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Bone metastasis: pathogenesis and therapeutic implications

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Abstract

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.

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Abbreviations

BMP:

Bone morphogenetic protein

BSP:

Bone sialoprotein

CDH11:

Cadherin 11

Cox-2:

Cycloxygenase 2

CXCL-12:

Chemokine (C-X-C motif) ligand 12

CXCR4:

Chemokine (C-X-C motif) receptor 4

Cx43:

Connexin 43

DKK-1:

Dickkopf

FGF:

Fibroblast growth factor

MSX2:

Homeo box homolog 2

OPG:

Osteoprotegerin

PDGF:

Platelet derived growth factor

PTHrP:

Parathyroid hormone related peptide

RANK:

Receptor activator of nuclear factor-κB

RANKL:

Receptor activator of nuclear factor-κB ligand

Runx2:

Runt-related transcription factor 2

SNO:

Spindle-shaped N-cadherin positive osteoblast

SPARC:

Secreted protein, acidic, cysteine-rich (osteonectin)

TGFβ:

Transforming growth factor β

VEGF:

Vascular endothelial growth factor

Wnt:

Wingless-type protein-1

References

  1. Gupta GP, Massague J (2006) Cancer metastasis: building a framework. Cell 127:679–695

    Article  PubMed  CAS  Google Scholar 

  2. Steeg PS (2006) Tumor metastasis: mechanistic insights and clinical challenges. Nat Med 12:895–904

    Article  PubMed  CAS  Google Scholar 

  3. Eccles SA, Welch DR (2007) Metastasis: recent discoveries and novel treatment strategies. Lancet 369:1742–1757

    Article  PubMed  CAS  Google Scholar 

  4. Hassan I (2006) Lung, metastases. In: Shoffer K, Coombs BD, Webb R, Krasny R, White CR, (eds) e-Medicine specialties—radiology—chest (http://www.emedicine.com/radio/topic404.htm). Cited October 25, 2006

  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 (http://www.emedicine.com/radio/topic394.htm). Cited January 24, 2007

  6. James JJ, Evans AJ, Pinder SE et al (2003) Bone metastases from breast carcinoma: histopathological–radiological correlations and prognostic features. Br J Cancer 89:660–665

    Article  PubMed  CAS  Google Scholar 

  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 (http://www.emedicine.com/radio/topic88.htm). Cited February 16, 2007

  8. Khosla A (2007) Brain, metastases. In: Creasy JL, Coombs BD, DeLaPaz RL, Krasny RM, Smirniotopoulos JG (eds) e-Medicine specialties—radiology—brain/spine (http://www.emedicine.com/radio/topic101.htm). Cited January 24, 2007

  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 (http://www.emedicine.com/radio/topic17.htm). Cited January 3, 2005

  10. Coleman RE (2006) Clinical features of metastatic bone disease and risk of skeletal morbidity. Clin Cancer Res 12:6243s–6249s

    Article  PubMed  Google Scholar 

  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 14:2197–2205

    PubMed  CAS  Google Scholar 

  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 130:708–711

    PubMed  CAS  Google Scholar 

  13. Coleman RE, Smith P, Rubens RD (1998) Clinical course and prognostic factors following bone recurrence from breast cancer. Br J Cancer 77:336–340

    PubMed  CAS  Google Scholar 

  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 21:173–180

    Article  PubMed  CAS  Google Scholar 

  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 59:271–278

    Article  PubMed  CAS  Google Scholar 

  16. Cook RJ, Major P (2006) Multistate analysis of skeletal events in patients with bone metastases. Clin Cancer Res 12:6264s–6269s

    Article  PubMed  Google Scholar 

  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 4246–4249

  18. Slade MJ, Coombes RC (2007) The clinical significance of disseminated tumor cells in breast cancer. Nat Clin Pract Oncol 4:30–41

    Article  PubMed  Google Scholar 

  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 4:42–55

    Article  PubMed  CAS  Google Scholar 

  20. Khosa AD, Nayyar MS, Beirne JC (2007) Osteochemonecrosis of jaws and bisphosphonates. Ir Med J 100:410–411

    PubMed  CAS  Google Scholar 

  21. Roodman GD (2004) Mechanism of bone metastases. N Eng J Med 350:1655–1664

    Article  CAS  Google Scholar 

  22. Guise TA, Mohammad KS, Clines G et al (2006) Basic mechanisms responsible for osteolytic and osteoblastic bone metastases. Clin Cancer Res 12:6213s–6216s

    Article  PubMed  CAS  Google Scholar 

  23. Virk MS, Lieberman JR (2007) Tumor metastasis to bone. Arthritis Res Ther 9:S5

    Article  PubMed  CAS  Google Scholar 

  24. Rose AAN, Siegel PM (2006) Breast cancer-derived factors facilitate osteolytic bone metastasis. Bull Cancer 93:931–943

    PubMed  CAS  Google Scholar 

  25. Ye L, Kynaston HG, Jiang WG (2007) Bone metastasis in prostate cancer: molecular and cellular mechanisms. Int J Mol Med 20:103–111

