Osteotropic Cancers: From Primary Tumor to Bone

  • Giacomina Brunetti
  • Graziana Colaianni
  • Maria Felicia Faienza
  • Silvia Colucci
  • Maria Grano
Original Paper

Abstract

Tumor-induced bone disease is a common clinical feature of hematological and metastatic solid cancer. Thus, numerous scientists have gained a better understanding of the mechanisms by which certain tumor types tend to invade specifically the bone. Firstly, Stephen Paget recognized the ‘seed and soil’ hypothesis, stating that cancer cells (the ‘seeds’) can only develop in secondary organs where the microenvironment (the ‘soil’–the bone) is permissive for their growth. Today, this theory has been enlarged to the metastatic process in general, because in order to grow in distant organs, tumor cells need special properties that suit them to those organs. Specifically, in order to metastasize to bone, cancer cells firstly detach from their tissue of origin, subsequently transit through circulation, reside in the bone marrow, and acquire a bone cell-like phenotype responsible for bone establishment and invasion. Each step in the metastatic cascade is rich in biological targets and mechanistic pathways, which are summarized in this review.

Keywords

Bone metastasis Osteolysis Osteomimicry Dormancy Bone marrow pre-metastatic niche Vicious cycle 

References

  1. 1.
    Coleman RE. Management of bone metastases. Oncologist. 2000;5(6):463–70.PubMedCrossRefGoogle Scholar
  2. 2.
    Paget S. The distribution of secondary growths in cancer of the breast. Lancet. 1889;1:571–3.CrossRefGoogle Scholar
  3. 3.
    Hart IR, Fidler IJ. Cancer invasion and metastasis. Q Rev Biol. 1980;55:121–42.PubMedCrossRefGoogle Scholar
  4. 4.
    Hanahan D, Folkman J. Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell. 1996;86:353–64.PubMedCrossRefGoogle Scholar
  5. 5.
    Folkman J. Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat Med. 1995;1:27–31.PubMedCrossRefGoogle Scholar
  6. 6.
    Boudreau N, Myers C. Breast cancer-induced angiogenesis: multiple mechanisms and the role of the microenvironment. Breast Cancer Res. 2003;5:140–6.PubMedCrossRefGoogle Scholar
  7. 7.
    Heimann R, Ferguson D, Powers C, Recant WM, Weichselbaum RR, Hellman S. Angiogenesis as a predictor of longterm survival for patients with node-negative breast cancer. J Natl Cancer Inst. 1996;88:1764–9.PubMedCrossRefGoogle Scholar
  8. 8.
    Allavena P, Sica A, Solinas G, Porta C, Mantovani A. The inflammatory microenvironment in tumor progression: the role of tumor-associated macrophages. Crit Rev Oncol Hematol. 2008;66(1):1–9.PubMedCrossRefGoogle Scholar
  9. 9.
    Jain RK. Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science. 2005;307(5706):58–62.PubMedCrossRefGoogle Scholar
  10. 10.
    Pepper MS. Lymphangiogenesis and tumor metastasis: myth or reality? Clin Cancer Res. 2001;7(3):462–8.PubMedGoogle Scholar
  11. 11.
    Nguyen DX, Massague J. Genetic determinants of cancer metastasis. Nat Rev Genet. 2007;8(5):341–52.PubMedCrossRefGoogle Scholar
  12. 12.
    Rodenhiser DI. Epigenetic contributions to cancer metastasis. Clin Exp Metastasis. 2009;26(1):5–18.PubMedCrossRefGoogle Scholar
  13. 13.
    Yilmaz M, Christofori G. EMT, the cytoskeleton, and cancer cell invasion. Cancer Metastasis Rev. 2009;28(1–2):15–33.PubMedCrossRefGoogle Scholar
  14. 14.
    Chambers AF, Groom AC, MacDonald IC. Dissemination and growth of cancer cells in metastatic sites. Nature Rev Cancer. 2002;2:563–72.CrossRefGoogle Scholar
  15. 15.
    Fidler IJ. Metastasis: quantitative analysis of distribution and fate of tumor emboli labeled with 125I-5-iodo-2′-deoxyuridine. J Natl Cancer Inst. 1970;45:773–82.PubMedGoogle Scholar
  16. 16.
