Clinical & Experimental Metastasis

, Volume 24, Issue 8, pp 599–608 | Cite as

Bone metastasis: pathogenesis and therapeutic implications

  • Philippe Clezardin
  • Anna Teti
Research Paper


Advanced cancers are prone to metastasize. Visceral metastases are more likely to be fatal, while patients with only metastases to bone can survive up to 10 years or more. However, effective treatments for bone metastases are not yet available and bisphosphonates improve the quality of life with no life-prolonging benefits. Bone metastases are classified as osteolytic, osteosclerotic or mixed lesions according to the bone cell types more prominently involved. Either conditions induce high morbidity and dramatically increase the risk of pathological fractures. Several molecular mechanisms bring about cancer cells to metastasize to bone, and osteotropic cancer cells are believed to acquire bone cell-like properties which improve homing, adhesion, proliferation and survival in the bone microenvironment. The acquisition of a bone cell pseudo-phenotype, denominated osteomimicry, is likely to rely on expression of osteoblastic and osteoclastic genes, thus requiring a multigenic programme. Several microenvironmental factors improve the ability of cancer cells to develop at skeletal sites, and a reciprocal deleterious stimulation generates a vicious cycle between the tumour cells and the cells residing in the bone environment. The impact of the stem cell niche in the development of bone metastases and in the phenomenon of tumour dormancy, that allows tumour cells to remain quiescent for decades before establishing overt lesions, is at present only speculative. However, the osteoblast niche, known to maintain the haematopoietic stem cell population in a quiescent status, is likely to be involved in the development of bone metastases and this promising research field is rapidly expanding.


Bone Breast Cancer Metastasis Osteolysis Osteoblast Osteoclast Prostate cancer 



Bone morphogenetic protein


Bone sialoprotein


Cadherin 11


Cycloxygenase 2


Chemokine (C-X-C motif) ligand 12


Chemokine (C-X-C motif) receptor 4


Connexin 43




Fibroblast growth factor


Homeo box homolog 2




Platelet derived growth factor


Parathyroid hormone related peptide


Receptor activator of nuclear factor-κB


Receptor activator of nuclear factor-κB ligand


Runt-related transcription factor 2


Spindle-shaped N-cadherin positive osteoblast


Secreted protein, acidic, cysteine-rich (osteonectin)


Transforming growth factor β


Vascular endothelial growth factor


Wingless-type protein-1



The original work was supported by the EU (MetaBre # LSHM-CT-2003-503049, to PC and AT), by the Associazione Italiana per la Ricerca sul Cancro (AIRC, to AT), the American Society for Bone and Mineral Research 2006 Bridge Funding Grant Award (to AT), and the Agence Nationale de la Recherche (GenHomme # 03 L 271, to PC).


