    PubMed  CAS  Google Scholar 

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

    Google Scholar 

  36. Roodman, G. D. (2004). Mechanisms of bone metastasis. New England Journal of Medicine, 350, 1655–1664.

    PubMed  CAS  Google Scholar 

  37. Roodman, G. D. (2001). Biology of osteoclast activation in cancer. Journal of Clinical Oncology, 19, 3562–3571.

    PubMed  CAS  Google Scholar 

  38. Yoneda, T. (1996). Mechanisms of preferential metastasis of breast cancer to bone. Journal of Clinical Oncology, 9, 103–109.

    Google Scholar 

  39. Powles, T., Paterson, S., Kanis, J. A., McCloskey, E. V., Ashley, S., Tidy, A., et al. (2002). Randomized, placebo-controlled trial of clodronate in patients with primary operable breast cancer. Journal of Clinical Oncology, 20, 3219–3224.

    PubMed  CAS  Google Scholar 

  40. Sasaki, A., Boyce, B. F., Story, B., Wright, K. R., Chapman, M., Boyce, R., et al. (1995). Bisphosphonate risedronate reduces metastatic human breast cancer cells and bone metastases development. Journal of Clinical Investigation, 103, 197–206.

    Google Scholar 

  41. Guise, T. A., Yin, J. J., Taylor, S. D., Kumagai, Y., Dallas, M. R., 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 

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

    PubMed  CAS  Google Scholar 

  43. Mastro, A. M., Gay, C. V., Welch, D. R., Donahue, H. J., Jewell, J., Mercer, R., et al. (2004). Breast cancer cells induce osteoblast apoptosis: a possible contributor to bone degradation. Journal of Cell Biology, 91, 265–276.

    CAS  Google Scholar 

  44. Mastro, A. M., Gay, C. V., & Welch, D. R. (2003). The skeleton as a unique environment for breast cancer cells. Clinical & Experimental Metastasis, 20, 275–284.

    CAS  Google Scholar 

  45. Mercer, R., Miyasaka, C., & Mastro, A. M. (2004). Metastatic breast cancer cells suppress osteoblast adhesion and differentiation. Clinical & Experimental Metastasis, 21, 427–435.

    CAS  Google Scholar 

  46. Guise, T. A., Yin, J. J., & Mohammad, K. S. (2003). Role of endothelin-1 in osteoblastic bone metastases. Cancer, 97, 779–784.

    PubMed  Google Scholar 

  47. Yin, J. J., Mohammad, K. S., Käkönen, 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, 100, 10954–10959.

    CAS  Google Scholar 

  48. Kasperk, C. H., Borcsok, I., Schairer, H. U., Schneider, U., Nawroth, P. P., Niethard, F. U., et al. (1997). Endothelin-1 is a potent regulator of human bone cell metabolism in vitro. Calcified Tissue International, 60, 368–374.

    PubMed  CAS  Google Scholar 

  49. Nelson, J. B., Hedican, S. P., George, D. J., Reddi, A. H., Piantadosi, S., Eisenberger, M. A., et al. (1995). Identification of endothelin-1 in the pathophysiology of metastatic adenocarcinoma of the prostate. Nature Medicine, 1, 944–949.

    PubMed  CAS  Google Scholar 

  50. 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 

  51. Hiraga, T., Williams, P. J., & Mundy, G. R. (2001). The bisphosphonate ibandronate promotes apoptosis in MDA-MB-231 human breast cancer cells in bone metastases. Cancer Research, 61, 4418–4424.

    PubMed  CAS  Google Scholar 

  52. Delmas, P. D., Demiaux, B., Malaval, L., Chapuy, M. C., Edouard, C., & Meunier, P. J. (1986). Serum bone gamma carboxyglutamic acid-containing protein in primary hyperthyroidism and in malignant hypercalcemia. Journal of Clinical Investigation, 77, 985–991.

    PubMed  CAS  Google Scholar 

  53. Kukreja, S. C., Rosol, T. J., Shevrin, D. H., & York, P. A. (1998). Quantitative bone histomorphometry in nude mice bearing a human squamous cell lung cancer. Journal of Bone and Mineral Research, 3, 341–346.

    Google Scholar 

  54. Stewart, A. F., Vignery, A., Silverglate, A., Ravin, N. D., Livolsi, V., Broadus, A. E., et al. (1982). Quantitative bone histomorphology in humoral hypercalcemia of malignancy: Uncoupling of bone cell activity. Journal of Clinical Endocrinology and Metabolism, 55, 219–227.