    Im JH, Fu W, Wang H, Bhatia SK, Hammer DA, Kowalska MA, et al. Coagulation facilitates tumor cell spreading in the pulmonary vasculature during early metastatic colony formation. Cancer Res. 2004;64:8613–9.PubMedCrossRefGoogle Scholar
  17. 17.
    Palumbo JS. Mechanisms linking tumor cell associated procoagulant function to tumor dissemination. Semin Thromb Hemost. 2008;34:154–60.PubMedCrossRefGoogle Scholar
  18. 18.
    Nieswandt B, Hafner M, Echtenacher B, Mannel DN. Lysis of tumor cells by natural killer cells in mice is impeded by platelets. Cancer Res. 1999;59:1295–300.PubMedGoogle Scholar
  19. 19.
    Palumbo JS, Talmage KE, Massari JV, La Jeunesse CM, Flick MJ, Kombrinck KW, et al. Tumor cell-associated tissue factor and circulating hemostatic factors cooperate to increase metastatic potential through natural killer cell-dependent and -independent mechanisms. Blood. 2007;110:133–41.PubMedCrossRefGoogle Scholar
  20. 20.
    Boucharaba A, Serre CM, Gres S, Saulnier-Blache JS, Bordet JC, Guglielmi J, et al. Platelet-derived lysophosphatidic acid supports the progression of osteolytic bone metastases in breast cancer. J Clin Invest. 2004;114:1714–25.PubMedGoogle Scholar
  21. 21.
    Jurasz P, Alonso-Escolano D, Radomski MW. Platelet–cancer interactions: mechanisms and pharmacology of tumour cell-induced platelet aggregation. Br J Pharmacol. 2004;143:819–26.PubMedCrossRefGoogle Scholar
  22. 22.
    Nash GF, Turner LF, Scully MF, Kakkar AK. Platelets and cancer. Lancet Oncol. 2002;3:425–30.PubMedCrossRefGoogle Scholar
  23. 23.
    Shiozawa Y, Pedersen EA, Patel LR, Ziegler AM, Havens AM, Jung Y, et al. GAS6/AXL axis regulates prostate cancer invasion, proliferation, and survival in the bone marrow niche. Neoplasia. 2010;12:116–27.PubMedGoogle Scholar
  24. 24.
    Aft R, Naughton M, Trinkaus K, Watson M, Ylagan L, Chavez-MacGregor M, et al. Effect of zoledronic acid on disseminated tumour cells in women with locally advanced breast cancer: an open label, randomised, phase 2 trial. Lancet Oncol. 2010;11:421–8.PubMedCrossRefGoogle Scholar
  25. 25.
    Clezardin P. Integrins in bone metastasis formation and potential therapeutic implications. Curr Cancer Drug Targets. 2009;9:801–6.PubMedCrossRefGoogle Scholar
  26. 26.
    Braun S, Pantel K, Müller P, Janni W, Hepp F, Kentenich CR, et al. Cytokeratin-positive cells in the bone marrow and survival of patients with stage I, II, or III breast cancer. N Engl J Med. 2000;342:525–33.PubMedCrossRefGoogle Scholar
  27. 27.
    Coleman RE, Guise TA, Lipton A, Roodman GD, Berenson JR, Body JJ, et al. Advancing treatment for metastatic bone cancer: consensus recommendations from the Second Cambridge Conference. Clin Cancer Res. 2008;14:6387–95.PubMedCrossRefGoogle Scholar
  28. 28.
    Zhang XH, Wang Q, Gerald W, Hudis CA, Norton L, Smid M, et al. Latent bone metastasis in breast cancer tied to Src-dependent survival signals. Cancer Cell. 2009;16:67–78.PubMedCrossRefGoogle Scholar
  29. 29.
    Kelly T. Expression of heparanase by primary breast tumors promotes bone resorption in the absence of detectable bone metastases. Cancer Res. 2005;65:5778–84.PubMedCrossRefGoogle Scholar
  30. 30.
