Pathophysiology of Bone Metastases

Chapter
First Online:
Part of the Cancer Metastasis - Biology and Treatment book series (CMBT, volume 21)

Abstract

Bone metastases are a late event in tumor progression, contributing to morbidity and mortality and decreasing patient quality of life. Cancer colonization of the skeleton is characteristic of advanced tumors of breast, prostate and other sites and of multiple myeloma. The pathophysiology of cancer in the skeleton can be conceptualized as a vicious cycle, where cancer-secreted factors activate bone cells to release factors that encourage further growth of tumor, which in turn secretes more factors into the microenvironment. Bone provides unusual physical conditions favorable to tumor growth: low pH and oxygen tension and high concentrations of calcium, phosphate and many growth factors. It also houses stem cells, bone marrow and immune cells, which can encourage the establishment, growth and survival of metastases. A plethora of bone and tumor factors contributes to the vicious cycle: too many to be individually targeted in the clinic. However, inhibition of bone resorption is invariably effective and may oppose the initial development of cancer in bone. Central pathways, such as hypoxia and TGFβ signaling, are important for both tumor and bone functions; they are promising targets for improved therapies, while other pathways may yield future treatments to decrease bone metastases and myeloma bone disease.

Keywords

Bone metastasis Multiple myeloma Bone resorption Osteoblast Osteoclast Osteocyte Vicious cycle 
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References

