Skip to main content

Advertisement

SpringerLink
Log in

The Role of the Microenvironment in Prostate Cancer-Associated Bone Disease

  • Osteoporosis and Cancer (M Nanes and M Drake, Section Editors)
  • Published:
Current Osteoporosis Reports Aims and scope Submit manuscript

Abstract

The bone is a common site for metastasis in patients with advanced prostate carcinoma, and provides a ‘fertile’ milieu which stimulates tumour growth and associated bone disease. For years, the concept of treatment strategies has remained targeting the tumour itself; however, the occurrence of chemoresistance remains a challenge now more than ever. The attraction of targeting the bone microenvironment in order to disrupt tumour localisation and proliferation stems from the idea that stromal cells are superiorly stable at a genetic level, thus decreasing the risk of resistance manifestation. In this review, we will discuss recent findings with regards to the pathogenesis of prostate cancer-induced bone disease and recent therapeutic strategies in an aim to evaluate the ever increasing role of the microenvironment in disease progression.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Coleman RE, 20 Pt 2. Clinical features of metastatic bone disease and risk of skeletal morbidity. Clin Cancer Res. 2006;12:6243s–9.

    Article  PubMed  Google Scholar 

  2. Friedl P, Alexander S. Cancer invasion and the microenvironment: plasticity and reciprocity. Cell. 2011;147(5):992–1009.

    Article  CAS  PubMed  Google Scholar 

  3. Roodman GD. Mechanisms of bone metastasis. N Engl J Med. 2004;350(16):1655–64.

    Article  CAS  PubMed  Google Scholar 

  4. Weilbaecher KN, Guise TA, McCauley LK. Cancer to bone: a fatal attraction. Nat Rev Cancer. 2011;11(6):411–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Hess KR et al. Metastatic patterns in adenocarcinoma. Cancer. 2006;106(7):1624–33.

    Article  PubMed  Google Scholar 

  6. Gundem G et al. The evolutionary history of lethal metastatic prostate cancer. Nature. 2015;520(7547):353–7. Uses whole genome sequencing to describe the pattern of metastatic spread in advanced prostate cancer.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Mundy GR. Metastasis to bone: causes, consequences and therapeutic opportunities. Nat Rev Cancer. 2002;2(8):584–93.

    Article  CAS  PubMed  Google Scholar 

  8. Jin JK, Dayyani F, Gallick GE. Steps in prostate cancer progression that lead to bone metastasis. Int J Cancer. 2011;128(11):2545–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Zheng X et al. Epithelial-to-mesenchymal transition is dispensable for metastasis but induces chemoresistance in pancreatic cancer. Nature. 2015;527(7579):525–30. Suggests that EMT is not critical for metastasis.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Fischer KR et al. Epithelial-to-mesenchymal transition is not required for lung metastasis but contributes to chemoresistance. Nature. 2015;527(7579):472–6. Suggests that EMT is not critical for metastasis.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Autio KA, Morris MJ. Targeting bone physiology for the treatment of metastatic prostate cancer. Clin Adv Hematol Oncol: H&O. 2013;11(3):134–43.

    Google Scholar 

  12. Buenrostro D, Park SI, Sterling JA. Dissecting the role of bone marrow stromal cells on bone metastases. Biomed Res Int. 2014;2014, 875305.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Taichman RS et al. The evolving biology and treatment of prostate cancer. J Clin Invest. 2007;117(9):2351–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Sun YX et al. Expression of CXCR4 and CXCL12 (SDF-1) in human prostate cancers (PCa) in vivo. J Cell Biochem. 2003;89(3):462–73.

    Article  CAS  PubMed  Google Scholar 

  15. Kaplan RN, Psaila B, Lyden D. Bone marrow cells in the ‘pre-metastatic niche’: within bone and beyond. Cancer Metastasis Rev. 2006;25(4):521–9.

    Article  PubMed  Google Scholar 

  16. Shiozawa Y et al. Human prostate cancer metastases target the hematopoietic stem cell niche to establish footholds in mouse bone marrow. J Clin Invest. 2011;121(4):1298–312.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Wang N et al. 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. 2014;29(12):2688–96.

    Article  CAS  PubMed  Google Scholar 

  18. Wang N et al. Mitotic quiescence, but not unique “stemness,” marks the phenotype of bone metastasis-initiating cells in prostate cancer. FASEB J. 2015;29(8):3141–50.

