Skip to main content

Biology and Pathophysiology of Bone Metastasis in Prostate Cancer

  • 1428 Accesses

Abstract

Several studies have attempted to correlate the extent of skeletal metastatic involvement, the number of bone metastases (BMTs) identified by bone scintigraphy or the distribution of BMTs (axial vs appendicular) with survival in patients with advanced prostate cancer (PC) [1, 2]. The number of BMTs has recently been evaluated as a prognostic predictor [3]. Patients with metastatic castration-resistant PC with a higher number of BMTs had a shorter progression-free survival (PFS) and overall survival (OS; hazard ratio 2.0; 95 % confidence interval 1.7–2.4). Patients with 1–4 BMTs have much better PFS and OS than those with 5–20 BMTs [4]. It should, however, be taken into account that among the predictors of prognosis, coexisting non-osseous metastatic disease is an important determinant of prognosis in patients with BMTs [5, 6].

Keywords

  • Prostate Cancer
  • Bone Resorption
  • Bone Metastasis
  • Prostate Cancer Cell
  • Bone Matrix

These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

This is a preview of subscription content, access via your institution.

Buying options

Chapter
USD   29.95
Price excludes VAT (USA)
  • DOI: 10.1007/978-3-319-42327-2_1
  • Chapter length: 12 pages
  • Instant PDF download
  • Readable on all devices
  • Own it forever
  • Exclusive offer for individuals only
  • Tax calculation will be finalised during checkout
eBook
USD   109.00
Price excludes VAT (USA)
  • ISBN: 978-3-319-42327-2
  • Instant PDF download
  • Readable on all devices
  • Own it forever
  • Exclusive offer for individuals only
  • Tax calculation will be finalised during checkout
Softcover Book
USD   149.99
Price excludes VAT (USA)
Hardcover Book
USD   149.99
Price excludes VAT (USA)
Fig. 1.1
Fig. 1.2

References

  1. Crawford ED, Eisenberger MA, McLeod DG, Spaulding JT, Benson R, Dorr FA, Blumenstein BA, Davis MA, Goodman PJ (1989) A controlled trial of leuprolide with and without flutamide in prostatic carcinoma. N Engl J Med 321(7):419–424

    CAS  CrossRef  PubMed  Google Scholar 

  2. Soloway MS, Hardeman SW, Hickey D, Raymond J, Todd B, Soloway S, Moinuddin M (1988) Stratification of patients with metastatic prostate cancer based on extent of disease on initial bone scan. Cancer 61(1):195–202

    CAS  CrossRef  PubMed  Google Scholar 

  3. Vargas HA, Wassberg C, Fox JJ, Wibmer A, Goldman DA, Kuk D, Gonen M, Larson SM, Morris MJ, Scher HI, Hricak H (2014) Bone metastases in castration-resistant prostate cancer: associations between morphologic CT patterns, glycolytic activity, and androgen receptor expression on PET and overall survival. Radiology 271(1):220–229

    CrossRef  PubMed  Google Scholar 

  4. Tait C, Moore D, Hodgson C, Brown M, Morris T, Growcott J, Malone M, Hughes A, Renehan A, Clarke NW, Dive C (2014) Quantification of skeletal metastases in castrate-resistant prostate cancer predicts progression-free and overall survival. BJU Int 114(6b):E70–E73

    CAS  CrossRef  PubMed  Google Scholar 

  5. Pond GR, Sonpavde G, de Wit R, Eisenberger MA, Tannock IF, Armstrong AJ (2014) The prognostic importance of metastatic site in men with metastatic castration-resistant prostate cancer. Eur Urol 65(1):3–6

    CrossRef  PubMed  Google Scholar 

  6. Ost P, Decaestecker K, Lambert B, Fonteyne V, Delrue L, Lumen N, Ameye F, De Meerleer G (2014) Prognostic factors influencing prostate cancer-specific survival in non-castrate patients with metastatic prostate cancer. Prostate 74(3):297–305