    Anborgh PH, Mutrie JC, Tuck AB, Chambers AF. Role of the metastasis-promoting protein osteopontin in the tumour microenvironment. J Cell Mol Med. 2006;14:2037–44.CrossRefGoogle Scholar
  31. 31.
    Lynch CC, Hikosaka A, Acuff HB, Martin MD, Kawai N, Singh RK, et al. MMP-7 promotes prostate cancer-induced osteolysis via the solubilization of RANKL. Cancer Cell. 2005;7:485–96.PubMedCrossRefGoogle Scholar
  32. 32.
    Guise TA, Mohammad KS, Clines G, Stebbins EG, Wong DH, Higgins LS, et al. Basic mechanisms responsible for osteolytic and osteoblastic bone metastases. Clin Cancer Res. 2006;12:6213s–6s.PubMedCrossRefGoogle Scholar
  33. 33.
    Oranger A, Colaianni G, Grano M. Bone Cells. In: Imaging of prosthetic joints a combined radiological and clinical perspective. Eds. Prof. Carlina Albanese and Prof. Carlo Faletti. (in press); doi:10.1007/978-88-470-5483-7_1. Springer, Italia, 2014.
  34. 34.
    Brunetti G, Di Benedetto A, Mori G. Bone remodeling. In: Imaging of prosthetic joints—a combined radiological and clinical perspective. Eds. Prof. Carlina Albanese and Prof. Carlo Faletti, Springer. (in press) doi:10.1007/978-88-470-5483-7_3. Springer, Italia, 2014.
  35. 35.
    Elliott RL, Blobe GC. Role of transforming growth factor β in human cancer. J Clin Oncol. 2005;23:2078–93.PubMedCrossRefGoogle Scholar
  36. 36.
    Powell GJ, Southby J, Danks JA, Stillwell RG, Hayman JA, Henderson MA, et al. Localization of parathyroid hormone-related protein in breast cancer metastases: increased incidence in bone compared with other sites. Cancer Res. 1991;51:3059–61.PubMedGoogle Scholar
  37. 37.
    Hiraga T, Myoui A, Choi ME, Yoshikawa H, Yoneda T. Stimulation of cyclooxygenase-2 expression by bone-derived transforming growth factor-β enhances bone metastases in breast cancer. Cancer Res. 2006;66:2067–73.PubMedCrossRefGoogle Scholar
  38. 38.
    Singh B, Berry JA, Shoher A, Ayers GD, Wei C, Lucci A. COX-2 involvement in breast cancer metastasis to bone. Oncogene. 2007;26(26):3789–96.PubMedCrossRefGoogle Scholar
  39. 39.
    Bendre MS, Margulies AG, Walser B, Akel NS, Bhattacharrya S, Skinner RA, et al. Tumor-derived interleukin-8 stimulates osteolysis independent of the receptor activator of nuclear factor-κB ligand pathway. Cancer Res. 2005;65:11001–9.PubMedCrossRefGoogle Scholar
  40. 40.
    Singh B, Berry JA, Shoher A, Lucci A. COX-2 induces IL-11 production in human breast cancer cells. J Surg Res. 2006;131:267–75.PubMedCrossRefGoogle Scholar
  41. 41.
    Horwood NJ, Elliott J, Martin TJ, Gillespie MT. Osteotropic agents regulate the expression of osteoclast differentiation factor and osteoprotegerin in osteoblastic stromal cells. Endocrinology. 1998;139:4743.PubMedCrossRefGoogle Scholar
  42. 42.
    Morgan H, Tumber A, Hill PA. Breast cancer cells induce osteoclast formation by stimulating host IL-11 production and downregulating granulocyte/macrophage colony-stimulating factor. Int J Cancer. 2004;109:653–60.PubMedCrossRefGoogle Scholar
  43. 43.
    Kang Y, Siegel PM, Shu W, Drobnjak M, Kakonen SM, Cordón-Cardo C, et al. A multigenic program mediating breast cancer metastasis to bone. Cancer Cell. 2003;3:537–49.PubMedCrossRefGoogle Scholar
  44. 44.
    Baserga R, Peruzzi F, Reiss K. The IGF-1 receptor in cancer biology. Int J Cancer. 2003;107:873–7.PubMedCrossRefGoogle Scholar
  45. 45.