    Article  PubMed  CAS  Google Scholar 

  55. Taube, T., Elomaa, I., Blomqvist, C., Benton, N. C., & Kanis, J. A. (1994). Histomorphometric evidence for osteoclast-mediated bone resorption in metastatic breast cancer. Bone, 15, 161–166.

    PubMed  CAS  Google Scholar 

  56. Galasko, C. S. (1982). Mechanisms of lytic and blastic metastatic disease of bone. Clinica Ortopedica, 169, 20–27.

    Google Scholar 

  57. Martin, T. J., & Moseley, J. M. (2000). Mechanisms in the skeletal complications of breast cancer. Endocrine Related Cancer, 7, 271–284.

    PubMed  CAS  Google Scholar 

  58. Mundy, G. R., & Guise, T. A. (2000). Pathophysiology of bone metastasis. In R. D. Rubens, & G. R. Mundy (Eds.) Cancer and the skeleton (pp. 43–64). London: Martin Dunitz Ltd.

    Google Scholar 

  59. Phadke, P. A., Mercer, R. R., Harms, J. F., Jia, Y., Kappes, J. C., Frost, A. R., et al. (2006). Kinetics of metastatic breast cancer cell trafficking in bone. Clinical Cancer Research, 12, 1431–1440.

    PubMed  Google Scholar 

  60. Everts, V., Delaisse, J. M., Korper, W., Jansen, D. C., Tigchelaar-Gutter, W., Saftig, P., et al. (2002). The bone lining cell: Its role in cleaning Howship’s lacunae and initiating bone formation. Journal of Bone and Mineral Research, 17, 77–90.

    PubMed  CAS  Google Scholar 

  61. Glinsky, V. V. (2006). Intravascular cell-to-cell adhesive interactions and bone metastasis. Cancer and Metastasis Reviews, 25, 531–540.

    PubMed  Google Scholar 

  62. Sasaki, A., Boyce, B. F., Story, B., Wright, K. R., Chapman, M., Boyce, R., et al. (1995). Bisphosphonate risedronate reduces metastatic human breast cancer burden in bone in nude mice. Cancer Research, 55, 3551–3557.

    PubMed  CAS  Google Scholar 

  63. Mazo, I. B., & von Andrian, U. H. (1999). Adhesion and homing of blood-borne cells in bone marrow microvessels. Journal of Leukocyte Biology, 66, 25–32.

    PubMed  CAS  Google Scholar 

  64. Buckwalter, J. A. (1995). Pharmacological treatment of soft-tissue injuries. Journal of Bone and Joint Surgery. American Volume, 77, 1902–1914.

    CAS  Google Scholar 

  65. Schnitzer, J. E., McKinstry, P., Light, T. R., & Ogden, J. A. (1982). Quantitation of regional chondro-osseous circulation in canine tibia and femur. American Journal of Physiology, 242, H365–H375.

    PubMed  CAS  Google Scholar 

  66. Stephenson, R. B. (1989). The splanchnic circulation. In H. D. Patton, A. F. Fuchs, B. Hille, A. M. Scher, & R. Steiner (Eds.) Textbook of physiology (pp. 911–923). Philadelphia: Saunders.

    Google Scholar 

  67. Mastro, A. M., Gay, C. V., & Welch, D. R. (2003). The skeleton as a unique environment for breast cancer cells. Clinical & Experimental Metastasis, 20, 275–284.

    CAS  Google Scholar 

  68. Makuch, L. A., Sosnoski, D. M., & Gay, C. V. (2006). Osteoblast-conditioned media influence the expression of E-selectin on bone-derived vascular endothelial cells. Journal of Cellular Biochemistry, 98, 1221–1229.

    PubMed  CAS  Google Scholar 

  69. Lehr, J. E., & Pienta, K. J. (1998). Preferential adhesion of prostate cancer cells to a human bone marrow endothelial cell line. Journal of the National Cancer Institute, 90, 118–123.

    PubMed  CAS  Google Scholar 

  70. Scott, L. J., Clarke, N. W., George, N. J., Shanks, J. H., Testa, N. G., & Lang, S. H. (2001). Interactions of human prostatic epithelial cells with bone marrow endothelium: Binding and invasion. British Journal of Cancer, 84, 1417–1423.

    PubMed  CAS  Google Scholar 

  71. Glinsky, V. V., Glinsky, G. V., Rittenhouse-Olson, K., Huflejt, M. E., Glinskii, O. V., Deutscher, S. L., et al. (2001). The role of Thomsen–Friedenreich antigen in adhesion of human breast and prostate cancer cells to the endothelium. Cancer Research, 61, 4851–4857.