    CAS  CrossRef  PubMed  Google Scholar 

  7. Wang CY, Wu GY, Shen MJ, Cui KW, Shen Y (2013) Comparison of distribution characteristics of metastatic bone lesions between breast and prostate carcinomas. Oncol Lett 5(1):391–397

    PubMed  Google Scholar 

  8. Kakhki VR, Anvari K, Sadeghi R, Mahmoudian AS, Torabian-Kakhki M (2013) Pattern and distribution of bone metastases in common malignant tumors. Nucl Med Rev Cent East Eur 16(2):66–69

    CrossRef  PubMed  Google Scholar 

  9. Conti G, La Torre G, Cicalese V, Micheletti G, Ludovico MG, Vestita GD, Cottonaro G, Introini C, Cecchi M (2008) Prostate cancer metastases to bone: observational study for the evaluation of clinical presentation, course and treatment patterns. Presentation of the METAURO protocol and of patient baseline features. Arch Ital Urol Androl 80(2):59–64

    PubMed  Google Scholar 

  10. Goltzman D (1997) Mechanisms of the development of osteoblastic metastases. Cancer 80(8 Suppl):1581–1587

    CAS  CrossRef  PubMed  Google Scholar 

  11. Clarke NW, McClure J, George NJ (1991) Morphometric evidence for bone resorption and replacement in prostate cancer. Br J Urol 68(1):74–80

    CAS  CrossRef  PubMed  Google Scholar 

  12. Roudier MP, Morrissey C, True LD, Higano CS, Vessella RL, Ott SM (2008) Histopathological assessment of prostate cancer bone osteoblastic metastases. J Urol 180(3):1154–1160

    CrossRef  PubMed  PubMed Central  Google Scholar 

  13. Sone T, Tamada T, Jo Y, Miyoshi H, Fukunaga M (2004) Analysis of three-dimensional microarchitecture and degree of mineralization in bone metastases from prostate cancer using synchrotron microcomputed tomography. Bone 35(2):432–438

    CrossRef  PubMed  Google Scholar 

  14. Jernberg E, Thysell E, Bovinder Ylitalo E, Rudolfsson S, Crnalic S, Widmark A, Bergh A, Wikström P (2013) Characterization of prostate cancer bone metastases according to expression levels of steroidogenic enzymes and androgen receptor splice variants. PLoS One 8(11):e77407. doi:10.1371/journal.pone.0077407

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  15. Larson SR, Zhang X, Dumpit R, Coleman I, Lakely B, Roudier M, Higano CS, True LD, Lange PH, Montgomery B, Corey E, Nelson PS, Vessella RL, Morrissey C (2013) Characterization of osteoblastic and osteolytic proteins in prostate cancer bone metastases. Prostate 73(9):932–940

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  16. Fang J, Xu Q (2015) Differences of osteoblastic bone metastases and osteolytic bone metastases in clinical features and molecular characteristics. Clin Transl Oncol 17(3):173–179

    CAS  CrossRef  PubMed  Google Scholar 

  17. Martin TJ (2004) Paracrine regulation of osteoclast formation and activity: milestones in discovery. J Muscoloskelet Neuronal Interact 4:243–253

    CAS  Google Scholar 

  18. Ohshiba T, Miyaura C, Inada M et al (2003) Role of RANKL induced osteoclast formation and MMP dependent matrix degradation in bone destruction by breast cancer metastasis. Br J Cancer 88:1318–1326

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  19. Dallas SL, Prideaux M, Bonewald LF (2013) The osteocyte: an endocrine cell … more. Endocr Rev 34(5):658–690

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  20. Kitazawa S, Kitazawa R (2002) RANK ligand is a prerequisite for cancer associated osteolytic lesions. J Pathol 198:228–236

    CAS  CrossRef  PubMed  Google Scholar 

  21. Strewler GI (2000) Mechanisms of disease: the physiology of parathyroid hormone related protein. N Engl J Med 342:177–185