  1. 1.
    Gupta GP, Massague J (2006) Cancer metastasis: building a framework. Cell 127:679–695PubMedCrossRefGoogle Scholar
  2. 2.
    Steeg PS (2006) Tumor metastasis: mechanistic insights and clinical challenges. Nat Med 12:895–904PubMedCrossRefGoogle Scholar
  3. 3.
    Eccles SA, Welch DR (2007) Metastasis: recent discoveries and novel treatment strategies. Lancet 369:1742–1757PubMedCrossRefGoogle Scholar
  4. 4.
    Hassan I (2006) Lung, metastases. In: Shoffer K, Coombs BD, Webb R, Krasny R, White CR, (eds) e-Medicine specialties—radiology—chest ( Cited October 25, 2006
  5. 5.
    Khan AN, Macdonald S (2007) Liver, metastasis. In: Amin Z, Coombs BD, Schmiedl UP, Krasny, RM, Karani J (eds) e-Medicine specialties—radiology—liver ( Cited January 24, 2007
  6. 6.
    James JJ, Evans AJ, Pinder SE et al (2003) Bone metastases from breast carcinoma: histopathological–radiological correlations and prognostic features. Br J Cancer 89:660–665PubMedCrossRefGoogle Scholar
  7. 7.
    Wilfred CG, Muttarak M (2007) Bone metastases. In: Abdel-Dayem HM, Coombs BD, Peh WCG, Krasny RM, Chew FS (eds) e-Medicine specialties—radiology—musculoskeletal ( Cited February 16, 2007
  8. 8.
    Khosla A (2007) Brain, metastases. In: Creasy JL, Coombs BD, DeLaPaz RL, Krasny RM, Smirniotopoulos JG (eds) e-Medicine specialties—radiology—brain/spine ( Cited January 24, 2007
  9. 9.
    Wansaicheong G, Goh J (2205) Adrenal metastases. In: Krinsky G Coombs BD, Friedman AC, Krasny RM, Lin EC (eds) e-Medicine specialties—radiology—genitourinary ( Cited January 3, 2005
  10. 10.
    Coleman RE (2006) Clinical features of metastatic bone disease and risk of skeletal morbidity. Clin Cancer Res 12:6243s–6249sPubMedCrossRefGoogle Scholar
  11. 11.
    Greenberg PA, Hortobagyi GN, Smith TL et al (1996) Long-term follow-up of patients with complete remission following combination chemotherapy for metastatic breast cancer. J Clin Oncol 14:2197–2205PubMedGoogle Scholar
  12. 12.
    Fan K, Peng CF (1983) Predicting the probability of bone metastasis through histological grading of prostate carcinoma: a retrospective correlative analysis of 81 autopsy cases with antemortem transurethral resection specimen. J Urol 130:708–711PubMedGoogle Scholar
  13. 13.
    Coleman RE, Smith P, Rubens RD (1998) Clinical course and prognostic factors following bone recurrence from breast cancer. Br J Cancer 77:336–340PubMedGoogle Scholar
  14. 14.
    Koenders PG, Beex LV, Kloppenborg PW et al (1992) Human breast cancer: survival from first metastasis. Breast Cancer Study Group. Breast Cancer Res Treat 21:173–180PubMedCrossRefGoogle Scholar
  15. 15.
    Solomayer EF, Diel IJ, Meyberg GC et al (2000) Metastatic breast cancer: clinical course, prognosis and therapy related to the first site of metastasis. Breast Cancer Res Treat 59:271–278PubMedCrossRefGoogle Scholar
  16. 16.
    Cook RJ, Major P (2006) Multistate analysis of skeletal events in patients with bone metastases. Clin Cancer Res 12:6264s–6269sPubMedCrossRefGoogle Scholar
  17. 17.
    Callaway MP, Briggs JC (1989) The incidence of late recurrence (greater than 10 years); an analysis of 536 consecutive cases of cutaneous melanoma. Br J Plast Surg 4246–4249Google Scholar
  18. 18.
    Slade MJ, Coombes RC (2007) The clinical significance of disseminated tumor cells in breast cancer. Nat Clin Pract Oncol 4:30–41PubMedCrossRefGoogle Scholar
  19. 19.
