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Genes associate with abnormal bone cell activity in bone metastasis

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Abstract

Bone is one of the most frequent sites of metastasis in patients with malignancies. Up to 90 % of patients with multiple myeloma, and 60 % to 75 % patients with prostate cancer and breast cancer develop bone metastasis at the later stages of their diseases. Bone metastases are responsible for tremendous morbidity in patients with cancer, including severe bone pain, pathologic fractures, spinal cord and nerve compression syndromes, life-threatening hypercalcemia, and increased mortality. Multiple factors produced by tumor cells or produced by the bone marrow microenvironment in response to tumor cells play important roles in activation of osteoclastic bone resorption and modulation of osteoblastic activity in patients with bone metastasis. In this chapter, we will review the genes that play important roles in bone destruction, tumor growth, and osteoblast activity in bone metastasis and discuss the potential therapies targeting the products of these genes to block both bone destruction and tumor growth.

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References

  1. Coleman, R. E. (2000). Management of bone metastases. The Oncologist, 5(6), 463–470.

    Article  PubMed  CAS  Google Scholar 

  2. Coleman, R. E. (2001). Metastatic bone disease: clinical features, pathophysiology and treatment strategies. Cancer Treatment Reviews, 27, 165–176.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  4. Lipton, A. (2004). Pathophysiology of bone metastases: how this knowledge may lead to therapeutic intervention. Journal of Supportive Oncology, 2(3), 205–213. discussion 213–214, 216–217, 219–220.

    PubMed  Google Scholar 

  5. Rosen, L. S., Gordon, D., Kaminski, M., Howell, A., Belch, A., Mackey, J., Apffelstaedt, J., Hussein, M. A., Coleman, R. E., Reitsma, D. J., Chen, B. L., & Seaman, J. J. (2003). Long-term efficacy and safety of zoledronic acid compared with pamidronate disodium in the treatment of skeletal complications in patients with advanced multiple myeloma or breast carcinoma: a randomized, double-blind, multicenter, comparative trial. Cancer, 98(8), 1735–1744.

    Article  PubMed  CAS  Google Scholar 

  6. Chirgwin, J. M., & Guise, T. A. (2000). Molecular mechanisms of tumor–bone interactions in osteolytic metastases. Critical Reviews in Eukaryotic Gene Expression, 10(2), 159–178.

    Article  PubMed  CAS  Google Scholar 

  7. Taube, T., Elomaa, I., Blomqvist, C., et al. (1994). Histomorphometric evidence for osteoclast-mediated bone resorption in metastatic breast cancer. Bone, 15(2), 161–166.

    Article  PubMed  CAS  Google Scholar 

  8. Boyde A, Maconnachie E, Reid SA, et al. (1986). Scanning electron microscopy in bone pathology: review of methods, potential and applications. Scan Electron Microsc (Pt 4), 1537–1554.

  9. Fowler, J. A., Edwards, C. M., & Croucher, P. I. (2011). Tumor-host cell interactions in the bone disease of myeloma. Molecular mechanisms of breast cancer metastases to bone. Bone, 48(1), 121–128.

    Article  PubMed  Google Scholar 

  10. 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(2)), S46–S53.

    Article  PubMed  CAS  Google Scholar 

  11. Roodman, G. D. (2004). Mechanisms of bone metastasis. The New England Journal of Medicine, 350(16), 1655–1664.

    Article  PubMed  CAS  Google Scholar 

  12. Cackowski, F. C., Anderson, J. L., Patrene, K. D., Choksi, R. J., Shapiro, S. D., Windle, J. J., Blair, H. C., & Roodman, G. D. (2010). Osteoclasts are important for bone angiogenesis. Blood, 115(1), 140–149.

    Article  PubMed  CAS  Google Scholar 

  13. Lacey, D. L., Timms, E., Tan, H. L., et al. (1998). Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell, 93(2), 165–176.

    Article  PubMed  CAS  Google Scholar 

  14. Dougall, W. C., Glaccum, M., Charrier, K., et al. (1999). RANK is essential for osteoclast and lymph node development. Genes & Development, 13(18), 2412–2424.

    Article  CAS  Google Scholar 

  15. Sezer, O., Heider, U., Jakob, C., et al. (2002). Human bone marrow myeloma cells express RANKL. Journal of Clinical Oncology, 20(1), 353–354.