    CAS  CrossRef  PubMed  Google Scholar 

  22. Falzon M, Du P (2000) Enhanced growth of MCF-7 breast cancer cells overexpressing parathyroid hormone related peptide. Endocrinology 141:1882–1892

    CAS  PubMed  Google Scholar 

  23. Vargas SJ, Gillespie MT, Powell GJ et al (1992) Localization of parathyroid hormone-related protein mRA expression in metastatic lesions by in situ hybridization. J Bone Miner Res 7:971–980

    CAS  CrossRef  PubMed  Google Scholar 

  24. Kohno N, Kitazawa S, Fukase M et al (1994) The expression of parathyroid hormone related protein in human breast cancer with skeletal metastases. Surg Today 24:215–220

    CAS  CrossRef  PubMed  Google Scholar 

  25. Arima Y, Matsueda S, Yano H et al (2005) Parathyroid hormone related protein as a common target molecule in specific immunotherapy for a wide variety of tumour types. Int J Oncol 27:981–988

    CAS  PubMed  Google Scholar 

  26. Yao A, Harada A, Matsueda S et al (2005) New epitope peptides derived from parathyroid hormone related protein which have the capacity to induce prostate cancer reactive cytotoxic T-lymphocytes in HLA-A2* prostate cancer patients. Prostate 62:233–242

    CAS  CrossRef  PubMed  Google Scholar 

  27. Karaptis AC, Goltzman D (2000) PTH PTHrP effects on the skeleton. Rev Endocr Metab Disord 1:331–341

    CrossRef  Google Scholar 

  28. Yamamoto I, Bringhurst FR, Potts JT et al (1988) Properties of parathyroid hormone receptors on circulating bovine lymphocytes. J Bone Miner Res 3:289–295

    CAS  CrossRef  PubMed  Google Scholar 

  29. Atkinson MJ, Hesch RD, Cade C et al (1987) Parathyroid hormone stimulation of mitosis in rat thymic lymphocytes is independent of cyclic AMP. J Bone Miner Res 2:303–309

    CAS  CrossRef  PubMed  Google Scholar 

  30. Wu X, Qian W, Ryan M et al (2005) Continuous PTH treatment causes bone loss through upregulated T cell localization to the bone surfaces. J Bone Miner Res 20(Suppl 1):S14

    Google Scholar 

  31. Graves DT, Jiang Y, Valente AJ (1999) The expression of monocyte chemoattractant protein 1 and other chemokines by osteoblasts. Front Biosci 4:571–580

    CrossRef  Google Scholar 

  32. Bendre M, Gaddy-Kurten D, Foote-Mon T et al (2006) Expression of interleukin 8 and not parathyroid hormone related protein by human breast cancer cells correlates with bone metastasis in vivo. Cancer Res 66:2250–2256

    CrossRef  Google Scholar 

  33. Bendre M, Montague D, Peery T et al (2003) Interleukin 8 stimulation of osteoclastogenesis and bone resorption is a mechanism for the increased osteolysis of metastatic bone disease. Bone 33:28–37

    CAS  CrossRef  PubMed  Google Scholar 

  34. Guise TA, Chirgwin JM (2003) Transforming growth factor beta in osteolytic breast cancer bone metastases. Clin Orthop Relat Res 4155:532–538

    Google Scholar 

  35. Dovio A, Sartori ML, Masera RG et al (2004) Effects of physiological concentration of steroid hormones and interleukin 11 on basal and stimulated production of interleukin 8 by human osteoblast like cells with different functional profiles. Clin Exp Rheumatol 22:79–84

    CAS  PubMed  Google Scholar 

  36. Founier P, Chirgwin JM, Guise T (2006) New insights into the role of T cells in the vicious cycle of bone metastases. Curr Opin Rheumatol 18(4):396–40410.1097/01.bor.0000231909.35043.da