    Dunstan CR, Felsenberg D, Seibel MJ (2007) Therapy insight: the risks and benefits of bisphosphonates for the treatment of tumor-induced bone disease. Nat Clin Pract Oncol 4:42–55PubMedCrossRefGoogle Scholar
  20. 20.
    Khosa AD, Nayyar MS, Beirne JC (2007) Osteochemonecrosis of jaws and bisphosphonates. Ir Med J 100:410–411PubMedGoogle Scholar
  21. 21.
    Roodman GD (2004) Mechanism of bone metastases. N Eng J Med 350:1655–1664CrossRefGoogle Scholar
  22. 22.
    Guise TA, Mohammad KS, Clines G et al (2006) Basic mechanisms responsible for osteolytic and osteoblastic bone metastases. Clin Cancer Res 12:6213s–6216sPubMedCrossRefGoogle Scholar
  23. 23.
    Virk MS, Lieberman JR (2007) Tumor metastasis to bone. Arthritis Res Ther 9:S5PubMedCrossRefGoogle Scholar
  24. 24.
    Rose AAN, Siegel PM (2006) Breast cancer-derived factors facilitate osteolytic bone metastasis. Bull Cancer 93:931–943PubMedGoogle Scholar
  25. 25.
    Ye L, Kynaston HG, Jiang WG (2007) Bone metastasis in prostate cancer: molecular and cellular mechanisms. Int J Mol Med 20:103–111PubMedGoogle Scholar
  26. 26.
    Karsdal MA, Martin TJ, Bollerslev J et al (2007) Are nonresorbing osteoclasts sources of bone anabolic activity? J Bone Miner Res 22:487–494PubMedCrossRefGoogle Scholar
  27. 27.
    Muller A, Homey B, Soto H et al (2001) Involvement of chemokine receptors in breast cancer metastasis. Nature 410:50–56PubMedCrossRefGoogle Scholar
  28. 28.
    Liang Z, Wu T, Lou H et al (2004) Inhibition of breast cancer metastasis by selective synthetic polypeptide against CXCR4. Cancer Res 64:4302–4308PubMedCrossRefGoogle Scholar
  29. 29.
    Sun YX, Schneider A, Jung Y 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. J Bone Miner Res 20:318–329PubMedCrossRefGoogle Scholar
  30. 30.
    Jones DH, Nakashima T, Sanchez OH et al (2006) Regulation of cancer cell migration and bone metastasis by RANKL. Nature 440:692–696PubMedCrossRefGoogle Scholar
  31. 31.
    Zhao Y, Bachelier R, Treilleux I et al (2007) Tumor αvβ3 integrin is a therapeutic target for breast cancer bone metastases. Cancer Res 67:5821–5830PubMedCrossRefGoogle Scholar
  32. 32.
    Hall CL, Dai J, van Golen KL et al (2006) Type I collagen receptor (α2β1) signaling promotes the growth of human prostate cancer cells within the bone. Cancer Res 66:8648–8654PubMedCrossRefGoogle Scholar
  33. 33.
    Rucci N, Šuša M, Teti A (2007) Inhibition of protein kinase c-Src as a therapeutic approach for cancer and bone metastases. Anti-Cancer Agents in Med Chem (in press)Google Scholar
  34. 34.
    Homsi J, Cubitt C, Daud A (2007) The Src signaling pathway: a potential target in melanoma and other malignancies. Expert Opin Ther Targets 11:91–100PubMedCrossRefGoogle Scholar
  35. 35.
    Soriano P, Montgomery C, Geske R et al (1991) Targeted disruption of the c-src proto-oncogene leads to osteopetrosis in mice. Cell 64:693–702PubMedCrossRefGoogle Scholar
  36. 36.
    Hiscox S, Morgan L, Green T et al (2006) Src as a therapeutic target in anti-hormone/anti-growth factor-resistant breast cancer. Endocr Relat Cancer 13(Suppl 1):S53–S59PubMedCrossRefGoogle Scholar
  37. 37.
    Myoui A, Nishimura R, Williams PJ et al (2003) c-SRC tyrosine kinase activity is associated with tumor colonization in bone and lung in an animal model of human breast cancer metastasis. Cancer Res 63:5028–5033PubMedGoogle Scholar
  38. 38.