  1. 1.
    Roodman GD (2004) Mechanisms of bone metastasis. N Engl J Med 350(16):1655–1664, PMID:15084698PubMedCrossRefGoogle Scholar
  2. 2.
    Coleman RE (1997) Skeletal complications of malignancy. Cancer 80(8 Suppl):1588–1594, PMID: 9362426PubMedCrossRefGoogle Scholar
  3. 3.
    Sturge J, Caley MP, Waxman J (2011) Bone metastasis in prostate cancer: emerging therapeutic strategies. Nat Rev Clin Oncol 8(6):357–368. doi: 10.1038/nrclinonc.2011.67, Epub 10 May 2011. Review. Erratum in: Nat Rev Clin Oncol. 2011;8(10):568. PMID: 21556025PubMedGoogle Scholar
  4. 4.
    Jemal A, Siegel R, Ward E et al (2007) Cancer statistics. CA Cancer J Clin 57(1):43–66, PMID: 17237035PubMedCrossRefGoogle Scholar
  5. 5.
    Santini D, Galluzzo S, Zoccoli A et al (2010) New molecular targets in bone metastases. Cancer Treat Rev 36(Suppl 3):S6–S10. doi: 10.1016/S0305-7372(10)70013-X, PMID: 21129612PubMedCrossRefGoogle Scholar
  6. 6.
    Kozlow W, Guise TA (2005) Breast cancer metastasis to bone: mechanisms of osteolysis and implications for therapy. J Mammary Gland Biol Neoplasia 10(2):169–180, PMID: 16025223PubMedCrossRefGoogle Scholar
  7. 7.
    Roudier MP, Corey E, True LD et al (2004) Histological, immunophenotypic and histomorphometric characterization of prostate cancer bone metastases. Cancer Treat Res 118:311–339, PMID: 15043198PubMedCrossRefGoogle Scholar
  8. 8.
    Liu W, Laitinen S, Khan S et al (2009) Copy number analysis indicates monoclonal origin of lethal metastatic prostate cancer. Nat Med 15(5):559–565. doi: 10.1038/nm.1944, Epub 12 Apr 2009. Erratum in: Nat Med 2009;15(7):819. PMID: 19363497PubMedCrossRefGoogle Scholar
  9. 9.
    Langley RR, Fidler IJ (2011) The seed and soil hypothesis revisited – the role of tumor-stroma interactions in metastasis to different organs. Int J Cancer 128(11):2527–2535. doi: 10.1002/ijc.26031, Epub 25 Mar 2011. Review. PMID: 213656651PubMedCrossRefGoogle Scholar
  10. 10.
    Yoneda T, Hiraga T (2005) Crosstalk between cancer cells and bone microenvironment in bone metastasis. Biochem Biophys Res Commun 328(3):679–687, PMID: 15694401PubMedCrossRefGoogle Scholar
  11. 11.
    Buijs JT, Juárez P, Guise TA (2011) Therapeutic strategies to target TGF-β in the treatment of bone metastases. Curr Pharm Biotechnol 12(12):2121–2137, PMID: 21619539PubMedCrossRefGoogle Scholar
  12. 12.
    van der Horst G, van der Pluijm G (2012) Preclinical models that illuminate the bone metastasis cascade. Recent Results Cancer Res 192:1–31. doi: 10.1007/978-642-21892-7_1, PMID: 22307368PubMedCrossRefGoogle Scholar
  13. 13.
    Mastro AM, Vogler EA (2009) A three-dimensional osteogenic tissue model for the study of metastatic tumor cell interactions with bone. Cancer Res 69(10):4097–4100. doi: 10.1158/0008-5472.CAN-08-4437, Epub 12 May. PMID: 19435905PubMedCrossRefGoogle Scholar
  14. 14.
    Shiozawa Y, Pedersen EA, Havens et al (2011) Human prostate cancer metastases target the hematopoietic stem cell niche to establish footholds in mouse bone marrow. J Clin Invest 121(4):1298–1312. doi: 10.1172/JCI43414, Epub 23 Mar. PMID: 21436587PubMedCrossRefGoogle Scholar
  15. 15.
    Chirgwin JM (2012) The stem cell niche as a pharmaceutical target for prevention of skeletal metastases. Anticancer Agents Med Chem 12(3):187–193, PMID: 22044002PubMedCrossRefGoogle Scholar
  16. 16.
    Kang Y, Siegel PM, Shu W et al (2003) A multigenic program mediating breast cancer metastasis to bone. Cancer Cell 3(6):537–549, PMID: 12842083PubMedCrossRefGoogle Scholar
  17. 17.
    Peinado H, Lavotshkin S, Lyden D (2011) The secreted factors responsible for pre-metastatic niche formation: old sayings and new thoughts. Semin Cancer Biol 21(2):139–146. doi: 10.1016/j.semcancer.2011.01.002, PMID: 21251983PubMedCrossRefGoogle Scholar
  18. 18.
    Thorpe MP, Valentine RJ, Moulton CJ et al (2011) Breast tumor induced by N-methyl-N-nitrosourea are damaging to bone strength, structure, and mineralization in the absence of metastasis in rats. J Bone Miner Res 26(4):769–776. doi: 10.1002/jbmr.277, PMID: 20939066PubMedCrossRefGoogle Scholar
  19. 19.