  37. Kostenuik PJ, Bolon B, Morony S et al (2004) Gene therapy with human recombinant osteoprotegerin reverses established osteopenia in ovariectomized mice. Bone 34(4):656–64

    Google Scholar 

  38. Whang PG, Schwarz EM, Gamradt SC et al (2005) The effects of RANK blockade and osteoclast depletion in a model of pure osteoblastic prostate cancer metastasis in bone. J Orthop Res 23:1475–1483

    CAS  CrossRef  PubMed  Google Scholar 

  39. Miller R, Jones J, Tometsko M et al (2005) Antituomour efficacy of the RANK ligand inhibitor OPG-Fc in the MDA-231 breast cancer and PC3 prostate cancer experimental osteolytic metastases models. J Bone Miner Res 20(Suppl 1):S117

    Google Scholar 

  40. Yonou H, Kanomata N, Goya M et al (2003) Osteprotegerin/osteoclastogenesis inhibitory factor decreases human prostate cancer burden in human adult bone implanted into nonobese diabetic/sever combined immunodeficient mice. Cancer Res 63:2096–2102

    CAS  PubMed  Google Scholar 

  41. Zhang J, Dai J, Qi Y et al (2001) Osteoprotegerin inhibits prostate cancer induced osteoclastogenesis and prevents prostate tumour growth in the bone. J Clin Invest 107:1235–1244

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  42. Wilson TJ, Nannuru KC, Futakuchi M, Sadanandam A, Singh RK (2008) Cathepsin G enhances mammary tumor-induced osteolysis by generating soluble receptor activator of nuclear factor-kappaB ligand. Cancer Res 68(14):5803–5811

    CAS  CrossRef  PubMed  Google Scholar 

  43. Brown J, Corey E, Lee Z et al (2001) Osteoprotegerin and rank ligand expression in prostate cancer. Urology 57:611–616

    CAS  CrossRef  PubMed  Google Scholar 

  44. Farrugia AN, Atkins GJ, To L et al (2003) Receptor activator of nuclear factor kappaB ligand expression by human myeloma cells mediates osteoclast formation in vitro and correlates with bone destruction in vivo. Cancer Res 63:5438–5445

    CAS  PubMed  Google Scholar 

  45. Terpos E, Dimopoulos MA (2005) Myeloma bone disease: pathophysiology and management. Ann Oncol 16:1223–1231

    CAS  CrossRef  PubMed  Google Scholar 

  46. Choi SJ, 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. J Clin Invest 108:1833–1841

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  47. Hall CL, Keller ET (2006) The role of Wnts in bone metastases. Cancer Metastasis Rev 25:551–558

    CAS  CrossRef  PubMed  Google Scholar 

  48. Hall CL, Kang S, Macdougald OA et al (2006) Role of Wnts in prostate cancer bone metastases. J Cell Biochem 97:661–672

    CAS  CrossRef  PubMed  Google Scholar 

  49. Clines GA, Mohammad KS, Bao Y, Stephens OW, Suva LJ, Shaughnessy JD Jr, Fox JW, Chirgwin JM, Guise TA (2007) Dickkopf homolog 1 mediates endothelin-1-stimulated new bone formation. Mol Endocrinol 21(2):486–498

    CAS  CrossRef  PubMed  Google Scholar 

  50. Chiao JW, Moonga BS, Yang YM, Kancherla R, Mittelman A, Wu-Wong JR, Ahmed T (2000) Endothelin-1 from prostate cancer cells is enhanced by bone contact which blocks osteoclastic bone resorption. Br J Cancer 83:360–365

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  51. Yin JJ, Mohammad KS, Kakonen SM, Harris S, Wu-Wong JR, Wessale JL, Padley RJ, Garrett IR, Chirgwin JM, Guise TA (2003) A causal role for endothelin-1 in the pathogenesis of osteoblastic bone metastases. Proc Natl Acad Sci U S A 100:10954–10959