    Rucci N, Recchia I, Angelucci A et al (2006) Inhibition of protein kinase c-Src reduces the incidence of breast cancer metastases and increases survival in mice: implications for therapy. J Pharmacol Exp Ther 318:161–172PubMedCrossRefGoogle Scholar
  39. 39.
    Hussar DA (2007) New drugs: paliperidone, dasatinib, and decitabine. J Am Pharm Assoc 47:298–302CrossRefGoogle Scholar
  40. 40.
    Boyce BF, Xing L, Shakespeare W et al (2003) Regulation of bone remodeling and emerging breakthrough drugs for osteoporosis and osteolytic bone metastases. Kidney Int Suppl 85:S2–S5PubMedCrossRefGoogle Scholar
  41. 41.
    Knerr K, Ackermann K, Neidhart T et al (2004) Bone metastasis: osteoblasts affect growth and adhesion regulons in prostate tumor cells and provoke osteomimicry. Int J Cancer 111:152–159PubMedCrossRefGoogle Scholar
  42. 42.
    Chung LW, Huang WC, Sung SY et al (2006) Stromal-epithelial interaction in prostate cancer progression. Clin Genitourin Cancer 5:162–170PubMedCrossRefGoogle Scholar
  43. 43.
    Pratap J, Javed A, Languino LR et al (2005) The Runx2 osteogenic transcription factor regulates matrix metalloproteinase 9 in bone metastatic cancer cells and controls cell invasion. Mol Cell Biol 25:8581–8591PubMedCrossRefGoogle Scholar
  44. 44.
    Barnes GL, Javed A, Waller SM et al (2003) Osteoblast-related transcription factors Runx2 (Cbfa1/AML3) and MSX2 mediate the expression of bone sialoprotein in human metastatic breast cancer cells. Cancer Res 63:2631–2637PubMedGoogle Scholar
  45. 45.
    Desai B, Rogers MJ, Chellaiah MA (2007) Mechanisms of osteopontin and CD44 as metastatic principles in prostate cancer cells. Mol Cancer 6:18PubMedCrossRefGoogle Scholar
  46. 46.
    Huang WC, Xie Z, Konaka H et al (2005) Human osteocalcin and bone sialoprotein mediating osteomimicry of prostate cancer cells: role of cAMP-dependent protein kinase A signaling pathway. Cancer Res 65:2303–2313PubMedCrossRefGoogle Scholar
  47. 47.
    Campo McKnight DA, Sosnoski DM, Koblinski JE et al (2006) Roles of osteonectin in the migration of breast cancer cells into bone. J Cell Biochem 97:288–302PubMedCrossRefGoogle Scholar
  48. 48.
    Adwan H, Bäuerle TJ, Berger MR (2004) Downregulation of osteopontin and bone sialoprotein II is related to reduced colony formation and metastasis formation of MDA-MB-231 human breast cancer cells. Cancer Gene Ther 11:109PubMedCrossRefGoogle Scholar
  49. 49.
    Minn AJ, Kang Y, Serganova I et al (2005) Distinct organ-specific metastatic potential of individual breast cancer cells and primary tumors. J Clin Invest 115:44–55PubMedGoogle Scholar
  50. 50.
    Javed A, Barnes GL, Pratap J et al (2005) Impaired intranuclear trafficking of Runx2 (AML3/CBFA1) transcription factors in breast cancer cells inhibits osteolysis in vivo. Proc Natl Acad Sci USA 102:1454–1459PubMedCrossRefGoogle Scholar
  51. 51.
    Bellahcène A, Bachelier R, Detry C et al (2007) Transcriptome analysis reveals an osteoblast-like phenotype for human osteotropic breast cancer cells. Breast Cancer Res Treat 101:135–148PubMedCrossRefGoogle Scholar
  52. 52.
    Littlewood-Evans AJ, Bilbe G, Bowler WB et al (1997) The osteoclast-associated protease cathepsin K is expressed in human breast carcinoma. Cancer Res 57:5386–5390PubMedGoogle Scholar
  53. 53.
    Le Gall C, Bellahcène A, Bonnelye E et al (2007) A cathepsin K inhibitor reduces breast cancer-induced osteolysis and skeletal tumor burden. Cancer Res 67:9894–9902PubMedCrossRefGoogle Scholar
  54. 54.