    PubMed  Google Scholar 

  16. Huang, L., Cheng, Y. Y., Chow, L. T. C., Zheng, M. H., & Kumta, S. M. (2002). Tumour cells produce receptor activator of NF-κB ligand (RANKL) in skeletal metastases. J Clin Path, 55(11), 877–878.

    Article  PubMed  CAS  Google Scholar 

  17. Hofbauer, L. C., Khosla, S., Dunstan, C. R., Lacey, D. L., Boyle, W. J., & Riggs, B. L. (2000). The roles of osteoprotegerin and osteoprotegerin ligand in the paracrine regulation of bone resorption. Journal of Bone and Mineral Research, 15(1), 2–12.

    Article  PubMed  CAS  Google Scholar 

  18. Fuller, K., Wong, B., Fox, S., Choi, Y., & Chambers, T. J. (1998). TRANCE is necessary and sufficient for osteoblast-mediated activation of bone resorption in osteoclasts. The Journal of Experimental Medicine, 188(5), 997–1001.

    Article  PubMed  CAS  Google Scholar 

  19. Roodman, G. D. (1999). Cell biology of the osteoclast. Experimental Hematology, 27(8), 1229–1241.

    Article  PubMed  CAS  Google Scholar 

  20. Tsukii, K., Shima, N., Mochizuki, S., et al. (1998). Osteoclast differentiation factor mediates an essential signal for bone resorption induced by 1 alpha, 25-dihydroxyvitamin D3, prostaglandin E2, or parathyroid hormone in the microenvironment of bone. Biochemical and Biophysical Research Communications, 246(2), 337–341.

    Article  PubMed  CAS  Google Scholar 

  21. Hofbauer, L. C., Neubauer, A., & Heufelder, A. E. (2001). Receptor activator of nuclear factor-kappaB ligand and osteoprotegerin: potential implications for the pathogenesis and treatment of malignant bone diseases. Cancer, 92(3), 460–470.

    Article  PubMed  CAS  Google Scholar 

  22. Feng, X. (2005). RANKing intracellular signaling in osteoclasts. IUBMB Life, 57(6), 389–395.

    Article  PubMed  CAS  Google Scholar 

  23. Santos, V. R., Lima, J. A., Gonçalves, T. E., Bastos, M. F., Figueiredo, L. C., Shibli, J. A., & Duarte, P. M. (2010). Receptor activator of nuclear factor-kappa B ligand/osteoprotegerin ratio in sites of chronic periodontitis of subjects with poorly and well-controlled type 2 diabetes. Journal of Periodontology, 81(10), 1455–1465.

    Article  PubMed  CAS  Google Scholar 

  24. Goranova-Marinova, V., Goranov, S., Pavlov, P., & Tzvetkova, T. (2007). Serum levels of OPG, RANKL and RANKL/OPG ratio in newly-diagnosed patients with multiple myeloma. Clinical Correlations. Haematologica, 92(7), 1000–1001.

    Article  Google Scholar 

  25. Terpos, E., Szydlo, R., Apperley, J. F., Hatjiharissi, E., Politou, M., Meletis, J., Viniou, N., Yataganas, X., Goldman, J. M., & Rahemtulla, A. (2003). Soluble receptor activator of nuclear factor KB ligand-osteoprotegerin ratio predicts survival in multiple myeloma: proposal for a novel prognostic index. Blood, 102(3), 1064–1069.

    Google Scholar 

  26. Canon, J., Bryant, R., Roudier, M., Osgood, T., Jones, J., Miller, R., Coxon, A., Radinsky, R., & Dougall, W. C. (2010). Inhibition of RANKL increases the anti-tumor effect of the EGFR inhibitor panitumumab in a murine model of bone metastasis. Bone, 46(6), 1613–1619.

    Article  PubMed  CAS  Google Scholar 

  27. Canon, J. R., Roudier, M., Bryant, R., Morony, S., Stolina, M., Kostenuik, P. J., & Dougall, W. C. (2008). Inhibition of RANKL blocks skeletal tumor progression and improves survival in a mouse model of breast cancer bone metastasis. Clinical & Experimental Metastasis, 25(2), 119–129.

    Article  CAS  Google Scholar 

  28. Tannehill-Gregg, S. H., Levine, A. L., Nadella, M. V., Iguchi, H., & Rosol, T. J. (2006). The effect of zoledronic acid and osteoprotegerin on growth of human lung cancer in the tibias of nude mice. Clinical & Experimental Metastasis, 23(1), 19–31.

