Skip to main content

Advertisement

SpringerLink
Log in

Role of the bone microenvironment in bone metastasis of malignant tumors - therapeutic implications

  • Review
  • Published:
Cellular Oncology Aims and scope Submit manuscript

Abstract

Background

Bone is one of the most common sites for solid tumor metastasis. Bone metastasis of a malignant tumor seriously affects the quality of life and the overall survival of patients. Evidence has suggested that bone provides a favorable microenvironment that enables disseminated tumor cells to home, proliferate and colonize, leading to the formation of metastases. In the process of bone metastasis the bone microenvironment may be considered as an orchestra that plays a dissonant melody through blending (e.g. cross-talk between osteoclasts, osteoblasts and/or other cells), adding (e.g. a variety of biological factors) or taking away (e.g. blocking a specific pathway) players.

Conclusions

Here, we review the normal bone microenvironment, bone microenvironment-related factors that promote bone metastasis, as well as mechanisms underlying bone metastasis. In addition, we elude on directions for clinical bone metastasis management, focusing on potential therapeutic approaches to target bone microenvironment-related factors, including bisphosphonate, denosumab, CXCR4/CXCL12 antagonists and cathepsin K inhibitors.

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
Fig. 2

Similar content being viewed by others

References

  1. N. Kamiya, H. Suzuk, T. Endo, M. Yano, M. Naoi, D. Nishimi, K. Kawamura, T. Imamoto, T. Ichikawa, Clinical usefulness of bone markers in prostate cancer with bone metastasis. Int. J. Urol. 19, 968–979 (2012)

    CAS  PubMed  Google Scholar 

  2. J. Fornetti, A.L. Welm, S.A. Stewart, Understanding the bone in Cancer metastasis. J. Bone Miner. Res. 33, 2099–2113 (2018)

    CAS  PubMed  Google Scholar 

  3. E.V. Morris, C.M. Edwards, Bone marrow adipose tissue: A new player in cancer metastasis to bone. Front. Endocrinol. (Lausanne) 7, 90 (2016)

    Google Scholar 

  4. U.H. Weidle, F. Birzele, G. Kollmorgen, R. Rüger, Molecular mechanisms of bone metastasis. Cancer Genomics Proteomics 13, 1–12 (2016)

    CAS  PubMed  Google Scholar 

  5. P. Nilendu, S.C. Sarode, D. Jahagirdar, I. Tandon, S. Patil, G.S. Sarode, J.K. Pal, N.K. Sharma, Mutual concessions and compromises between stromal cells and cancer cells: Driving tumor development and drug resistance. Cell. Oncol. 41, 353–367 (2018)

  6. A. Schmid-Alliana, H. Schmid-Antomarchi, R. Al-Sahlanee, P. Lagadec, J.C. Scimeca, E. Verron, Understanding the progression of bone metastases to identify novel therapeutic targets. Int. J. Mol. Sci. 19, 148 (2018)

  7. M. van Driel, J.P. van Leeuwen, Cancer and bone: A complex complex. Arch. Biochem. Biophys. 561, 159–166 (2014)

    PubMed  Google Scholar 

  8. A.M. Mastro, C.V. Gay, D.R. Welch, The skeleton as a unique environment for breast cancer cells. Clin. Exp. Metastasis 20, 275–284 (2003)

    CAS  PubMed  Google Scholar 

  9. Tu Q, Zhang J, Fix A, Brewer E, Li Y. P, Zhang Z. Y, Chen J. Targeted overexpression of BSP in osteoclasts promotes bone metastasis of breast Cancer cells. J. Cell. Physiol. 218, 135–145 (2009)

  10. L.J. Suva, C. Washam, R.W. Nicholas, R.J. Griffin, Bone metastasis: Mechanisms and therapeutic opportunities. Nat. Rev. Endocrinol. 7, 208–218 (2011)

    CAS  PubMed  PubMed Central  Google Scholar 

  11. A.S. Gdowski, A. Ranjan, J.K. Vishwanatha, Current concepts in bone metastasis, contemporary therapeutic strategies and ongoing clinical trials. J. Exp. Clin. Cancer Res. 36, 108 (2017)

    PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  13. D. Cruceriu, O. Baldasici, O. Balacescu, I. Berindan-Neagoe, The dual role of tumor necrosis factor-alpha (TNF-alpha) in breast cancer: Molecular insights and therapeutic approaches. Cell. Oncol. 43, 1–18 (2020)

  14. A.C. Hirbe, E.A. Morgan, K.N. Weilbaecher, The CXCR4/SDF-1 chemokine axis: A potential therapeutic target for bone metastases? Curr. Pharm. Des. 16, 1284–1290 (2010)

    CAS  PubMed  Google Scholar 

  15. G.R. Mundy, Metastasis to bone: Causes, consequences and therapeutic opportunities. Nat. Rev. Cancer 2, 584–593 (2002)

    CAS  PubMed  Google Scholar 

  16. P. Clezardin, Pathophysiology of bone metastases from solid malignancies. Joint Bone Spine 84, 677–684 (2017)

    CAS  PubMed  Google Scholar 

  17. L. D'Amico, I. Roato, The impact of immune system in regulating bone metastasis formation by Osteotropic tumors. J. Immunol. Res. 2015, 143526 (2015)