    Article  CAS  PubMed  Google Scholar 

  19. Pedersen EA et al. The prostate cancer bone marrow niche: more than just ‘fertile soil’. Asian J Androl. 2012;14(3):423–7.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Shiozawa Y et al. Annexin II/annexin II receptor axis regulates adhesion, migration, homing, and growth of prostate cancer. J Cell Biochem. 2008;105(2):370–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Zheng Y et al. The role of the bone microenvironment in skeletal metastasis. J Bone Oncol. 2013;2(1):47–57.

    Article  PubMed  Google Scholar 

  22. Chantrain CF et al. Bone marrow microenvironment and tumor progression. Cancer Microenviron. 2008;1(1):23–35.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Hall CL et al. Prostate cancer cells promote osteoblastic bone metastases through Wnts. Cancer Res. 2005;65(17):7554–60.

    CAS  PubMed  Google Scholar 

  24. Hall CL et al. Role of Wnts in prostate cancer bone metastases. J Cell Biochem. 2006;97(4):661–72.

    Article  CAS  PubMed  Google Scholar 

  25. Logothetis CJ, Lin SH. Osteoblasts in prostate cancer metastasis to bone. Nat Rev Cancer. 2005;5(1):21–8.

    Article  CAS  PubMed  Google Scholar 

  26. Shariat SF et al. Preoperative plasma levels of transforming growth factor beta(1) (TGF-beta(1)) strongly predict progression in patients undergoing radical prostatectomy. J Clin Oncol. 2001;19(11):2856–64.

    CAS  PubMed  Google Scholar 

  27. Autzen P et al. Bone morphogenetic protein 6 in skeletal metastases from prostate cancer and other common human malignancies. Br J Cancer. 1998;78(9):1219–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Street J et al. Vascular endothelial growth factor stimulates bone repair by promoting angiogenesis and bone turnover. Proc Natl Acad Sci U S A. 2002;99(15):9656–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Sottnik JL, Keller ET. Understanding and targeting osteoclastic activity in prostate cancer bone metastases. Curr Mol Med. 2013;13(4):626–39.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Dougall WC et al. RANK is essential for osteoclast and lymph node development. Genes Dev. 1999;13(18):2412–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Keller ET, Brown J. Prostate cancer bone metastases promote both osteolytic and osteoblastic activity. J Cell Biochem. 2004;91(4):718–29.

    Article  CAS  PubMed  Google Scholar 

  32. Hardaway AL et al. Bone marrow fat: linking adipocyte-induced inflammation with skeletal metastases. Cancer Metastasis Rev. 2014;33(2–3):527–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Herroon MK et al. Bone marrow adipocytes promote tumor growth in bone via FABP4-dependent mechanisms. Oncotarget. 2013;4(11):2108–23.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Hardaway AL et al. Marrow adipocyte-derived CXCL1 and CXCL2 contribute to osteolysis in metastatic prostate cancer. Clin Exp Metastasis. 2015;32(4):353–68.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Luo J et al. Infiltrating bone marrow mesenchymal stem cells increase prostate cancer stem cell population and metastatic ability via secreting cytokines to suppress androgen receptor signaling. Oncogene. 2014;33(21):2768–78.

    Article  CAS  PubMed  Google Scholar 

  36. Jung Y et al. Recruitment of mesenchymal stem cells into prostate tumours promotes metastasis. Nat Commun. 2013;4:1795. Demonstrates a role for CXCR16 in recruiting MSCs into prostate tumours and promoting metastasis.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Olechnowicz SW, Edwards CM. Contributions of the host microenvironment to cancer-induced bone disease. Cancer Res. 2014;74(6):1625–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Li X et al. Loss of TGF-beta responsiveness in prostate stromal cells alters chemokine levels and facilitates the development of mixed osteoblastic/osteolytic bone lesions. Mol Cancer Res. 2012;10(4):494–503.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Ottewell PD et al. Castration-induced bone loss triggers growth of disseminated prostate cancer cells in bone. Endocr Relat Cancer. 2014;21(5):769–81.

    Article  CAS  PubMed  Google Scholar 

  40. Quail DF, Joyce JA. Microenvironmental regulation of tumor progression and metastasis. Nat Med. 2013;19(11):1423–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Sturge J, Caley MP, Waxman J. Bone metastasis in prostate cancer: emerging therapeutic strategies. Nat Rev Clin Oncol. 2011;8(6):357–68.