    Article  CAS  Google Scholar 

  29. Gonzalez-Suarez, E., Jacob, A. P., Jones, J., Miller, R., Roudier-Meyer, M. P., Erwert, R., Pinkas, J., Branstetter, D., & Dougall, W. C. (2010). RANK ligand mediates progestin-induced mammary epithelial proliferation and carcinogenesis. Nature, 468(7320), 103–107.

    Article  PubMed  CAS  Google Scholar 

  30. Azim, H., Michiels, S., Bedard, P. L., Singhal, S. K., Criscitiello, C., Ignatiadis, M., Haibe-Kains, B., Piccart, M. J., Sotiriou, C., & Loi, S. (2012). Elucidating prognosis and biology of breast cancer arising in young women using gene expression profiling. Clin Cancer Res, 18, 1341–1351.

    Article  PubMed  CAS  Google Scholar 

  31. Tang, Z. N., Zhang, F., Tang, P., Qi, X. W., & Jiang, J. (2011). RANKL-induced migration of MDA-MB-231 human breast cancer cells via Src and MAPK activation. Oncology Reports, 26(5), 1243–1250. doi:10.3892/or.11.1368.

    PubMed  CAS  Google Scholar 

  32. Jones, D. H., Nakashima, T., Sanchez, O. H., Kozieradzki, I., Komarova, S. V., Sarosi, I., Morony, S., Rubin, E., Sarao, R., Hojilla, C. V., Komnenovic, V., Kong, Y. Y., Schreiber, M., Dixon, S. J., Sims, S. M., Khokha, R., Wada, T., & Penninger, J. M. (2006). Regulation of cancer cell migration and bone metastasis by RANKL. Nature, 440(7084), 692–696.

    Article  PubMed  CAS  Google Scholar 

  33. Stopeck, A. T., Lipton, A., Body, J. J., Steger, G. G., Tonkin, K., de Boer, R. H., Lichinitser, M., Fujiwara, Y., Yardley, D. A., Viniega, M., Fan, M., Jiang, Q., Dansey, R., Jun, S., & Braun, A. (2010). Denosumab compared with zoledronic acid for the treatment of bone metastases in patients with advanced breast cancer: a randomized double-blind study. Journal of Clinical Oncology, 28(35), 5123–5129.

    Article  Google Scholar 

  34. Fizazi, K., Carducci, M., Smith, M., Damião, R., Brown, J., Karsh, L., Milecki, P., Shore, N., Rader, M., Wang, H., Jiang, Q., Tadros, S., Dansey, R., & Goessl, C. (2011). Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomized, double-blind study. Lancet, 337(9768), 813–822.

    Article  Google Scholar 

  35. Henry, D. H., Costa, L., Goldwasser, F., Hirsh, V., Hungria, V., Prausova, J., Scagliotti, G. V., Sleeboom, H., Spencer, A., Vadhan-Raj, S., von Moos, R., Willenbacher, W., Woll, P. J., Wang, J., Jiang, Q., Jun, S., Dansey, R., & Yeh, H. (2011). Randomized, double-blind study of denosumab versus zoledronic acid in the treatment of bone metastases in patients with advanced cancer (excluding breast and prostate cancer) or multiple myeloma. Journal of Clinical Oncology, 29(9), 1125–1132.

    Article  PubMed  CAS  Google Scholar 

  36. Choi, S. J., Cruz, J. C., Craig, F., et al. (2000). Macrophage inflammatory protein 1-alpha is a potential osteoclast stimulatory factor in multiple myeloma. Blood, 96(2), 671–675.

    PubMed  CAS  Google Scholar 

  37. Han, J. H., Choi, S. J., Kurihara, N., et al. (2001). Macrophage inflammatory protein-1alpha is an osteoclastogenic factor in myeloma that is independent of receptor activator of nuclear factor kappaB ligand. Blood, 97(11), 3349–3353.

    Article  PubMed  CAS  Google Scholar 

  38. Choi, S. J., Oba, Y., Gazitt, Y., et al. (2001). Antisense inhibition of macrophage inflammatory protein 1-alpha blocks bone destruction in a model of myeloma bone disease. The Journal of Clinical Investigation, 108(12), 1833–1841.

    PubMed  CAS  Google Scholar 

  39. Oyajobi, B. O., Franchin, G., Williams, P. J., et al. (2003). Dual effects of macrophage inflammatory protein-1alpha on osteolysis and tumor burden in the murine 5TGM1 model of myeloma bone disease. Blood, 102(1), 311–319.