    PubMed  CAS  Google Scholar 

  72. Glinsky, V. V., Huflejt, M. E., Glinsky, G. V., Deutscher, S. L., & Quinn, T. P. (2000). Effects of Thomsen–Friedenreich antigen-specific peptide P-30 on beta-galactoside-mediated homotypic aggregation and adhesion to the endothelium of MDA-MB-435 human breast carcinoma cells. Cancer Research, 60, 2584–2588.

    PubMed  CAS  Google Scholar 

  73. McEver, R. P. (1997). Selectin-carbohydrate interactions during inflammation and metastasis. Glycoconjugate Journal, 14, 585–591.

    PubMed  CAS  Google Scholar 

  74. Cooper, C. R., Bhatia, J. K., Muenchen, H. J., McLean, L., Hayasaka, S., Taylor, J., et al. (2002). The regulation of prostate cancer cell adhesion to human bone marrow endothelial cell monolayers by androgen dihydrotestosterone and cytokines. Clinical & Experimental Metastasis, 19, 25–33.

    CAS  Google Scholar 

  75. Glinskii, O. V., Turk, J. R., Pienta, K. J., Huxley, V. H., & Glinsky, V. V. (2004). Evidence of porcine and human endothelium activation by cancer-associated carbohydrates expressed on glycoproteins and tumour cells. Journal of Physiology, 554, 89–99.

    PubMed  CAS  Google Scholar 

  76. Krause, T., & Turner, G. A. (1999). Are selectins involved in metastasis? Clinical & Experimental Metastasis, 17, 183–192.

    CAS  Google Scholar 

  77. Khaldoyanidi, S. K., Glinsky, V. V., Sikora, L., Glinskii, A. B., Mossine, V. V., Quinn, T. P., et al. (2003). MDA-MB-435 human breast carcinoma cell homo- and heterotypic adhesion under flow conditions is mediated in part by Thomsen–Friedenreich antigen-galectin-3 interactions. Journal of Biological Chemistry, 278, 4127–4134.

    PubMed  CAS  Google Scholar 

  78. Jacobsen, K., Kravitz, J., Kincade, P. W., & Osmond, D. G. (1996). Adhesion receptors on bone marrow stromal cells: in vivo expression of vascular cell adhesion molecule-1 by reticular cells and sinusoidal endothelium in normal and gamma-irradiated mice. Blood, 87, 73–82.

    PubMed  CAS  Google Scholar 

  79. Pecheur, I., Peyruchaud, O., Serre, C. M., Guglielmi, J., Voland, C., Bourre, F., et al. (2002). Integrin alpha(v)beta3 expression confers on tumor cells a greater propensity to metastasize to bone. FASEB Journal, 16, 1266–1268.

    PubMed  CAS  Google Scholar 

  80. Faccio, R., Grano, M., Colucci, S., Zallone, A. Z., Quaranta, V., & Pelletier, A. J. (1998). Activation of alphav beta3 integrin on human osteoclast-like cells stimulates adhesion and migration in response to osteopontin. Biochemical and Biophysical Research Communications, 249, 522–525.

    PubMed  CAS  Google Scholar 

  81. Carron, C. P., Meyer, D. M., Engleman, V. W., Rico, J. G., Ruminski, P. G., Ornberg, R. L., et al. (2000). Peptidomimetic antagonists of alphavbeta3 inhibit bone resorption by inhibiting osteoclast bone resorptive activity, not osteoclast adhesion to bone. Journal of Endocrinology, 165, 587–598.

    PubMed  CAS  Google Scholar 

  82. 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 

  83. Chellaiah, M., Kizer, N., Silva, M., Alvarez, U., Kwiatkowski, D., & Hruska, K. A. (2000). Gelsolin deficiency blocks podosome assembly and produces increased bone mass and strength. Journal of Cell Biology, 148, 665–678.

    PubMed  CAS  Google Scholar 

  84. Harms, J. F., Welch, D. R., Samant, R. S., Shevde, L. A., Miele, M. E., Babu, G. R., et al. (2003). A small molecule antagonist of the alpha v beta 3 integrin suppresses MDA-MB-435 skeletal metastasis. Clinical & Experimental Metastasis, 21, 119–128.

    Google Scholar 

  85. Horton, M. A., Nesbitt, S. A., Bennett, J. H., & Stenbeck, G. (2002). Integrins and other cell surface attachment molecules of bone cells. In J. P. Bilezikian, L. G. Raisz, & G. A. Rodan (Eds.) Principles of bone biology (vol. 1 (pp. 265–286). San Diego: Academic.