    PubMed  CAS  Google Scholar 

  26. Karsdal MA, Martin TJ, Bollerslev J et al (2007) Are nonresorbing osteoclasts sources of bone anabolic activity? J Bone Miner Res 22:487–494

    Article  PubMed  CAS  Google Scholar 

  27. Muller A, Homey B, Soto H et al (2001) Involvement of chemokine receptors in breast cancer metastasis. Nature 410:50–56

    Article  PubMed  CAS  Google Scholar 

  28. Liang Z, Wu T, Lou H et al (2004) Inhibition of breast cancer metastasis by selective synthetic polypeptide against CXCR4. Cancer Res 64:4302–4308

    Article  PubMed  CAS  Google Scholar 

  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 20:318–329

    Article  PubMed  CAS  Google Scholar 

  30. Jones DH, Nakashima T, Sanchez OH et al (2006) Regulation of cancer cell migration and bone metastasis by RANKL. Nature 440:692–696

    Article  PubMed  CAS  Google Scholar 

  31. Zhao Y, Bachelier R, Treilleux I et al (2007) Tumor αvβ3 integrin is a therapeutic target for breast cancer bone metastases. Cancer Res 67:5821–5830

    Article  PubMed  CAS  Google Scholar 

  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 66:8648–8654

    Article  PubMed  CAS  Google Scholar 

  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)

  34. Homsi J, Cubitt C, Daud A (2007) The Src signaling pathway: a potential target in melanoma and other malignancies. Expert Opin Ther Targets 11:91–100

    Article  PubMed  CAS  Google Scholar 

  35. Soriano P, Montgomery C, Geske R et al (1991) Targeted disruption of the c-src proto-oncogene leads to osteopetrosis in mice. Cell 64:693–702

    Article  PubMed  CAS  Google Scholar 

  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–S59

    Article  PubMed  CAS  Google Scholar 

  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 63:5028–5033

    PubMed  CAS  Google Scholar 

  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 318:161–172

    Article  PubMed  CAS  Google Scholar 

  39. Hussar DA (2007) New drugs: paliperidone, dasatinib, and decitabine. J Am Pharm Assoc 47:298–302

    Article  Google Scholar 

  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–S5

    Article  PubMed  CAS  Google Scholar 

  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 111:152–159

    Article  PubMed  CAS  Google Scholar 

  42. Chung LW, Huang WC, Sung SY et al (2006) Stromal-epithelial interaction in prostate cancer progression. Clin Genitourin Cancer 5:162–170

    Article  PubMed  Google Scholar 

  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 25:8581–8591

    Article  PubMed  CAS  Google Scholar 

  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 63:2631–2637

    PubMed  CAS  Google Scholar 

  45. Desai B, Rogers MJ, Chellaiah MA (2007) Mechanisms of osteopontin and CD44 as metastatic principles in prostate cancer cells. Mol Cancer 6:18

    Article  PubMed  CAS  Google Scholar 

  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 65:2303–2313

    Article  PubMed  CAS  Google Scholar 

  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 97:288–302

    Article  PubMed  CAS  Google Scholar 

  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 11:109

    Article  PubMed  CAS  Google Scholar 

  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 115:44–55

    PubMed  CAS  Google Scholar 

  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 102:1454–1459

    Article  PubMed  CAS  Google Scholar 

  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 101:135–148

    Article  PubMed  CAS  Google Scholar 

  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 57:5386–5390

    PubMed  CAS  Google Scholar 

  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 67:9894–9902

    Article  PubMed  CAS  Google Scholar 

  54. Morrissey C, Vessella RL (2007) The role of tumor microenvironment in prostate cancer bone metastasis. J Cell Biochem 101:873–886

    Article  PubMed  CAS  Google Scholar 

  55. Raisz LG (2005) Pathogenesis of osteoporosis: concepts, conflicts, prospects. J Clin Invest 115:3318–3325

    Article  PubMed  CAS  Google Scholar 

  56. Hadjidakis DJ, Androulakis II (2006) Bone remodeling. Ann N Y Acad Sci 1092:385–396

    Article  PubMed  CAS  Google Scholar 

  57. Zaidi M (2007) Skeletal remodeling in health and disease. Nature Med 13:791–801

    Article  PubMed  CAS  Google Scholar 

  58. Takayanagi H (2007) Osteoimmunology: shared mechanisms and crosstalk between the immune and bone systems. Nat Rev Immunol 7:292–304

    Article  PubMed  CAS  Google Scholar 

  59. Varghese S (2006) Matrix metalloproteinases and their inhibitors in bone: an overview of regulation and functions. Front Biosci 11:2949–2966

    Article  PubMed  CAS  Google Scholar 

  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 25:51–69

    Article  PubMed  CAS  Google Scholar 

  61. Aguila HL, Rowe DW (2005) Skeletal development, bone remodeling, and hematopoiesis. Immunol Rev 208:7–18

    Article  PubMed  CAS  Google Scholar 

  62. Paget S (1889) The distribution of secondary growths in cancer of the breast. Lancet 1:571–573

    Article  Google Scholar 

  63. Fidler IJ (2003) The pathogenesis of cancer metastasis: the ‘seed and soil’ hypothesis revisited. Nat Rev Cancer 3:453–458