    CAS  PubMed  Google Scholar 

  42. Saad F et al. A randomized, placebo-controlled trial of zoledronic acid in patients with hormone-refractory metastatic prostate carcinoma. J Natl Cancer Inst. 2002;94(19):1458–68.

    Article  CAS  PubMed  Google Scholar 

  43. Saad F et al. Long-term efficacy of zoledronic acid for the prevention of skeletal complications in patients with metastatic hormone-refractory prostate cancer. J Natl Cancer Inst. 2004;96(11):879–82.

    Article  CAS  PubMed  Google Scholar 

  44. Coleman RE, McCloskey EV. Bisphosphonates in oncology. Bone. 2011;49(1):71–6.

    Article  CAS  PubMed  Google Scholar 

  45. Ando K et al. RANKL/RANK/OPG: key therapeutic target in bone oncology. Curr Drug Discov Technol. 2008;5(3):263–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Smith MR et al. Denosumab and bone-metastasis-free survival in men with castration-resistant prostate cancer: results of a phase 3, randomised, placebo-controlled trial. Lancet. 2012;379(9810):39–46.

    Article  CAS  PubMed  Google Scholar 

  47. Lipton A et al. Superiority of denosumab to zoledronic acid for prevention of skeletal-related events: a combined analysis of 3 pivotal, randomised, phase 3 trials. Eur J Cancer. 2012;48(16):3082–92.

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  PubMed Central  Google Scholar 

  49. Di Lorenzo G et al. Combination of bevacizumab and docetaxel in docetaxel-pretreated hormone-refractory prostate cancer: a phase 2 study. Eur Urol. 2008;54(5):1089–94.

    Article  PubMed  Google Scholar 

  50. Kelly WK et al. Randomized, double-blind, placebo-controlled phase III trial comparing docetaxel and prednisone with or without bevacizumab in men with metastatic castration-resistant prostate cancer: CALGB 90401. J Clin Oncol. 2012;30(13):1534–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Huang D et al. Anti-angiogenesis or pro-angiogenesis for cancer treatment: focus on drug distribution. Int J Clin Exp Med. 2015;8(6):8369–76.

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Wong PP et al. Dual-action combination therapy enhances angiogenesis while reducing tumor growth and spread. Cancer Cell. 2015;27(1):123–37.

    Article  CAS  PubMed  Google Scholar 

  53. Fang H, DeClerck YA. Targeting the tumor microenvironment: from understanding pathways to effective clinical trials. Cancer Res. 2013;73(16):4965–77.

    Article  CAS  PubMed  Google Scholar 

  54. Muralidharan A, Smith MT. Pathobiology and management of prostate cancer-induced bone pain: recent insights and future treatments. Inflammopharmacology. 2013;21(5):339–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Todenhofer T et al. Targeting bone metabolism in patients with advanced prostate cancer: current options and controversies. Int J Endocrinol. 2015;2015:838202.

    Article  PubMed  PubMed Central  Google Scholar 

  56. Parker C et al. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med. 2013;369(3):213–23.

    Article  CAS  PubMed  Google Scholar 

  57. Shore ND. Radium-223 dichloride for metastatic castration-resistant prostate cancer: the urologist’s perspective. Urology. 2015;85(4):717–24.

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by the Prostate Cancer UK and Cancer Research UK (CR-UK) grant number C38302/A12278, through the Oxford Cancer Research Centre Development Fund and through the University of Oxford Medical Research Fund.

Author information

Authors and Affiliations

  1. Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK

    Christina J. Turner & Claire M. Edwards

  2. Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Botnar Research Centre, University of Oxford, Old Road, Oxford, OX3 7LD, UK

    Claire M. Edwards

Authors
  1. Christina J. Turner
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Claire M. Edwards
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Claire M. Edwards.

Ethics declarations

Conflict of Interest

Christina J. Turner and Claire M. Edwards declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Additional information

This article is part of the Topical Collection on Osteoporosis and Cancer

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Turner, C.J., Edwards, C.M. The Role of the Microenvironment in Prostate Cancer-Associated Bone Disease. Curr Osteoporos Rep 14, 170–177 (2016). https://doi.org/10.1007/s11914-016-0323-2

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11914-016-0323-2

Keywords

Search

Navigation