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  52. Nelson JB, Chan-Tack K, Hedican SP, Magnuson SR, Opgenorth TJ, Bova GS, Simons JW (1996) Endothelin-1 production and decreased endothelin B receptor expression in advanced prostate cancer. Cancer Res 56:663–668

    CAS  PubMed  Google Scholar 

  53. Russo A, Bronte G, Rizzo S, Fanale D, Di Gaudio F, Gebbia N, Bazan V (2010) Anti- endothelin drugs in solid tumors. Expert Opin Emerg Drugs 15:27–40

    CAS  CrossRef  PubMed  Google Scholar 

  54. Kobayashi A, Okuda H, Xing F, Pandey PR, Watabe M, Hirota S, Pai SK, Liu W, Fukuda K, Chambers C, Wilber A, Watabe K (2011) Bone morphogenetic protein 7 in dormancy and metastasis of prostate cancer stem-like cells in bone. J Exp Med 208(13):2641–2655

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  55. Lee GT, Kang DI, Ha Y-S, Jung YS, Chung J, Min K, Kim TH, Moon KH, Chung JM, Lee DH, Kim W-J, Kim IY (2014) Prostate cancer bone metastases acquire resistance to androgen deprivation via WNT5A-mediated BMP-6 induction. Br J Cancer 110(6):1634–1644

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  56. Van de WM, Cavallo R, Dooijes D et al (1997) Armadillo coactivates transcription driven by the product of the Drosophila segment polarity gene dTCF. Cell 88:789–799

    CrossRef  Google Scholar 

  57. Day TF, Guo X, Garrett-Beal L et al (2005) Wnt/β-catenin signalling in mesenchymal progenitors controls osteoblast and chondrocyte differentiation during vertebrate skeletogenesis. Dev Cell 8:739–750

    CAS  CrossRef  PubMed  Google Scholar 

  58. Glass DA, Bialek P, Ahn JD et al (2005) Canonical Wnt signalling in differentiated osteoblasts controls osteoclast differentiation. Dev Cell 8:751–764

    CAS  CrossRef  PubMed  Google Scholar 

  59. Zhang Y, Wang Y, Li X et al (2004) The LRP 5 high-bone-mass G171V mutation disrupts LRP5 interaction with Mesd. Mol Cell Biol 24:4677–4684

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  60. Bafico A, Liu G, Yaniv A et al (2001) Novel mechanism of Wnt signalling inhibition mediated by Dikkopf 1 interaction with LRP6/Arrow. Nat Cell Biol 3:683–686

    CAS  CrossRef  PubMed  Google Scholar 

  61. MacDonald BT, Joiner D, Oyserman S et al (2007) Bone mass is inversely proportional to DKK1 levels in mice. Bone 41:331–339

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  62. Pearse R (2006) Wnt antagonism in multiple myeloma: a potential cause of uncoupled bone remodelling. Clin Cancer Res 12(Suppl 20):6274S–6278S

    CAS  CrossRef  PubMed  Google Scholar 

  63. Rosol TJ, Tannehill-Gregg SH, Corn S et al (2004) Animal models of bone metastasis. Cancer Treat Res 118:47–81

    CrossRef  PubMed  PubMed Central  Google Scholar 

  64. Dai J, Hall CL, Escara-Wilke J, Mizokami A, Keller JM, Keller ET (2008) Prostate cancer induces bone metastasis through Wnt-induced bone morphogenetic protein-dependent and independent mechanisms. Cancer Res 68:5785–5794

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  65. Rahim F, Hajizamani S, Mortaz E, Ahmadzadeh A, Shahjahani M, Shahrabi S, Saki N (2014) Molecular regulation of bone marrow metastasis in prostate and breast cancer. Bone Marrow Res 2014:405920

    CrossRef  PubMed  PubMed Central  Google Scholar 

  66. Roberts E, Cossigny DA, Quan GM (2013) The role of vascular endothelial growth factor in metastatic prostate cancer to the skeleton. Prostate Cancer 2013:418340