    Article  PubMed  CAS  Google Scholar 

  40. Vallet, S., Raje, N., Ishitsuka, K., Hideshima, T., Podar, K., Chhetri, S., Pozzi, S., Breitkreutz, I., Kiziltepe, T., Yasui, H., Ocio, E. M., Shiraishi, N., Jin, J., Okawa, Y., Ikeda, H., Mukherjee, S., Vaghela, N., Cirstea, D., Ladetto, M., Boccadoro, M., & Anderson, K. C. (2007). MLN3897, a novel CCR1 inhibitor, impairs osteoclastogenesis and inhibits the interaction of multiple myeloma cells and osteoclasts. Blood, 110(10), 3744–3752.

    Article  PubMed  CAS  Google Scholar 

  41. Oba, Y., Lee, J. W., Ehrlich, L. A., Chung, H. Y., Jelinek, D. F., Callander, N. S., Horuk, R., Choi, S. J., & Roodman, G. D. (2005). MIP-1alpha utilizes both CCR1 and CCR5 to induce osteoclast formation and increase adhesion of myeloma cells to marrow stromal cells. Experimental Hematology, 33(3), 272–278.

    Article  PubMed  CAS  Google Scholar 

  42. Lentzsch, S., Chatterjee, M., Gries, M., Bommert, K., Gollasch, H., Dörken, B., & Bargou. (2004). RC PI3-K/AKT/FKHR and MAPK signaling cascades are redundantly stimulated by a variety of cytokines and contribute independently to proliferation and survival of multiple myeloma cells. Leukemia, 18(11), 1883–1890.

    Article  PubMed  CAS  Google Scholar 

  43. Roussou, M., Tasidou, A., Dimopoulos, M. A., Kastritis, E., Migkou, M., Christoulas, D., Gavriatopoulou, M., Zagouri, F., Matsouka, C., Anagnostou, D., & Terpos, E. (2009). Increased expression of macrophage inflammatory protein-1alpha on trephine biopsies correlates with extensive bone disease, increased angiogenesis and advanced stage in newly diagnosed patients with multiple myeloma. Leukemia, 23(11), 2177–2181.

    Article  PubMed  CAS  Google Scholar 

  44. Terpos, E., Politou, M., Szydlo, R., Goldman, J. M., Apperley, J. F., & Rahemtulla. (2003). A Serum levels of macrophage inflammatory protein-1 alpha (MIP-1alpha) correlate with the extent of bone disease and survival in patients with multiple myeloma. British Journal of Haematology, 123(1), 106–109.

    Article  PubMed  CAS  Google Scholar 

  45. Cross, N. A., Hillman, L. S., & Forte, L. R. (1998). The effects of calcium supplementation, duration of lactation, and time of day on concentrations of parathyroid hormone-related protein in human milk: a pilot study. Journal of Human Lactation, 14(2), 111–117.

    Article  PubMed  CAS  Google Scholar 

  46. Guise, T. A. (2000). Molecular mechanisms of osteolytic bone metastases. Cancer, 88(12 Suppl), 2892–2898.

    Article  PubMed  CAS  Google Scholar 

  47. Kremer, R., Li, J., Camirand, A., & Karaplis, A. C. (2011). Parathyroid hormone related protein (PTHrP) in tumor progression. Advances in Experimental Medicine and Biology, 720, 145–160.

    Article  PubMed  CAS  Google Scholar 

  48. Yin, J. J., Selander, K., Chirgwin, J. M., Dallas, M., Grubbs, B. G., Wieser, R., Massagué, J., Mundy, G. R., & Guise, T. A. (1999). TGF-beta signaling blockade inhibits PTHrP secretion by breast cancer cells and bone metastases development. The Journal of Clinical Investigation, 103(2), 197–206.

    Article  PubMed  CAS  Google Scholar 

  49. Guise, T. A., Yin, J. J., Taylor, S. D., Kumagai, Y., Dallas, M., Boyce, B. F., Yoneda, T., & Mundy, G. R. (1996). Evidence for a causal role of parathyroid hormone-related protein in the pathogenesis of human breast cancer-mediated osteolysis. The Journal of Clinical Investigation, 98(7), 1544–1549.

    Article  PubMed  CAS  Google Scholar 

  50. Tan, A. R., Alexe, G., & Reiss, M. (2008). Transforming growth factor-beta signaling: emerging stem cell target in metastatic breast cancer? Breast Cancer Research and Treatment, 115(3), 453–495.