    Google Scholar 

  86. Rodan, G. A. (2003). The development and function of the skeleton and bone metastases. Cancer, 97, 726–732.

    PubMed  Google Scholar 

  87. Kikuchi, T., Matsuguchi, T., Tsuboi, N., Mitani, A., Tanaka, S., Matsuoka, M., et al. (2001). Gene expression of osteoclast differentiation factor is induced by lipopolysaccharide in mouse osteoblasts via Toll-like receptors. Journal of Immunology, 166, 3574–3579.

    CAS  Google Scholar 

  88. Fritz, E., Jacobs, J., Glant, T., & Roebuck, K. (2005). Chemokine IL-8 induction by particulate wear debris in osteoblasts is mediated by NF-kappaB. Journal of Orthopaedic Research, 23, 1249–1257.

    PubMed  CAS  Google Scholar 

  89. Lisignoli, G., Toneguzzi, S., Grassi, F., Piacentini, A., Tschon, M., Cristino, S., et al. (2002). Different chemokines are expressed in human arthritic bone biopsies: IFN-gamma and IL-6 differently modulate IL-8, MCP-1 and rantes production by arthritic osteoblasts. Cytokine, 20, 231–238.

    PubMed  CAS  Google Scholar 

  90. Fritz, E., Glant, T., Vermes, C., Jacobs, J., & Roebuck, K. (2005). Chemokine gene activation in human bone marrow-derived osteoblasts following exposure to particulate wear debris. Journal of Biomedical Materials Research A, 77, 192–201.

    Google Scholar 

  91. 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 

  92. Bendre, M., Montague, D. C., Peery, T., Akel, N. S., Gaddy, D., & Suva, L. J. (2003). Interleukin-8 stimulation of osteoclastogenesis and bone resorption is a mechanism for the increased osteolysis of metastatic bone disease. Bone, 33, 28–37.

    PubMed  CAS  Google Scholar 

  93. Bendre, M., Gaddy, D., Nicholas, R. W., & Suva, L. J. (2003). Breast cancer metastasis to bone. Clinical Orthopaedics and Related Research, 415S, S39–S45.

    Google Scholar 

  94. Bendre, M., Gaddy-Kurten, D., Foote-Mon, T., Akel, N. S., Skinner, R. A., Nicholas, R. W., et al. (2002). Expression of interleukin 8 and not parathyroid hormone-related protein by human breast cancer cells correlates with bone metastasis in vivo. Cancer Research, 62, 5571–5579.

    PubMed  CAS  Google Scholar 

  95. Henderson, M. A., Danks, J. A., Slavin, J. L., Bryrnes, G. B., Choong, P. F. M., Spillane, J. B., et al. (2006). Parathyroid hormone-related protein localization in breast cancers predict improved prognosis. Cancer Research, 66, 2250–2256.

    PubMed  CAS  Google Scholar 

  96. Horowitz, M. C., & Lorenzo, J. A. (2002). Principles of bone biology. San Diego: Academic.

    Google Scholar 

  97. Graves, D. T., Jiang, Y., & Valente, A. J. (1999). The expression of monocyte chemoattractant protein-1 and other chemokines by osteoblasts. Frontiers in Bioscience, 4, 571–580.

    Google Scholar 

  98. Guise, T. A., & Chirgwin, J. M. (2003). Transforming growth factor-beta in osteolytic breast cancer bone metastases. Clinical Orthopaedics and Related Research, 4155, 532–538.

    Google Scholar 

  99. Dovio, A., Sartori, M. L., Masera, R. G., Peretti, L., Perotti, L., & Angeli, A. (2004). Effects of physiological concentrations of steriod hormones and interleukin-11 on basal and stimulated production of interleukin-8 by human osteoblast-like cells with different functional profiles. Clinical and Experimental Rheumatology, 22, 79–84.

    PubMed  CAS  Google Scholar 

  100. Kundu, N., Yang, Q., Dorsey, R., & Fulton, A. M. (2001). Increased cyclooxygenase-2 (COX-2) expression and activity in a murine model of metastatic breast cancer. International Journal of Cancer, 94, 681–686.

    Google Scholar 

  101. Liu, C. H., Chang, S.-H., Narko, K., Trifan, O. C., Wu, M.-T., Smith, E., et al. (2001). Overexpression of cyclooxygenase-2 is sufficient to induce tumorigenesis in transgenic mice. Journal of Biological Chemistry, 276, 18563–18569.