    Brubaker KD, Corey E, Brown LG, Vessella RL. Bone morphogenetic protein signaling in prostate cancer cell lines. J Cell Biochem. 2004;91:151–60.PubMedCrossRefGoogle Scholar
  46. 46.
    Feeley BT, Gamradt SC, Hsu WK, Liu N, Krenek L, Robbins P, et al. Influence of BMPs on the formation of osteoblastic lesions in metastatic prostate cancer. J Bone Miner Res. 2005;20:2189–99.PubMedCrossRefGoogle Scholar
  47. 47.
    Harris AL. Hypoxia—a key regulatory factor in tumour growth. Nat Rev Cancer. 2002;2:38–47.PubMedCrossRefGoogle Scholar
  48. 48.
    Le QT, Denko NC, Giaccia AJ. Hypoxic gene expression and metastasis. Cancer Metastasis Rev. 2004;23:293–310.PubMedCrossRefGoogle Scholar
  49. 49.
    Peng XH, Karna P, Cao Z, Jiang BH, Zhou M, Yang L. Cross-talk between epidermal growth factor receptor and hypoxia-inducible factor-1α signal pathways increases resistance to apoptosis by up-regulating survivin gene expression. J Biol Chem. 2006;281:25903–14.PubMedCrossRefGoogle Scholar
  50. 50.
    McMahon S, Charbonneau M, Grandmont S, Richard DE, Dubois CM. Transforming growth factor β1 induces hypoxia-inducible factor-1 stabilization through selective inhibition of PHD2 expression. J Biol Chem. 2006;281:24171–81.PubMedCrossRefGoogle Scholar
  51. 51.
    Arnett T. Regulation of bone cell function by acid-base balance. Proc Nutr Soc. 2003;62:511–20.PubMedCrossRefGoogle Scholar
  52. 52.
    Brandao-Burch A, Utting JC, Orriss IR, Arnett TR. Acidosis inhibits bone formation by osteoblasts in vitro by preventing mineralization. Calcif Tissue Int. 2005;77:167–74.PubMedCrossRefGoogle Scholar
  53. 53.
    Raghunand N, Gatenby RA, Gillies RJ. Microenvironmental and cellular consequences of altered blood flow in tumours. Br J Radiol. 2003;76 Spec no 1:S11–22.Google Scholar
  54. 54.
    Gatenby RA, Gawlinski ET, Gmitro AF, Kaylor B, Gillies RJ. Acid-mediated tumor invasion: a multidisciplinary study. Cancer Res. 2006;66:5216–23.PubMedCrossRefGoogle Scholar
  55. 55.
    Shannon AM, Bouchier-Hayes DJ, Condron CM, Toomey D. Tumour hypoxia, chemotherapeutic resistance and hypoxia-related therapies. Cancer Treat Rev. 2003;29:297–307.PubMedCrossRefGoogle Scholar
  56. 56.
    Xie K, Huang S. Regulation of cancer metastasis by stress pathways. Clin Exp Metastasis. 2003;20:31–43.PubMedCrossRefGoogle Scholar
  57. 57.
    Dvorak MM, Siddiqua A, Ward DT, Carter DH, Dallas SL, Nemeth EF, et al. Physiological changes in extracellular calcium concentration directly control osteoblast function in the absence of calciotropic hormones. Proc Natl Acad Sci USA. 2004;101:5140–5.PubMedCrossRefGoogle Scholar
  58. 58.
    Berger CE, Rathod H, Gillespie JI, Horrocks BR, Datta HK. Scanning electrochemical microscopy at the surface of bone-resorbing osteoclasts: evidence for steady-state disposal and intracellular functional compartmentalization of calcium. J Bone Miner Res. 2001;16:2092–102.PubMedCrossRefGoogle Scholar
  59. 59.
    Sanders JL, Chattopadhyay N, Kifor O, Yamaguchi T, Butters RR, Brown EM. Extracellular calcium-sensing receptor expression and its potential role in regulating parathyroid hormone-related peptide secretion in human breast cancer cell lines. Endocrinology. 2000;141:4357–64.PubMedCrossRefGoogle Scholar
  60. 60.