    Article  PubMed  Google Scholar 

  51. Jung, Y., Wang, J., Song, J., et al. (2007). Annexin II expressed by osteoblasts andendothelial cells regulates stem cell adhesion, homing, and engraftment following transplantation. Blood, 110(1), 82–90.

    Article  PubMed  CAS  Google Scholar 

  52. Rescher, U., & Gerke, V. (2004). Annexins-unique membrane binding proteins with diverse functions. Journal of Cell Science, 117(Pt 13), 2631–2639.

    Article  PubMed  CAS  Google Scholar 

  53. Waisman, D. M. (1995). Annexin II tetramer: structure and function. Mol Cell Biochem, 149–150, 301–322.

    Article  PubMed  Google Scholar 

  54. Lu, G., Maeda, H., Reddy, S. V., et al. (2006). Cloning and characterization of the annexin II receptor on human marrow stromal cells. Journal of Biological Chemistry, 281(41), 30542–30550.

    Article  PubMed  CAS  Google Scholar 

  55. Shiozawa, Y., Havens, A. M., Jung, Y., et al. (2008). Annexin II/Annexin II receptor axis regulates adhesion, migration, homing, and growth of prostate cancer. Journal of Cellular Biochemistry, 105(2), 370–380.

    Article  PubMed  CAS  Google Scholar 

  56. Li, F., Chung, H., Reddy, S. V., et al. (2005). Annexin II stimulates RANKL expression through MAPK. Journal of Bone and Mineral Research, 20(7), 1161–1167.

    Article  PubMed  CAS  Google Scholar 

  57. Takahashi, S., Reddy, S. V., Chirgwin, J. M., et al. (1994). Cloning and identification of annexin II as an autocrine/paracrine factor that increases osteoclast formation and bone resorption. Journal of Biological Chemistry, 269(46), 28696–28701.

    PubMed  CAS  Google Scholar 

  58. Claudio, J. O., Masih-Khan, E., Tang, H., et al. (2002). A molecular compendium of genes expressed in multiple myeloma. Blood, 100(6), 2175–2186.

    Article  PubMed  CAS  Google Scholar 

  59. Bao, H., Jiang, M., Zhu, M., Sheng, F., Ruan, J., & Ruan, C. (2009). Overexpression of Annexin II affects the proliferation, apoptosis, invasion and production of proangiogenic factors in multiple myeloma. International Journal of Hematology, 90(2), 177–185.

    Article  PubMed  CAS  Google Scholar 

  60. D’Souza, S., Kurihara, N., Shiozawa, Y., Joseph, J., Taichman, R., Galson, D. L., & Roodman, G. D. (2012). Annexin II interactions with the annexin II receptor enhance multiple myeloma cell adhesion and growth in the bone marrow microenvironment. Blood, 119, 1888–1896.

    Article  PubMed  Google Scholar 

  61. Lee, J. W., Chung, H. Y., Ehrlich, L. A., et al. (2004). IL-3 expression by myeloma cells increases both osteoclast formation and growth of myeloma cells. Blood, 103(6), 2308–2315.

    Article  PubMed  CAS  Google Scholar 

  62. Rebecca Silbermann, Marina Bolzoni, Paola Storti, Benedetta Dalla Palma, Sabrina Bonomini, Judy Anderson, G. David Roodman, and Nicola Giuliani. (2011). Bone marrow monocyte/macrophage derived activin A mediates the osteoclastogenic effects of IL-3 in myeloma. Blood (ASH Annual Meeting Abstracts) 118: 3933.

  63. Cheung, W. C., & Van Ness, B. (2002). Distinct IL-6 signal transduction leads to growth arrest and death in B cells or growth promotion and cell survival in myeloma cells. Leukemia, 16(6), 1182–1188.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  Google Scholar 

  65. Gupta, D., Treon, S. P., Shima, Y., Hideshima, T., Podar, K., Tai, Y. T., Lin, B., Lentzsch, S., Davies, F. E., Chauhan, D., Schlossman, R. L., Richardson, P., Ralph, P., Wu, L., Payvandi, F., Muller, G., Stirling, D. I., & Anderson, K. C. (2001). Adherence of multiple myeloma cells to bone marrow stromal cells upregulates vascular endothelial growth factor secretion: therapeutic applications. Leukemia, 15(12), 1950–1961.