    PubMed  CAS  Google Scholar 

  102. Ristimaki, A., Sivula, A., Lundin, J., Lundin, M., Salminen, T., Haglund, C., et al. (2002). Prognostic significance of elevated cycloozygenase-2 expression in breast cancer. Cancer Research, 62, 632–635.

    PubMed  CAS  Google Scholar 

  103. Rozic, J. G., Chakraborty, C., & Lala, P. K. (2001). Cyclooxygenase inhibitors retard murine mammary tumor progression by reducing tumor cell migration, invasiveness and angiogenesis. International Journal of Cancer, 93, 497–506.

    CAS  Google Scholar 

  104. Witters, L. M., Crispino, J., Fraterrigo, T., Green, J., Lipton, A. (2003). Effects of the combination of docetaxel, zoledronic acid, and a COX-2 inhibitor on the growth of human breast cancer cell line. American Journal of Clinical Oncology, 26.

  105. Davies, G., Salter, J., Hills, M., Martin, L. A., Sacks, N., & Dowsett, M. (2003). Correlation between cyclooxygenase-2 expression and angiogenesis in human breast cancer. Clinical Cancer Research, 9, 2651–2656.

    PubMed  CAS  Google Scholar 

  106. Denkert, C., Winzer, K. J., Muller, B. M., Weichert, W., Pest, S., Kobel, M., et al. (2003). Elevated expression of cyclooxygenase-2 is a negative prognostic factor for disease free survival and overall survival in patients with breast carcinoma. Cancer, 97, 2978–2987.

    PubMed  CAS  Google Scholar 

  107. Singh, B., Berry, J. A., Vincent, L. E., & Lucci, A.(2006). Involvement of IL-8 in COX-2-mediated bone metastases from breast cancer. Journal of Surgical Research.

  108. Benoy, I. H., Salgado, R., Van Dam, P., Geboers, K., Van Marck, E., Scharpe, S., et al. (2004). Increased serum interleukin-8 in patients with early and metastatic breast cancer correlates with early dissemination and survival. Clinical Cancer Research, 10, 7157–7162.

    PubMed  CAS  Google Scholar 

  109. Li, X., Pilbeam, C. C., Pan, L., Breyer, R. M., & Raisz, L. G. (2002). Effects of prostaglandin E2 on gene expression in primary osteoblastic cells from prostaglandin receptor knockout mice. Bone, 30, 567–573.

    PubMed  CAS  Google Scholar 

  110. Hiraga, T., Myoui, A., Choi, M. E., Yoshikawa, H., & Yoneda, T. (2006). Stimulation of cyclooxygenase-2 expression by bone-derived transforming growth factor-β enhances bone metastases in breast cancer. Cancer Research, 66, 2067–2073.

    PubMed  CAS  Google Scholar 

  111. Westendorf, J. J., Kahler, R. A., & Schroeder, T. M. (2004). Wnt signaling in osteoblasts and bone diseases. Gene, 341, 19–39.

    PubMed  CAS  Google Scholar 

  112. Hall, C. L., Bafico, A., Dai, J., Aaronson, S. A., & Keller, E. T. (2005). Prostate cancer cells promote osteoblastic bone metastases through Wnts. Cancer Research, 65, 7554–7560.

    PubMed  CAS  Google Scholar 

  113. Manolagas, S. C. (1995). Role of cytokines in bone resorption. Bone, 17, 63S–67S.

    PubMed  CAS  Google Scholar 

  114. Morinaga, Y., Fujita, N., Ohishi, K., & Tsurot, T. (1997). Stimulation of interleukin-11 production from osteoclast-like cells by transforming growth factor-beta and tumor cell factors. International Journal of Cancer, 71, 422–428.

    CAS  Google Scholar 

  115. Zhang, G. J., & Adachi, I. (1999). Serum interleukin-6 levels correlate to tumor progression and prognosis in metastatic breast carcinoma. Anticancer Research, 19, 1427–1432.

    PubMed  CAS  Google Scholar 

  116. Yoneda, T., Sasaki, A., & Mundy, G. R. (1994). Osteolytic bone metastasis in breast cancer. Breast Cancer Research and Treatment, 32, 273–284.

    Google Scholar 

  117. Sasaki, A., Williams, P., Mundy, G. R., & Yoneda, T. (1994). Osteolysis and tumor growth are enhanced in sites of increased bone turnover in vivo. Journal of Bone and Mineral Research, 9, S294.