    Soki FN, Park SI, McCauley LK (2012) The multifaceted actions of PTHrP in skeletal metastasis. Future Oncol 8(7):803–817. doi: 10.2217/fon.12.76, PMID: 22830401PubMedCrossRefGoogle Scholar
  20. 20.
    Sanderson RD, Iozzo RV (2012) Targeting heparanase for cancer therapy at the tumor-matrix interface. Matrix Biol 31(5):283–284. doi: 10.1016/j.matbio.2012.05.001, PMID: 22655968PubMedCrossRefGoogle Scholar
  21. 21.
    Hall CL, Keller ET (2006) The role of Wnts in bone metastases. Cancer Metastasis Rev 25(4):551–558, PMID: 17160558PubMedCrossRefGoogle Scholar
  22. 22.
    Faccio R (2011) Immune regulation of the tumor/bone vicious cycle. Ann N Y Acad Sci 1237:71–78. doi: 10.1111/j.1749-6632.2011.06244.x, PMID: 22082368PubMedCrossRefGoogle Scholar
  23. 23.
    O’Brien CA, Nakashima T, Takayanagi H (2013) Osteocyte control of osteoclastogenesis. (review). Bone 54(2):258–263. doi: 10.1016/j.bone2012.08.121 (Epub 23 Aug 2012, PMID: 22939943)Google Scholar
  24. 24.
    Roodman GD (2012) Genes associate with abnormal bone cell activity in bone metastasis. Cancer Metastasis Rev 31(3–4):569–578. doi: 10.1007/s10555-012-9372-x, PMID: 22706844PubMedCrossRefGoogle Scholar
  25. 25.
    Clines GA, Mohammad KS, Bao Y et al (2007) Dickkopf homolog 1 mediates endothelin-1-stimulated new bone formation. Mol Endocrinol 21(2):486–498, PMID: 17068196PubMedCrossRefGoogle Scholar
  26. 26.
    Yin JJ, Mohammad KS, Käkönen SM et al (2003) A causal role for endothelin-1 in the pathogenesis of osteoblastic bone metastases. Proc Natl Acad Sci U S A 100(19):10954–10959, PMID: 12941866PubMedCrossRefGoogle Scholar
  27. 27.
    Robinson DR, Zylstra CR, Williams BO (2008) Wnt signaling and prostate cancer. Curr Drug Targets 9(7):571–580, PMID: 18673243PubMedCrossRefGoogle Scholar
  28. 28.
    Pinzone JJ, Hall BM, Thudi NK et al (2009) The role of Dickkopf-1 in bone development, homeostasis, and disease. Blood 113(3):517–525. doi: 10.1182/blood-2008-03-145169, PMID: 18687985PubMedCrossRefGoogle Scholar
  29. 29.
    Sethi N, Kang Y (2011) Notch signalling in cancer progression and bone metastasis. Br J Cancer 105(12):1805–1810. doi: 10.1038/bjc.2011.497, PMID: 22075946PubMedCrossRefGoogle Scholar
  30. 30.
    Boyce B, Xing L (2011) Src inhibitors in the treatment of metastatic bone disease: rationale and clinical data. Clin Investig (Lond) 1(12):1695–1706, PMID: 22384312CrossRefGoogle Scholar
  31. 31.
    Pratap J, Lian JB, Stein GS (2011) Metastatic bone disease: role of transcription factors and future targets. Bone 48(1):30–36. doi: 10.1016/j.bone.2010.05.035, PMID: 20561908PubMedCrossRefGoogle Scholar
  32. 32.
    Kingsley LA, Fournier PG, Chirgwin JM et al (2007) Molecular biology of bone metastasis. Mol Cancer Ther 6(10):2609–2617, PMID: 17938257PubMedCrossRefGoogle Scholar
  33. 33.
    Le QT, Denko NC, Giaccia AJ (2004) Hypoxic gene expression and metastasis. Cancer Metastasis Rev 23(3–4):293–310, PMID: 15197330PubMedCrossRefGoogle Scholar
  34. 34.
    Dunn LK, Mohammad KS, Fournier PG et al (2009) Hypoxia and TGF-beta drive breast cancer bone metastases through parallel signaling pathways in tumor cells and the bone microenvironment. PLoS One 4(9):e6896. doi: 10.1371/journal.pone.0006896, PMID: 19727403PubMedCrossRefGoogle Scholar
  35. 35.
    Gatenby RA, Gawlinski ET, Gmitro et al (2006) Acid-mediated tumor invasion: a multidisciplinary study. Cancer Res 66(10):5216–5223, PMID: 16707446PubMedCrossRefGoogle Scholar
  36. 36.
    Bendre MS, Margulies AG, Walser B et al (2005) Tumor-derived interleukin-8 stimulates osteolysis independent of the receptor activator of nuclear factor-kappaB ligand pathway. Cancer Res 65(23):11001–11009, PMID: 16322249PubMedCrossRefGoogle Scholar
  37. 37.
    Berger CE, Rathod H, Gillespie JI et al (2001) 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 16(11):2092–2102, PMID 11697806PubMedCrossRefGoogle Scholar
  38. 38.
    Quarles LD (2012) Role of FGF23 in vitamin D and phosphate metabolism: implications in chronic kidney disease. Exp Cell Res 318(9):1040–1048. doi: 10.1016/j.yexcr.2012.02.027, PMID: 22421513PubMedCrossRefGoogle Scholar
  39. 39.
    Bodine PV, Komm BS (2006) Wnt signaling and osteoblastogenesis. Rev Endocr Metab Disord 7(1–2):33–39, Review. PMID: 16960757PubMedGoogle Scholar