    Morrissey C, Vessella RL (2007) The role of tumor microenvironment in prostate cancer bone metastasis. J Cell Biochem 101:873–886PubMedCrossRefGoogle Scholar
  55. 55.
    Raisz LG (2005) Pathogenesis of osteoporosis: concepts, conflicts, prospects. J Clin Invest 115:3318–3325PubMedCrossRefGoogle Scholar
  56. 56.
    Hadjidakis DJ, Androulakis II (2006) Bone remodeling. Ann N Y Acad Sci 1092:385–396PubMedCrossRefGoogle Scholar
  57. 57.
    Zaidi M (2007) Skeletal remodeling in health and disease. Nature Med 13:791–801PubMedCrossRefGoogle Scholar
  58. 58.
    Takayanagi H (2007) Osteoimmunology: shared mechanisms and crosstalk between the immune and bone systems. Nat Rev Immunol 7:292–304PubMedCrossRefGoogle Scholar
  59. 59.
    Varghese S (2006) Matrix metalloproteinases and their inhibitors in bone: an overview of regulation and functions. Front Biosci 11:2949–2966PubMedCrossRefGoogle Scholar
  60. 60.
    Kollet O, Dar A, Lapidot T (2007) The multiple roles of osteoclasts in host defense: bone remodeling and hematopoietic stem cell mobilization. Annu Rev Immunol 25:51–69PubMedCrossRefGoogle Scholar
  61. 61.
    Aguila HL, Rowe DW (2005) Skeletal development, bone remodeling, and hematopoiesis. Immunol Rev 208:7–18PubMedCrossRefGoogle Scholar
  62. 62.
    Paget S (1889) The distribution of secondary growths in cancer of the breast. Lancet 1:571–573CrossRefGoogle Scholar
  63. 63.
    Fidler IJ (2003) The pathogenesis of cancer metastasis: the ‘seed and soil’ hypothesis revisited. Nat Rev Cancer 3:453–458PubMedCrossRefGoogle Scholar
  64. 64.
    Schwaninger R, Rentsch CA, Wetterwald A et al (2007) Lack of noggin expression by cancer cells is a determinant of the osteoblast response in bone metastases. Am J Pathol 170:160–175PubMedCrossRefGoogle Scholar
  65. 65.
    Guise TA, Yin JJ, Mohammad KS (2003) Role of endothelin-1 in osteoblastic bone metastases. Cancer 97:779–784PubMedCrossRefGoogle Scholar
  66. 66.
    Carducci MA, Jimeno A (2006) Targeting bone metastasis in prostate cancer with endothelin receptor antagonists. Clin Cancer Res 12:6296s–6300sPubMedCrossRefGoogle Scholar
  67. 67.
    Chaffer CL, Thompson EW, Williams ED (2007) Mesenchymal to epithelial transition in development and disease. Cells Tissues Organs 185:7–19PubMedCrossRefGoogle Scholar
  68. 68.
    Li L, Neaves WB (2006) Normal stem cells and cancer stem cells: the niche matters. Cancer Res 66:4553–4557PubMedCrossRefGoogle Scholar
  69. 69.
    Liu S, Dontu G, Wicha MS (2005) Mammary stem cells, self renewal pathways, and carcinogenesis. Breast Cancer Res 7:86–95PubMedCrossRefGoogle Scholar
  70. 70.
    Wicha MS, Liu S, Dontu G (2006) Cancer stem cells: an old idea-a paradigm shift. Cancer Res 66:1883–1890PubMedCrossRefGoogle Scholar
  71. 71.
    Bapat SA (2007) Evolution of cancer stem cells. Semin Cancer Biol 17:204–213PubMedCrossRefGoogle Scholar
  72. 72.
    Felsher DW (2006) Tumor dormancy. Cell cycle 5:1808–1811PubMedGoogle Scholar
  73. 73.
    Karrison TG, Ferguson DJ, Meier P (1999) Dormancy of mammary carcinoma after mastectomy. J Natl Cancer Inst 91:80–85PubMedCrossRefGoogle Scholar
  74. 74.
    Cameron DM, Schmidt EE, Kerkvliet N et al (2000) Temporal progression of metastasis in lung: cell survival, dormancy and location dependence of metastatic inefficiency. Cancer Res 60:2541–2546PubMedGoogle Scholar
  75. 75.
    Marches R, Scheuermann R, Uhr J (2006) Cancer dormancy. From mice to man. Cell Cycle 5:1772–1778PubMedGoogle Scholar
  76. 76.