    Article  PubMed  CAS  Google Scholar 

  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 170:160–175

    Article  PubMed  CAS  Google Scholar 

  65. Guise TA, Yin JJ, Mohammad KS (2003) Role of endothelin-1 in osteoblastic bone metastases. Cancer 97:779–784

    Article  PubMed  Google Scholar 

  66. Carducci MA, Jimeno A (2006) Targeting bone metastasis in prostate cancer with endothelin receptor antagonists. Clin Cancer Res 12:6296s–6300s

    Article  PubMed  CAS  Google Scholar 

  67. Chaffer CL, Thompson EW, Williams ED (2007) Mesenchymal to epithelial transition in development and disease. Cells Tissues Organs 185:7–19

    Article  PubMed  Google Scholar 

  68. Li L, Neaves WB (2006) Normal stem cells and cancer stem cells: the niche matters. Cancer Res 66:4553–4557

    Article  PubMed  CAS  Google Scholar 

  69. Liu S, Dontu G, Wicha MS (2005) Mammary stem cells, self renewal pathways, and carcinogenesis. Breast Cancer Res 7:86–95

    Article  PubMed  CAS  Google Scholar 

  70. Wicha MS, Liu S, Dontu G (2006) Cancer stem cells: an old idea-a paradigm shift. Cancer Res 66:1883–1890

    Article  PubMed  CAS  Google Scholar 

  71. Bapat SA (2007) Evolution of cancer stem cells. Semin Cancer Biol 17:204–213

    Article  PubMed  CAS  Google Scholar 

  72. Felsher DW (2006) Tumor dormancy. Cell cycle 5:1808–1811

    PubMed  CAS  Google Scholar 

  73. Karrison TG, Ferguson DJ, Meier P (1999) Dormancy of mammary carcinoma after mastectomy. J Natl Cancer Inst 91:80–85

    Article  PubMed  CAS  Google Scholar 

  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 60:2541–2546

    PubMed  CAS  Google Scholar 

  75. Marches R, Scheuermann R, Uhr J (2006) Cancer dormancy. From mice to man. Cell Cycle 5:1772–1778

    PubMed  CAS  Google Scholar 

  76. Naumov GN, MacDonald IC, Chambers AF et al (2001) Solitary cancer cells as a possible source of tumour dormancy? Cancer Biol 11:271–276

    Article  CAS  Google Scholar 

  77. Calvi LM, Adams GB, Weibrecht KW et al (2003) Osteoblastic cells regulate the hematopoietic stem cell niche. Nature 425:841–846

    Article  PubMed  CAS  Google Scholar 

  78. Yin T, Li L (2006) The stem cell niche in bone. J Clin Invest 116:1195–1201

    Article  PubMed  CAS  Google Scholar 

  79. Lu H, Ouyang W, Huang C (2006) Inflammation, a key event in cancer development. Mol Cancer Res 4:221–233

    Article  PubMed  CAS  Google Scholar 

  80. Yoshimura A (2006) Signal transduction of inflammation cytokines and tumor development. Cancer Sci 97:439–447

    Article  PubMed  CAS  Google Scholar 

  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 66:2067–2073

    Article  PubMed  CAS  Google Scholar 

  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 7:599–608

    Article  PubMed  CAS  Google Scholar 

  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 61:4432–4436

    PubMed  CAS  Google Scholar 

  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 12:1221–1228

    Article  PubMed  CAS  Google Scholar 

  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]

  86. Tsuchida K, Sunada Y, Noji S et al (2006) Inhibitors of the TGF-beta superfamily and their clinical applications. Mini Rev Med Chem 6:1255–1261

    Article  PubMed  CAS  Google Scholar 

  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 98:127–133

    Article  PubMed  CAS  Google Scholar 

  88. Eichhorn ME, Kleespies A, Angele MK et al (2007) Angiogenesis in cancer: molecular mechanisms, clinical impact. Langenbecks Arch Surg 392:371–379

    Article  PubMed  CAS  Google Scholar 

  89. Kitagawa Y, Dai J, Zhang J et al (2005) Vascular endothelial growth factor contributes to prostate cancer-mediated osteoblastic activity. Cancer Res 65:10921–10929

    Article  PubMed  CAS  Google Scholar 

  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 67:3560–3564

    Article  PubMed  CAS  Google Scholar 

  91. Thakkar SG, Choueiri TK, Garcia JA (2006) Endothelin receptor antagonists: rationale, clinical development, and role in prostate cancer therapeutics. Curr Oncol Rep 8:108–113

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

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).

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  1. INSERM, Research Unit 664, Laennec School of Medicine, Lyon, France

    Philippe Clezardin

  2. Department of Experimental Medicine, University of L’Aquila, Via Vetoio – Coppito 2, 67100, L’Aquila, Italy

    Anna Teti

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  1. Philippe Clezardin
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Correspondence to Anna Teti.

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Clezardin, P., Teti, A. Bone metastasis: pathogenesis and therapeutic implications. Clin Exp Metastasis 24, 599–608 (2007). https://doi.org/10.1007/s10585-007-9112-8

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