  40. 40.
    Mitsiades CS, Mitsiades NS, Richardson PG et al (2007) Multiple myeloma: a prototypic disease model for the characterization and therapeutic targeting of interactions between tumor cells and their local microenvironment. J Cell Biochem 101(4):950–968, PMID: 17546631PubMedCrossRefGoogle Scholar
  41. 41.
    Siclari VA, Guise TA, Chirgwin JM (2006) Molecular interactions between breast cancer cells and the bone microenvironment drive skeletal metastases. Cancer Metastasis Rev 25(4):621–633, PMID: 17165131PubMedCrossRefGoogle Scholar
  42. 42.
    Virk MS, Alaee F, Petrigliano FA, Sugiyama O et al (2011) Combined inhibition of the BMP pathway and the RANK-RANKL axis in a mixed lytic/blastic prostate cancer lesion. Bone 48(3):578–587. doi: 10.1016/j.bone.2010.11.003, PMID: 21073986PubMedCrossRefGoogle Scholar
  43. 43.
    Hauschka PV, Mavrakos AE, Iafrati MD et al (1986) Growth factors in bone matrix. Isolation of multiple types by affinity chromatography on heparin-Sepharose. J Biol Chem 261(27):12665–12674, PMID: 3745206PubMedGoogle Scholar
  44. 44.
    Birmann BM, Neuhouser ML, Rosner B et al (2012) Prediagnosis biomarkers of insulin-like growth factor-1, insulin, and interleukin-6 dysregulation and multiple myeloma risk in the multiple myeloma cohort consortium. Blood 120(25):4929–4937. doi: 10.1182/blood-2012-03-417253, Epub 16 Oct 2012. PMID: 23074271PubMedCrossRefGoogle Scholar
  45. 45.
    Klein A, Olendrowitz C, Schmutzler R et al (2009) Identification of brain- and bone-specific breast cancer metastasis genes. Cancer Lett 276(2):212–220. doi: 10.1016/j.canlet.2008.11.017, PMID: 19114293PubMedCrossRefGoogle Scholar
  46. 46.
    Roodman GD (2011) Osteoblast function in myeloma. Bone 48(1):135–140. doi: 10.1016/j.bone.2010.06.016, Epub 19 Jun 2010. PMID: 20601285PubMedCrossRefGoogle Scholar
  47. 47.
    Oyajobi BO, Garrett IR, Gupta A et al (2007) Stimulation of new bone formation by the proteasome inhibitor, bortezomib: implications for myeloma bone disease. Br J Haematol 139(3):434–438, PMID: 17910634PubMedCrossRefGoogle Scholar
  48. 48.
    Pennisi A, Ling W, Li X et al (2010) Consequences of daily administered parathyroid hormone on myeloma growth, bone disease, and molecular profiling of whole myelomatous bone. PLoS One 5(12):e15233, PMID: 21188144PubMedCrossRefGoogle Scholar
  49. 49.
    Silbermann R, Roodman GD (2011) Bone effects of cancer therapies: pros and cons. Curr Opin Support Palliat Care 5(3):251–257. doi: 10.1097/SPC.0b013e328349c524, PMID: 21768880PubMedCrossRefGoogle Scholar
  50. 50.
    Whang PG, Gamradt SC, Gates JL et al (2005) Effects of the proteasome inhibitor bortezomib on osteolytic human prostate cancer cell metastases. Prostate Cancer Prostatic Dis 8(4):327–334, PMID:16130017PubMedCrossRefGoogle Scholar
  51. 51.
    Gomes RR Jr, Buttke P, Paul EM et al (2009) Osteosclerotic prostate cancer metastasis to murine bone are enhanced with increased bone formation. Clin Exp Metastasis 26(7):641–651. doi: 10.1007/s10585-009-9263-x, Epub 7 May 2009. PMID: 19421879PubMedCrossRefGoogle Scholar
  52. 52.
    Baselga J, Campone M, Piccart M et al (2012) Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N Engl J Med 366(6):520–529. doi: 10.1056/NEJMoa1109653, Epub 7 Dec 2011. PMID: 22149876PubMedCrossRefGoogle Scholar
  53. 53.
    Price JT, Quinn JM, Sims NA et al (2005) The heat shock protein 90 inhibitor, 17-allylamino-17-demethoxygeldanamycin, enhances osteoclast formation and potentiates bone metastasis of a human breast cancer cell line. Cancer Res 65(11):4929–4938, PMID: 15930315PubMedCrossRefGoogle Scholar
  54. 54.
    Yano A, Tsutsumi S, Soga S et al (2008) Inhibition of Hsp90 activates osteoclast c-Src signaling and promotes growth of prostate carcinoma cells in bone. Proc Natl Acad Sci U S A 105(40):15541–15546. doi: 10.1073/pnas.0805354.105, PMID: 18840695PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2014

Authors and Affiliations

  1. 1.Department of MedicineIndiana University School of MedicineIndianapolisUSA

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