    Sanders JL, Chattopadhyay N, Kifor O, Yamaguchi T, Brown EM. Ca(2+)-sensing receptor expression and PTHrP secretion in PC-3 human prostate cancer cells. Am J Physiol Endocrinol Metab. 2001;281:E1267–74.PubMedGoogle Scholar
  61. 61.
    Liao J, Schneider A, Datta NS, McCauley LK. Extracellular calcium as a candidate mediator of prostate cancer skeletal metastasis. Cancer Res. 2006;66:9065–73.PubMedCrossRefGoogle Scholar
  62. 62.
    Mihai R, Stevens J, McKinney C, Ibrahim NB. Expression of the calcium receptor in human breast cancer-a potential new marker predicting the risk of bone metastases. Eur J Surg Oncol. 2006;32:511–5.PubMedCrossRefGoogle Scholar
  63. 63.
    Knerr K, Ackermann K, Neidhart T, Pyerin W. Bone metastasis: osteoblasts affect growth and adhesion regulons in prostate tumor cells and provoke osteomimicry. Int J Cancer. 2004;111:152–9.PubMedCrossRefGoogle Scholar
  64. 64.
    Chung LW, Huang WC, Sung SY, Wu D, Odero-Marah V, Nomura T, et al. Stromal-epithelial interaction in prostate cancer progression. Clin Genitourin Cancer. 2006;5:162–70.PubMedCrossRefGoogle Scholar
  65. 65.
    Barnes GL, Javed A, Waller SM, Kamal MH, Hebert KE, Hassan MQ, et al. Osteoblast-related transcription factors Runx2 (Cbfa1/AML3) and MSX2 mediate the expression of bone sialoprotein in human metastatic breast cancer cells. Cancer Res. 2003;63:2631–7.PubMedGoogle Scholar
  66. 66.
    Huang WC, Xie Z, Konaka H, Sodek J, Zhau HE, Chung LW. Human osteocalcin and bone sialoprotein mediating osteomimicry of prostate cancer cells: role of cAMP-dependent protein kinase A signaling pathway. Cancer Res. 2005;65:2303–13.PubMedCrossRefGoogle Scholar
  67. 67.
    Desai B, Rogers MJ, Chellaiah MA. Mechanisms of osteopontin and CD44 as metastatic principles in prostate cancer cells. Mol Cancer. 2007;6:18.PubMedCrossRefGoogle Scholar
  68. 68.
    Campo McKnight DA, Sosnoski DM, Koblinski JE, Gay CV. Roles of osteonectin in the migration of breast cancer cells into bone. J Cell Biochem. 2006;97:288–302.PubMedCrossRefGoogle Scholar
  69. 69.
    Clezardin P, Teti A. Bone metastasis: pathogenesis and therapeutic implications. Clin Exp Metastasis. 2007;24(8):599–608.PubMedCrossRefGoogle Scholar
  70. 70.
    Colla S, Morandi F, Lazzaretti M, Rizzato R, Lunghi P, Bonomini S, et al. Human myeloma cells express the bone regulating gene Runx2/Cbfa1 and produce osteopontin that is involved in angiogenesis in multiple myeloma patients. Leukemia. 2005;19(12):2166–76.PubMedCrossRefGoogle Scholar
  71. 71.
    Akech J, Wixted JJ, Bedard K, van der Deen M, Hussain S, Guise TA, et al. Runx2 association with progression of prostate cancer in patients: mechanisms mediating bone osteolysis and osteoblastic metastatic lesions. Oncogene. 2010;29:811–21.PubMedCrossRefGoogle Scholar
  72. 72.
    Pratap J, Wixted JJ, Gaur T, Zaidi SK, Dobson J, Gokul KD, et al. Runx2 transcriptional activation of Indian Hedgehog and a downstream bone metastatic pathway in breast cancer cells. Cancer Res. 2008;68(19):7795–802.PubMedCrossRefGoogle Scholar
  73. 73.
    Das S, Samant RS, Shevde LA. Hedgehog signaling induced by breast cancer cells promotes osteoclastogenesis and osteolysis. J Biol Chem. 2011;286(11):9612–22.PubMedCrossRefGoogle Scholar
  74. 74.