    Naumov GN, MacDonald IC, Chambers AF et al (2001) Solitary cancer cells as a possible source of tumour dormancy? Cancer Biol 11:271–276CrossRefGoogle Scholar
  77. 77.
    Calvi LM, Adams GB, Weibrecht KW et al (2003) Osteoblastic cells regulate the hematopoietic stem cell niche. Nature 425:841–846PubMedCrossRefGoogle Scholar
  78. 78.
    Yin T, Li L (2006) The stem cell niche in bone. J Clin Invest 116:1195–1201PubMedCrossRefGoogle Scholar
  79. 79.
    Lu H, Ouyang W, Huang C (2006) Inflammation, a key event in cancer development. Mol Cancer Res 4:221–233PubMedCrossRefGoogle Scholar
  80. 80.
    Yoshimura A (2006) Signal transduction of inflammation cytokines and tumor development. Cancer Sci 97:439–447PubMedCrossRefGoogle Scholar
  81. 81.
    Hiraga T, Myoui A, Choi ME et al (2006) Stimulation of cyclooxygenase-2 expression by bone-dervided transforming growth factor-beta enhances bone metastases in breast cancer. Cancer Res 66:2067–2073PubMedCrossRefGoogle Scholar
  82. 82.
    Sarkar FH, Adsule S, Li Y, Padhye S (2007) Back to the future: COX-2 inhibitors for chemoprevention and cancer therapy. Mini Rev Med Chem 7:599–608PubMedCrossRefGoogle Scholar
  83. 83.
    Morony S, Capparelli C, Sarosi I et al (2001) Osteoprotegerin inhibits osteolysis and decreases skeletal tumor burden in syngeneic and nude mouse models of experimental bone metastasis. Cancer Res 61:4432–4436PubMedGoogle Scholar
  84. 84.
    Body JJ, Facon T, Coleman RE et al (2006) A study of the biological receptor activator of nuclear factor-kappaB ligand inhibitor, denosumab, in patients with multiple myeloma or bone metastases from breast cancer. Clin Cancer Res 12:1221–1228PubMedCrossRefGoogle Scholar
  85. 85.
    Lipton A, Steger GG, Figueroa J et al (2007) Randomized active-controlled phase II Study Of Denosumab Efficacy And Safety In Patients With Breast Cancer-Related Bone Metastases. J Clin Oncol Sep 4; [Epub ahead of print]Google Scholar
  86. 86.
    Tsuchida K, Sunada Y, Noji S et al (2006) Inhibitors of the TGF-beta superfamily and their clinical applications. Mini Rev Med Chem 6:1255–1261PubMedCrossRefGoogle Scholar
  87. 87.
    Ehata S, Hanyu A, Fujime M et al (2007) Ki26894, a novel transforming growth factor-beta type I receptor kinase inhibitor, inhibits in vitro invasion and in vivo bone metastasis of a human breast cancer cell line. Cancer Sci 98:127–133PubMedCrossRefGoogle Scholar
  88. 88.
    Eichhorn ME, Kleespies A, Angele MK et al (2007) Angiogenesis in cancer: molecular mechanisms, clinical impact. Langenbecks Arch Surg 392:371–379PubMedCrossRefGoogle Scholar
  89. 89.
    Kitagawa Y, Dai J, Zhang J et al (2005) Vascular endothelial growth factor contributes to prostate cancer-mediated osteoblastic activity. Cancer Res 65:10921–10929PubMedCrossRefGoogle Scholar
  90. 90.
    Folkins C, Man S, Xu P et al (2007) Anticancer therapies combining antiangiogenic and tumor cell cytotoxic effects reduce the tumor stem-like cell fraction in glioma xenograft tumors. Cancer Res 67:3560–3564PubMedCrossRefGoogle Scholar
  91. 91.
    Thakkar SG, Choueiri TK, Garcia JA (2006) Endothelin receptor antagonists: rationale, clinical development, and role in prostate cancer therapeutics. Curr Oncol Rep 8:108–113PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2007

Authors and Affiliations

  1. 1.INSERM, Research Unit 664Laennec School of MedicineLyonFrance
  2. 2.Department of Experimental MedicineUniversity of L’AquilaL’AquilaItaly

Personalised recommendations