    CrossRef  PubMed  PubMed Central  Google Scholar 

  67. Sottnik JL, Dai J, Zhang H, Campbell B, Keller ET (2015) Tumor-induced pressure in the bone microenvironment causes osteocytes to promote the growth of prostate cancer bone metastases. Cancer Res 75(11):1–8

    CrossRef  Google Scholar 

  68. Monolagas SC, Jilka RL (1995) Bone marrow, cytokines and bone remodelling. N Engl J Med 332:305–311

    CrossRef  Google Scholar 

  69. Dallas SL, Rosser JL, Mundy GR et al (2002) Proteolysis of latent tranforming growth factor beta binding protein1 by osteoclasts. A cellular mechanism for release of TGF beta from bone matrix. J Biol Chem 277:21352–21360

    CAS  CrossRef  PubMed  Google Scholar 

  70. Liao J, Schneider A, Datta NS, McCauley LK (2006) Extracellular calcium as a candidate mediator of prostate cancer skeletal metastasis. Cancer Res 66(18):9065–9073

    CAS  CrossRef  PubMed  Google Scholar 

  71. Javelaud D, Alexaki VI, Dennler S, Mohammad KS, Guise TA, Mauviel A (2011) TGF-β/SMAD/GLI2 signaling axis in cancer progression and metastasis. Cancer Res 71(17):5606–5610

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  72. Wakefield LM, Hill CS (2013) Beyond TGFβ: roles of other TGFβ superfamily members in cancer. Nat Rev Cancer 13(5):328–341

    CAS  CrossRef  PubMed  Google Scholar 

  73. Lee HL, Pienta KJ, Kim WJ, Cooper CR (2003) The effect of bone-associated growth factors and cytokines on the growth of prostate cancer cells derived from soft tissue versus bone metastases in vitro. Int J Oncol 22(4):921–926

    CAS  PubMed  Google Scholar 

  74. Bogdanos J, Karamanolakis D, Tenta R, Tsintavis A, Milathianakis C, Mitsiades C, Koutsilieris M (2003) Endocrine/paracrine/autocrine survival factor activity of bone microenvironment participates in the development of androgen ablation and chemotherapy refractoriness of prostate cancer metastasis in skeleton. Endocr Relat Cancer 10(2):279–289

    CAS  CrossRef  PubMed  Google Scholar 

  75. Wang N, Docherty FE, Brown HK, Reeves KJ, Fowles AC, Ottewell PD, Dear TN, Holen I, Croucher PI, Eaton CL (2014) Prostate cancer cells preferentially home to osteoblast-rich areas in the early stages of bone metastasis: evidence from in vivo models. J Bone Miner Res 29(12):2688–2696

    CAS  CrossRef  PubMed  Google Scholar 

  76. Rubin J, Fan X, Rahnert J et al (2006) IGF1 secretion by prostate carcinoma cell does not alter tumor bone cell interactions in vitro or in vivo. Prostate 66:789–800

    CAS  CrossRef  PubMed  Google Scholar 

  77. Morrison CD, Parvani JG, Schiemann WP (2013) The relevance of the TGF-β Paradox to EMT-MET programs. Cancer Lett 341(1):30–40

    CAS  CrossRef  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Francesco Bertoldo MD .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and Permissions

Copyright information

© 2017 Springer International Publishing Switzerland

About this chapter

Cite this chapter

Bertoldo, F. (2017). Biology and Pathophysiology of Bone Metastasis in Prostate Cancer. In: Bertoldo, F., Boccardo, F., Bombardieri, E., Evangelista, L., Valdagni, R. (eds) Bone Metastases from Prostate Cancer . Springer, Cham. https://doi.org/10.1007/978-3-319-42327-2_1

Download citation

  • DOI: https://doi.org/10.1007/978-3-319-42327-2_1

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-319-42326-5

  • Online ISBN: 978-3-319-42327-2

  • eBook Packages: MedicineMedicine (R0)