    Google Scholar 

  118. Manolagas, S. C. (1995). Role of cytokines in bone resorption. Bone, 17, 63S–67S.

    PubMed  CAS  Google Scholar 

  119. Girasole, G., Passeri, G., Jilka, R. L., & Monolagas, S. C. (1994). Interleukin-11: A new cytokine critical for osteoclast development. Journal of Clinical Investigation, 93, 1516–1524.

    PubMed  CAS  Google Scholar 

  120. Manolagas, S. C., Jilka, R. L., Girasole, G., Passeri, G., & Bellido, T. (1994). Estrogens, cytokines, and the pathophysiology of osteoporosis. In P. O. Kohler (Ed.) Current opinion in endocrinology and diabetes (pp. 275–281). Philadelphia: Current Science.

    Google Scholar 

  121. Hauschka, P. V., Mavrakos, A. E., Iafrati, M. D., Doleman, S. E., & Klagsburn, 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 

  122. Pfeilschifter, J., & Mundy, G. R. (1987). Modulation of transforming growth factor beta activity in bone cultures by osteotropic hormones. Proceedings of the National Academy of Sciences, 84, 2024–2028.

    CAS  Google Scholar 

  123. 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 Research, 3, 537–549.

    CAS  Google Scholar 

  124. Mundy, G. R., DeMartino, S., & Rowe, D. W. (1981). Collagen and collagen fragments are chemotactic for tumor cells. Journal of Clinical Investigation, 68, 1102–1105.

    PubMed  CAS  Google Scholar 

  125. Orr, F. W., Varani, J., Gondek, M. D., Ward, P. A., & Mundy, G. R. (1979). Chemotactic response of tumor cells to productions of resorbing bone. Science, 203, 176–179.

    PubMed  CAS  Google Scholar 

  126. Zou, Y.-R., Kottmann, A. H., Kuroda, M., Tainwchi, I., & Littman, D. R. (1998). Function of the chemokine receptor CXCR4 in hematopoiesis and in cerebellar development. Nature, 393, 595–599.

    PubMed  CAS  Google Scholar 

  127. Nagasawa, T., Hirota, S., Tachibana, K., Takakura, N., Nishikawa, S., Kitamura, Y., et al. (1996). Defects of B-cell lymphopoiesis and bone marrow myelopoiesis in mice lacking the CXC chemokine PBSF/SDF-1. Nature, 382, 635–638.

    PubMed  CAS  Google Scholar 

  128. Bluel, C. C., Fuhlbrigge, R. C., Casanovas, J. M., Aiuiti, A., & Springer, T. A. (1996). Highly efficacious lymphocyte chemoattractant, stromal cell-derived factor 1 (SDF-1). Journal of Experimental Medicine, 184, 1101–1109.

    Google Scholar 

  129. D’Apuzzo, M., Rolink, A., Loetscher, M., Hoxie, J. A., Clark-Lewis, I., Melchers, F., et al. (1997). The chemokine SDF-1, stromal cell-derived factor-1, attracts early stage B cell precursors via the chemokine receptor CXCR4. European Journal of Immunology, 27, 1788–1793.

    PubMed  CAS  Google Scholar 

  130. Jung, Y., Wang, J., Schneider, A., Sun, Y.-X., Koh-Paige, A. J., Osman, N. I., et al. (2006). Regulation of SDF-1 (CXCL12) production by osteoblasts; a possible mechanism for stem cell homing. Bone, 38, 497–508.

    PubMed  CAS  Google Scholar 

  131. Wang, J., Wang, J., Sun, Y.-X., Song, W., Nor, J. E., Wang, C. Y., et al. (2005). Diverse signaling pathways through the SDF-1/CXCR4 chemokine axis in prostate cancer cell lines leads to altered patterns of cytokine secretion and angiogenesis. Cellular Signalling, 17, 1578–1592.

    PubMed  CAS  Google Scholar 

  132. Luker, K. E., & Luker, G. D. (2005). Functions of CXCL12 and CXCR4 in breast cancer. Cancer Letters.

  133. 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 

  134. 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 

  135. Siclari, V. A., Guise, T. A., & Chirgwin, J. M. (2006). Molecular interactions between breast cancer cells and the bone microenvironment drive skeletal metastases. Cancer and Metastasis Reviews, 25, 621–633.

    PubMed  CAS  Google Scholar 

  136. Yoneda, T. (2000). Cellular and molecular basis of preferential metastasis of breast cancer to bone. Journal of Orthopaedic Science, 5, 75–81.