    Article  PubMed  CAS  Google Scholar 

  66. Riancho, J. A., & Mundy, G. R. (1995). The role of cytokines and growth factors as mediators of the effects of systemic hormones at the bone local level. Critical Reviews in Eukaryotic Gene Expression, 5(3–4), 193–217.

    Article  PubMed  CAS  Google Scholar 

  67. Raje, N., & Roodman, G. D. (2011). Advances in the biology and treatment of bone disease in multiple myeloma. Clinical Cancer Research, 17(6), 1278–1286.

    Article  PubMed  CAS  Google Scholar 

  68. Li, X., Pennisi, A., & Yaccoby, S. (2008). Role of decorin in the antimyeloma effects of osteoblasts. Blood, 112(1), 159–168.

    Article  PubMed  CAS  Google Scholar 

  69. Yang, X., & Karsenty, G. (2002). Transcription factors in bone: developmental and pathological aspects. Trends in Molecular Medicine, 8, 340.

    Article  PubMed  CAS  Google Scholar 

  70. Roodman, G. D. (2011). Osteoblast function in myeloma. Bone, 48(1), 135–140.

    Article  PubMed  Google Scholar 

  71. Tian, E., Zhan, F., Walker, R., et al. (2003). The role of the Wnt-signaling antagonist DKK1 in the development of osteolytic lesions in multiple myeloma. The New England Journal of Medicine, 349(26), 2483–2494.

    Article  PubMed  CAS  Google Scholar 

  72. Yaccoby, S., Ling, W., Zhan, F., Walker, R., Barlogie, B., & Shaughnessy, J. D., Jr. (2007). Antibody-based inhibition of DKK1 suppresses tumor-induced bone resorption and multiple myeloma growth in vivo. Blood, 109(5), 2106–2111.

    Article  PubMed  CAS  Google Scholar 

  73. Fulciniti, M., Tassone, P., Hideshima, T., et al. (2009). Anti-DKK1 mAb (BHQ880) as a potential therapeutic agent for multiple myeloma. Blood, 114(2), 371–379.

    Article  PubMed  CAS  Google Scholar 

  74. Oshima, T., Abe, M., Asano, J., et al. (2005). Myeloma cells suppress bone formation by secreting a soluble Wnt inhibitor, sFRP-2. Blood, 106(9), 3160–3165.

    Article  PubMed  CAS  Google Scholar 

  75. Ehrlich, L. A., Chung, H. Y., Ghobrial, I., et al. (2005). IL-3 is a potential inhibitor of osteoblast differentiation in multiple myeloma. Blood, 106(4), 1407–1414.

    Article  PubMed  CAS  Google Scholar 

  76. Giuliani, N., Colla, S., Morandi, F., et al. (2005). Myeloma cells block RUNX2/CBFA1 activity in human bone marrow osteoblast progenitors and inhibit osteoblast formation and differentiation. Blood, 106(7), 2472–2483.

    Article  PubMed  CAS  Google Scholar 

  77. Hjorth-Hansen, H., Seifert, M. F., Börset, M., Aarset, H., Ostlie, A., Sundan, A., & Waage, A. (1999). Marked osteoblastopenia and reduced bone formation in a model of multiple myeloma bone disease in severe combined immunodeficiency mice. Journal of Bone and Mineral Research, 14(2), 256–263.

    Article  PubMed  CAS  Google Scholar 

  78. Rokstad, A. M., Holtan, S., Strand, B., Steinkjer, B., Ryan, L., Kulseng, B., & Skjåk-Braek, G. (2002). Microencapsulation of cells producing therapeutic proteins: optimizing cell growth and secretion. TCell Transplant, 11(4), 313–324.

    Google Scholar 

  79. Kawasaki, T., Niki, Y., Miyamoto, T., Horiuchi, K., Matsumoto, M., Aizawa, M., & Toyama, Y. (2010). The effect of timing in the administration of hepatocyte growth factor to modulate BMP-2-induced osteoblast differentiation. Biomaterials, 31(6), 1191–1198.

    Article  PubMed  CAS  Google Scholar 

  80. Standal, T., Abildgaard, N., Fagerli, U. M., Stordal, B., Hjertner, O., Borset, M., & Sundan, A. (2007). HGF inhibits BMP-induced osteoblastogenesis: possible implications for the bone disease of multiple myeloma. Blood, 109(7), 3024–3030.