    Mi Z, Guo H, Wai PY, Gao C, Wei J, Kuo PC. Differential osteopontin expression in phenotypically distinct subclones of murine breast cancer cells mediates metastatic behavior. J Biol Chem. 2004;279(45):46659–67.PubMedCrossRefGoogle Scholar
  75. 75.
    Kapoor P, Suva LJ, Welch DR, Donahue HJ. Osteoprotegrin and the bone homing and colonization potential of breast cancer cells. J Cell Biochem. 2008;103(1):30–41.PubMedCrossRefGoogle Scholar
  76. 76.
    Holen I, Cross SS, Neville-Webbe HL, Cross NA, Balasubramanian SP, Croucher PI, et al. Osteoprotegerin (OPG) expression by breast cancer cells in vitro and breast tumours in vivo—a role in tumour cell survival? Breast Cancer Res Treat. 2005;92(3):207–15.PubMedCrossRefGoogle Scholar
  77. 77.
    Fisher JL, Thomas-Mudge RJ, Elliott J, Hards DK, Sims NA, Slavin J, et al. Osteoprotegerin overexpression by breast cancer cells enhances orthotopic and osseous tumor growth and contrasts with that delivered therapeutically. Cancer Res. 2006;66(7):3620–8.PubMedCrossRefGoogle Scholar
  78. 78.
    Teitelbaum SL, Ross FP. Genetic regulation of osteoclast development and function. Nat Rev Genet. 2003;4(8):638–49.PubMedCrossRefGoogle Scholar
  79. 79.
    Takayama S, Ishii S, Ikeda T, Masamura S, Doi M, Kitajima M. The relationship between bone metastasis from human breast cancer and integrin alpha(v)beta3 expression. Anticancer Research. 2005;25(1A):79–83.PubMedGoogle Scholar
  80. 80.
    Bu G, Lu W, Liu CC, Selander K, Yoneda T, Hall C, et al. Breast cancer-derived Dickkopf1 inhibits osteoblast differentiation and osteoprotegerin expression: implication for breast cancer osteolytic bone metastases. Int J Cancer. 2008;123(5):1034–42.PubMedCrossRefGoogle Scholar
  81. 81.
    Brunetti G, Oranger A, Mori G, Specchia G, Rinaldi E, Curci P, et al. Sclerostin is overexpressed by plasma cells from multiple myeloma patients. Ann N Y Acad Sci. 2011;1237:19–23.PubMedCrossRefGoogle Scholar
  82. 82.
    Colucci S, Brunetti G, Oranger A, Mori G, Sardone F, Specchia G, et al. Myeloma cells suppress osteoblasts through sclerostin secretion. Blood Cancer J. 2011;1:e27.PubMedCrossRefGoogle Scholar
  83. 83.
    Mendoza-Villanueva D, Zeef L, Shore P. Metastatic breast cancer cells inhibit osteoblast differentiation through the Runx2/CBFβ-dependent expression of the Wnt antagonist, sclerostin. Breast Cancer Res. 2011;13(5):R106.PubMedCrossRefGoogle Scholar
  84. 84.
    Vallet S, Mukherjee S, Vaghela N, Hideshima T, Fulciniti M, Pozzi S, et al. Activin A promotes multiple myeloma-induced osteolysis and is a promising target for myeloma bone disease. PNAS. 2010;107(11):5124–9.PubMedCrossRefGoogle Scholar
  85. 85.
    Roodman GD. Mechanisms of bone metastasis. N Engl J Med. 2004;350:1655–64.PubMedCrossRefGoogle Scholar
  86. 86.
    Brown JE, Cook RJ, Major P, Lipton A, Saad F, Smith M, et al. Bone turnover markers as predictors of skeletal complications in prostate cancer, lung cancer, and other solid tumors. J Natl Cancer Inst. 2005;97:59–69.PubMedCrossRefGoogle Scholar
  87. 87.
    Coleman RE, Major P, Lipton A, Brown JE, Lee KA, Smith M, et al. Predictive value of bone resorption and formation markers in cancer patients with bone metastases receiving the bisphosphonate zoledronic acid. J Clin Oncol. 2005;23:4925–35.PubMedCrossRefGoogle Scholar
  88. 88.