    PubMed  CAS  Google Scholar 

  137. Guise, T. A. (2000). Molecular mechanisms of osteolytic bone metastases. Cancer, 88, 2892–2898.

    PubMed  CAS  Google Scholar 

  138. Pederson, L., Winding, B., Foged, N. T., Spelsberg, T. C., & Oursler, M. J. (1999). Identification of breast cancer cell line-derived paracrine factors that stimulate osteoclast activity. Cancer Research, 59, 5849–5855.

    PubMed  CAS  Google Scholar 

  139. Badache, A., & Hynes, N. E. (2001). Interleukin 6 inhibits proliferation and, in cooperation with an epidermal growth factor receptor autocrine loop, increases migration of T47D breast cancer cells. Cancer Research, 61, 383–391.

    PubMed  CAS  Google Scholar 

  140. Kotake, S., Sato, K., Kim, K. J., Takahashi, N., Udagawa, N., Nakamura, I., et al. (1996). Interleukin-6 and soluble interleukin-6 receptors in the synovial fluids from rheumatoid arthritis patients are responsible for osteoclast-like cell formation. Journal of Bone and Mineral Research, 11, 88–95.

    Article  PubMed  CAS  Google Scholar 

  141. Scapini, P., Morini, M., Tecchio, C., Minghelli, S., Di Carlo, E., Tanghetti, E., et al. (2004). CXCL1/macrophage inflammatory protein-2-induced angiogenesis in vivo is mediated by neutrophil-derived vascular endothelial growth factor-A. Journal of Immunology, 172, 5034–5040.

    CAS  Google Scholar 

  142. Goede, V., Brogelli, L., Ziche, M., & Augustin, H. G. (1999). Induction of inflammatory angiogenesis by monocyte chemoattractant protein-1. International Journal of Cancer, 82, 765–770.

    CAS  Google Scholar 

  143. Fitzgerald, K. A., O’Neill, L. A. J., Gearing, A. J. H., & Callard, R. E. (2001). The cytokine facts book. New York: Academic.

    Google Scholar 

  144. Kinder, M. , Chislock, E. M., Bussard, K. M., Shuman, L. A., & Mastro, A. M. (2007). Metastatic breast cancer induces an osteoblast inflammatory response. Experimental Cell Research, Oct. 4 (in press).

  145. Neumark, E., Cohn, M. A., Lukanidin, E., Witz, I. P., & Ben-Baruch, A. (2002). Possible co-regulation of genes associated with enhanced progression of mammary adenocarcinomas. Immunology Letters, 82, 111–121.

    PubMed  CAS  Google Scholar 

  146. Neumark, E., Sagi-Assif, O., Shalmon, B., Ben-Baruch, A., & Witz, I. P. (2003). Progression of mouse mammary tumors: MCP-1-TNF-alpha cross regulatory pathway and clonal expression of promalignancy and antimalignancy factors. International Journal of Cancer, 106, 879–886.

    CAS  Google Scholar 

  147. Ueno, T., Toi, M., Saji, J., Muta, M., Bando, H., Kuroi, K., et al. (2000). Significance of macrophage chemoattractant protein-1 in macrophage recruitment, angiogenesis, and survival in human breast cancer. Clinical Cancer Research, 6, 3282–3289.

    PubMed  CAS  Google Scholar 

  148. Mukaida, N., Ketlunsky, S. A., & Matsushima, K. (2003). The cytokine handbook. Amsterdam: Academic.

    Google Scholar 

  149. Bischoff, D. S., Zhu, J. H., Makhijani, N. S., & Yamaguchi, D. T. (2005). KC chemokine expression by TGF-B in C3H10T1/2 cells induced towards osteoblasts. Biochemical and Biophysical Research Communications, 326, 364–370.

    PubMed  CAS  Google Scholar 

  150. Wolfle, U., Muller, V., & Pantel, K. (2006). Disseminated tumor cells in breast cancer: detection, characterization and clinical relevance. Future Oncology, 2, 553–561.

    PubMed  Google Scholar 

  151. Dhurjati, R., Liu, X., Gay, C. V., Mastro, A. M., & Vogler, E. A. (2006). Extended-term culture of bone cells in a compartmentalized bioreactor. Tissue Engineering, 12, 3045–3054.

    PubMed  CAS  Google Scholar 

  152. Dhurjati, R., Shuman, L. A., Krishnan, V., Mastro, A. M., Gay, C. V., & Vogler, E. A. (2006). Compartmentalized bioreactor: In vitro model for osteobiology and osteopathology. 28th Annual Meeting of the American Society for Bone and Mineral Research, 21, 349.