    PubMed  CAS  Google Scholar 

  81. Hideshima, T., Chauhan, D., Podar, K., Schlossman, R. L., Richardson, P., & Anderson, K. C. (2001). Novel therapies targeting the myeloma cell and its bone marrow microenvironment. Seminars in Oncology, 28(6), 607–612.

    Article  PubMed  CAS  Google Scholar 

  82. Zhao, L., Huang, J., Zhang, H., Wang, Y., Matesic, L. E., Takahata, M., Awad, H., Chen, D., & Xing, L. (2011). Tumor necrosis factor inhibits mesenchymal stem cell differentiation into osteoblasts via the ubiquitin E3 ligase Wwp1. Stem Cells, 29(10), 1601–1610. doi:10.1002/stem.703.

    Article  PubMed  CAS  Google Scholar 

  83. Olfa, G., Christophe, C., Philippe, L., Romain, S., Khaled, H., Pierre, H., Odile, B., & Jean-Christophe, D. (2010). RUNX2 regulates the effects of TNFalpha on proliferation and apoptosis in SaOs-2 cells. Bone, 46(4), 901–910.

    Article  PubMed  CAS  Google Scholar 

  84. Vallet, S., Mukherjee, S., Vaghela, N., Hideshima, T., Fulciniti, M., Pozzi, S., Santo, L., Cirstea, D., Patel, K., Sohani, A. R., Guimaraes, A., Xie, W., Chauhan, D., Schoonmaker, J. A., Attar, E., Churchill, M., Weller, E., Munshi, N., Seehra, J. S., Weissleder, R., Anderson, K. C., Scadden, D. T., & Raje, N. (2010). Activin A promotes multiple myeloma-induced osteolysis and is a promising target for myeloma bone disease. Proceedings of the National Academy of Sciences of the United States of America, 107(11), 5124–5129.

    Article  PubMed  CAS  Google Scholar 

  85. Chantry, A. D., Heath, D., Mulivor, A. W., Pearsall, S., Baud'huin, M., Coulton, L., Evans, H., Abdul, N., Werner, E. D., Bouxsein, M. L., Key, M. L., Seehra, J., Arnett, T. R., Vanderkerken, K., & Croucher, P. (2010). Inhibiting activin-A signaling stimulates bone formation and prevents cancer-induced bone destruction in vivo. Journal of Bone and Mineral Research, 25(12), 2633–2646. doi:10.1002/jbmr.142. Erratum in: J Bone Miner Res, 26(2), 439.

    Article  PubMed  Google Scholar 

  86. Lotinun, S., Pearsall, R. S., Davies, M. V., Marvell, T. H., Monnell, T. E., Ucran, J., Fajardo, R. J., Kumar, R., Underwood, K. W., Seehra, J., Bouxsein, M. L., & Baron, R. (2010). A soluble activin receptor Type IIA fusion protein (ACE-011) increases bone mass via a dual anabolic-antiresorptive effect in Cynomolgus monkeys. Bone, 46(4), 1082–1088.

    Article  PubMed  CAS  Google Scholar 

  87. Abdulkadyrov KM, Salogub GN, Khuazheva NK, Woolf R, Haltom E, Borgstein NG, Knight R, Renshaw G, Yang Y, Sherman ML. (2009). ACE-011, a Soluble Activin Receptor Type Iia IgG-Fc Fusion Protein, Increases Hemoglobin (Hb) and Improves Bone Lesions in Multiple Myeloma Patients Receiving Myelosuppressive Chemotherapy: Preliminary Analysis, American Society of Hematology (ASH) Meeting, Abstract 749.

  88. Brunetti, G., Oranger, A., Mori, G., Specchia, G., Rinaldi, E., Curci, P., Zallone, A., Rizzi, R., Grano, M., & Colucci, S. (2011). Sclerostin is overexpressed by plasma cells from multiple myeloma patients. Ann NY Acad Sci, 1237, 19–23. doi:10.1111/j.1749-6632.2011.06196.x.

    Article  PubMed  CAS  Google Scholar 

  89. Mendoza-Villanueva, D., Zeef, L., & Shore, P. (2011). Metastatic breast cancer cells inhibit osteoblast differentiation through the Runx2/CBFβ-dependent expression of the Wnt antagonist, sclerostin. Breast Cancer Research, 13(5), R106.