    Mori G, D’Amelio P, Faccio R, Brunetti G. The interplay between the bone and the immune cells. Clin Dev Immunol. 2013;2013:720504.PubMedCrossRefGoogle Scholar
  89. 89.
    Roato I. Interaction among cells of bone, immune system, and solid tumors leads to bone metastases. Clin Dev Immunol. 2013;2013:315024.PubMedCrossRefGoogle Scholar
  90. 90.
    Zhang K, Kim S, Cremasco V, Hirbe AC, Collins L, Piwnica-Worms D, Novack DV, Weilbaecher K, Faccio R. CD8+ T cells regulate bone tumor burden independent of osteoclast resorption. Cancer Res. 2011;71(14):4799–808.PubMedCrossRefGoogle Scholar
  91. 91.
    Grano M, Brunetti G, Colucci S. Immunomodulation of multiple myeloma bone disease. Clin Rev Bone Miner Metab. 2009;7(4):293–300.CrossRefGoogle Scholar
  92. 92.
    Grano M, Brunetti G, Colucci S. Immunoregulation of osteoclast differentiation in multiple myeloma bone disease. In: Dominique H, editor. Bone cancer—progression and therapeutic approaches. London: Academic Press Elsevier; 2010. p. 67–75.Google Scholar
  93. 93.
    Colucci S, Brunetti G, Rizzi R, Zonno A, Mori G, Colaianni G, et al. T cells support osteoclastogenesis in an in vitro model derived from human multiple myeloma bone disease: the role of the OPG/TRAIL interaction. Blood. 2004;104(12):3722–30.PubMedCrossRefGoogle Scholar
  94. 94.
    Brunetti G, Colucci S, Rizzi R, Mori G, Colaianni G, Oranger A, et al. The role of OPG/TRAIL complex in multiple myeloma. Ann N Y Acad Sci. 2006;1068:334–40.PubMedCrossRefGoogle Scholar
  95. 95.
    Roato I, Grano M, Brunetti G, Colucci S, Mussa A, Bertetto O, et al. Mechanisms of spontaneous osteoclastogenesis in cancer with bone involvement. FASEB J. 2005;19(2):228–30.PubMedGoogle Scholar
  96. 96.
    Roato I, Brunetti G, Gorassini E, Grano M, Colucci S, Bonello L, et al. IL-7 up-regulates TNF-α-dependent osteoclastogenesis in patients affected by solid tumor. PLoS ONE. 2006;1:e124; 11.Google Scholar
  97. 97.
    Roato I, Gorassini E, Brunetti G, Grano M, Ciuffreda L, Mussa A, et al. IL-7 modulates osteoclastogenesis in patients affected by solid tumors. Ann N Y Acad Sci. 2007;1117:377–84.PubMedCrossRefGoogle Scholar
  98. 98.
    Colucci S, Brunetti G, Mori G, Oranger A, Centonze M, Mori C, et al. Soluble decoy receptor 3 (DcR3) modulates the survival and formation of osteoclasts from multiple myeloma bone disease patients. Leukemia. 2009;23(11):2139–46.PubMedCrossRefGoogle Scholar
  99. 99.
    Brunetti G, Oranger A, Mori G, Centonze M, Colaianni G, Rizzi R, et al. The formation of osteoclasts in multiple myeloma bone disease patients involves the secretion of soluble decoy receptor 3. Ann N Y Acad Sci. 2010;1192(1):298–302.PubMedCrossRefGoogle Scholar
  100. 100.
    Casas A, Llombart A, Martín M. Denosumab for the treatment of bone metastases in advanced breast cancer. Breast. 2013. doi:10.1016/j.breast.2013.05.007.

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Giacomina Brunetti
    • 1
  • Graziana Colaianni
    • 1
  • Maria Felicia Faienza
    • 2
  • Silvia Colucci
    • 1
  • Maria Grano
    • 1
  1. 1.Section of Human Anatomy and Histology, Department of Basic Medical Sciences, Neurosciences and Sense OrgansUniversity of BariBariItaly
  2. 2.Section of Pediatrics, Department of Biomedical Sciences and Human OncologyUniversity of BariBariItaly

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