    Google Scholar 

  153. Deyama, Y., Takeyama, S., Suzuki, K., Yoshimura, Y., Nishikata, M., & Matsumoto, A. (2001). Inactivation of NF-KB involved in osteoblast development through interleukin-6. Biochemical and Biophysical Research Communications, 282, 1080–1084.

    PubMed  CAS  Google Scholar 

  154. Ishimi, Y., Miyaura, C., Jin, C. H., Akatsu, T., Abe, E., Nakamura, Y., et al. (1990). IL-6 is produced by osteoblasts and induces bone resorption. Journal of Immunology, 145, 3297–3303.

    CAS  Google Scholar 

  155. Bendre, M., Gaddy, D., Nicholas, R. W., & Suva, L. J. (2003). Breast cancer metastasis to bone: It is not all about PTHrP. Clinical Orthopaedics and Related Research, 415S, S39–S45.

    Google Scholar 

  156. Girasole, G., Jilka, R. L., Passeri, G., Boswell, S., Boder, G., Williams, D. C., et al. (1992). 17 beta-estradiol inhibits interleukin-6 production by bone marrow-derived stromal cells and osteoblasts in vitro: A potential mechanism for the antiosteoporotic effect of estrogens. Journal of Clinical Investigation, 89, 883–891.

    Article  PubMed  CAS  Google Scholar 

  157. Linkhart, T. A., Linkhart, S. G., MacCharles, D. C., Long, D. L., & Strong, D. D. (1991). Interleukin-6 messenger RNA expression and interleukin-6 protein secretion in cells isolated from normal human bone. Journal of Bone and Mineral Research, 6, 1285–1294.

    PubMed  CAS  Google Scholar 

  158. O’Keefe, R. J., Teot, L. A., Singh, D., Puzas, J. E., Rosier, R. N., & Hicks, D. G. (1997). Osteoclasts constitutively express regulators of bone resorption: An immunohistochemical and in situ hybridization study. Laboratory Investigation, 76, 457–465.

    PubMed  CAS  Google Scholar 

  159. Chaudhary, L. R., & Avioli, L. V. (1994). Dexamethasone regulates IL-1 beta and TNF-alpha-induced interleukin-8 production in human bone marrow stromal and osteoblast-like cells. Calcified Tissue International, 55, 16–20.

    PubMed  CAS  Google Scholar 

  160. 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 

  161. Rothe, L., Collin-Osdoby, P., Chen, Y., Sunyer, T., Chaudhary, L., Tsay, A., et al. (1998). Human osteoclasts and osteoclast-like cells synthesize and release high basal and inflammatory stimulated levels of the potent chemokine interleukin-8. Endocrinology, 139, 4353–4363.

    PubMed  CAS  Google Scholar 

  162. Sozzani, S., Locati, M., Allavena, P., Van Damme, J., & Mantovani, A. (1996). Chemokines: A superfamily of chemotactic cytokines. International Journal of Clinical & Laboratory Research, 26, 69–82.

    CAS  Google Scholar 

  163. Lipton, A. (2000). Bisphosphonates and breast carcinoma: Present and future. Cancer, 88, 3033–3037.

    PubMed  CAS  Google Scholar 

  164. Oslen, N. J., Gu, X., & Kovacs, W. J. (2001). Bone marrow stromal cells mediate androgenic suppression of B lymphocyte development. Journal of Clinical Investigation, 108, 1697–1704.

    Google Scholar 

  165. Schultz-Cherry, S., Ribeiro, S., Gentry, L., & Murphy-Ullrich, J. E. (1994). Thrombospondin binds and activates the small and large forms of latent transforming growth factor-beta in a chemically defined system. Journal of Biological Chemistry, 269, 26775–26782.

    PubMed  CAS  Google Scholar 

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Acknowledgments

KMB was supported by a predoctoral traineeship from the U.S. Army Medical and Materiel Research Command Breast Cancer Program (W81XWH-06-1-0363). The authors’ work was supported by was supported by the U.S. Army Medical and Material Research Command Breast Cancer Program; (DAMD 17-02-1-0358 and W81XWH-06-1-0432 to AMM,); National Foundation for Cancer Research, Center for Metastasis Research; The Susan G. Komen Breast Cancer Foundation, BCTR104406; The American Institute of Cancer Research, #06A027-REV2; The authors thank Richard Ball of the Immunomodulation Core, Penn State GCRC (work supported by NIHM01RR10732) for technical advice regarding ELISAs.

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Bussard, K.M., Gay, C.V. & Mastro, A.M. The bone microenvironment in metastasis; what is special about bone?. Cancer Metastasis Rev 27, 41–55 (2008). https://doi.org/10.1007/s10555-007-9109-4

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