    Article  PubMed  CAS  Google Scholar 

  90. van Lierop, A. H., Hamdy, N. A., Hamersma, H., van Bezooijen, R. L., Power, J., Loveridge, N., & Papapoulos, S. E. (2011). Patients with sclerosteosis and disease carriers: human models of the effect of sclerostin on bone turnover. Journal of Bone and Mineral Research, 26(12), 2804–2811. doi:10.1002/jbmr.474.

    Article  PubMed  Google Scholar 

  91. Paszty, C., Turner, C. H., & Robinson, M. K. (2010). Sclerostin: a gem from the genome leads to bone-building antibodies. Journal of Bone and Mineral Research, 25(9), 1897–1904.

    Article  PubMed  CAS  Google Scholar 

  92. Terpos, E., Christoulas, D., Katodritou, E., Bratengeier, C., Gkotzamanidou, M., Michalis, E., Delimpasi, S., Pouli, A., Meletis, J., Kastritis, E., Zervas, K., & Dimopoulos, M. A. (2011). Elevated circulating sclerostin correlates with advanced disease features and abnormal bone remodeling in symptomatic myeloma: reduction post-bortezomib monotherapy. International Journal of Cancer. doi:10.1002/ijc.27342.

  93. D'Souza, S., del Prete, D., Jin, S., Sun, Q., Huston, A. J., Kostov, F. E., Sammut, B., Hong, C. S., Anderson, J. L., Patrene, K. D., Yu, S., Velu, C. S., Xiao, G., Grimes, H. L., Roodman, G. D., & Galson, D. L. (2011). Gfi1 expressed in bone marrow stromal cells is a novel osteoblast suppressor in patients with multiple myeloma bone disease. Blood, 118(26), 6871–6880.

    Article  PubMed  Google Scholar 

  94. Guise, T. A., Yin, J. J., & Mohammad, K. S. (2003). Role of endothelin-1 in osteoblastic bone metastases. Cancer, 97(3 Suppl), 779–784.

    Article  PubMed  Google Scholar 

  95. Granchi, S., Brocchi, S., Bonaccorsi, L., Baldi, E., Vinci, M. C., Forti, G., Serio, M., & Maggi, M. (2001). Endothelin-1 production by prostate cancer cell lines is up-regulated by factors involved in cancer progression and down-regulated by androgens. Prostate, 49(4), 267–277.

    Article  PubMed  CAS  Google Scholar 

  96. Clines, G. A., Mohammad, K. S., Bao, Y., et al. (2007). Dickkopf homolog 1 mediates endothelin-1-stimulated new bone formation. Molecular Endocrinology, 21(2), 486–498.

    Article  PubMed  CAS  Google Scholar 

  97. Yuyama, H., Koakutsu, A., Fujiyasu, N., Tanahashi, M., Fujimori, A., Sato, S., Shibasaki, K., Tanaka, S., Sudoh, K., Sasamata, M., & Miyata, K. (2004). Effects of selective endothelin ET(A) receptor antagonists on endothelin-1-induced potentiation of cancer pain. European Journal of Pharmacology, 492(2–3), 177–182.

    Article  PubMed  CAS  Google Scholar 

  98. Yi, B., Williams, P. J., Niewolna, M., et al. (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(3), 917–923.

    PubMed  CAS  Google Scholar 

  99. Dai, J., Keller, J., Zhang, J., et al. (2005). Bone morphogenetic protein-6 promotes osteoblastic prostate cancer bone metastases through a dual mechanism. Cancer Research, 65(18), 8274–8285.

    Article  PubMed  CAS  Google Scholar 

  100. Hall, C. L., Bafico, A., Dai, J., et al. (2005). Prostate cancer cells promote osteoblastic bone metastases through Wnts. Cancer Research, 65(17), 7554–7560.

    PubMed  CAS  Google Scholar 

  101. Achbarou, A., Kaiser, S., Tremblay, G., et al. (1994). Urokinase overproduction results in increased skeletal metastasis by prostate cancer cells in vivo. Cancer Research, 54(9), 2372–2377.

    PubMed  CAS  Google Scholar 

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Acknowledgments

This work was supported in part by research funds from the Multiple Myeloma Research Foundation, the Veterans Administration and the National Institutes of Health. I want to thank Susan Johnston for her help in producing the manuscript.

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Correspondence to G. David Roodman.

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Roodman, G.D. Genes associate with abnormal bone cell activity in bone metastasis. Cancer Metastasis Rev 31, 569–578 (2012). https://doi.org/10.1007/s10555-012-9372-x

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