  18. A.L. Hardaway, M.K. Herroon, E. Rajagurubandara, I. Podgorski, Bone marrow fat: Linking adipocyte induced inflammation with skeletal metastases. Cancer Metastasis Rev. 33, 527–543 (2014)

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Y. Shiozawa, M.R. Eber, J.E. Berry, R.S. Taichman, Bone marrow as a metastatic niche for disseminated tumor cells from solid tumors. Bonekey Rep. 4, 689 (2015)

    CAS  PubMed  PubMed Central  Google Scholar 

  20. A.C. Carreira, F.H. Lojudice, E. Halcsik, R.D. Navarro, M.C. Sogayar, J.M. Granjeiro, Bone morphogenetic proteins: Facts, challenges, and future perspectives. J. Dent. Res. 93, 335–345 (2014)

    CAS  PubMed  Google Scholar 

  21. L. Rosano, F. Spinella, A. Bagnato, Endothelin 1 in cancer: Biological implications and therapeutic opportunities. Nat. Rev. Cancer 13, 637–651 (2013)

    CAS  PubMed  Google Scholar 

  22. J.Y. Krzeszinski, Y. Wan, New therapeutic targets for cancer bone metastasis. Trends Pharmacol. Sci. 36, 360–373 (2015)

    CAS  PubMed  PubMed Central  Google Scholar 

  23. K.M. Bussard, C.V. Gay, A.M. Mastro, The bone microenvironment in metastasis; what is special about bone? Cancer Metastasis Rev. 27, 41–55 (2008)

    PubMed  Google Scholar 

  24. K.N. Weilbaecher, T.A. Guise, L.K. McCauley, Cancer to bone: A fatal attraction. Nat. Rev. Cancer 11, 411–425 (2011)

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Z.S. Templeton, W.R. Lie, W. Wang, Y. Rosenberg-Hasson, R.V. Alluri, J.S. Tamaresis, M.H. Bachmann, K. Lee, W.J. Maloney, C.H. Contag, B.L. King, Breast Cancer cell colonization of the human bone marrow adipose tissue niche. Neoplasia 17, 849–861 (2015)

    CAS  PubMed  PubMed Central  Google Scholar 

  26. M.K. Herroon, E. Rajagurubandara, A.L. Hardaway, K. Powell, A. Turchick, D. Feldmann, I. Podgorski, Bone marrow adipocytes promote tumor growth in bone via FABP4-dependent mechanisms. Oncotarget 4, 2108–2123 (2013)

    PubMed  PubMed Central  Google Scholar 

  27. Y.S. Hwang, P.F. Lindholm, Constitutive and inducible expression of invasion-related factors in PC-3 prostate cancer cells. J. Cancer Prev. 20, 121–128 (2015)

    PubMed  PubMed Central  Google Scholar 

  28. J.S. Nam, A.R. Sharma, L.T. Nguyen, S. Jagga, Y.H. Lee, G. Sharma, S.S. Lee, Lysophosphatidic acid enhances breast cancer cells-mediated. Korean J. Physiol. Pharmacol. 22, 503–511 (2018)

    CAS  PubMed  PubMed Central  Google Scholar 

  29. M. David, J. Ribeiro, F. Descotes, C.M. Serre, M. Barbier, M. Murone, P. Clézardin, O. Peyruchaud, Targeting lysophosphatidic acid receptor type 1 with Debio 0719 inhibits spontaneous metastasis dissemination of breast cancer cells independently of cell proliferation and angiogenesis. Int. J. Oncol. 40, 1133–1141 (2012)

    CAS  PubMed  Google Scholar 

  30. A. Salmaninejad, S.F. Valilou, A. Soltani, S. Ahmadi, Y.J. Abarghan, R.J. Rosengren, A. Sahebkar, Tumor-associated macrophages: Role in cancer development and therapeutic implications. Cell. Oncol. 42, 591–608 (2019)

  31. K. Hiraoka, M. Zenmyo, K. Watari, H. Iguchi, A. Fotovati, Y.N. Kimura, F. Hosoi, T. Shoda, K. Nagata, H. Osada, M. Ono, M. Kuwano, Inhibition of bone and muscle metastases of lung cancer cells by a decrease in the number of monocytes/ macrophages. Cancer Sci. 99, 1595–1602 (2008)

    CAS  PubMed  Google Scholar 

  32. M.K. Herroon, E. Rajagurubandara, D.L. Rudy, A. Chalasani, A.L. Hardaway, I. Podgorski, Macrophage cathepsin K promotes prostate tumor progression in bone. Oncogene 32, 1580–1593 (2013)

    CAS  PubMed  Google Scholar 

  33. S.J. Coniglio, Role of tumor-derived chemokines in osteolytic bone metastasis. Front. Endocrinol. (Lausanne) 9, 313 (2018)

    Google Scholar 

  34. J. Wang, Y. Shiozawa, Y. Wang, Y. Jung, K.J. Pienta, R. Mehra, R. Loberg, R.S. Taichman, The role of CXCR7/RDC1 as a chemokine receptor for CXCL12/SDF-1 in prostate cancer. J. Biol. Chem. 283, 4283–4294 (2008)

    CAS  PubMed  Google Scholar 

  35. O. Wald, CXCR4 based therapeutics for Non-Small Cell Lung Cancer (NSCLC). J. Clin. Med. 7, 303 (2018)

  36. P. Clézardin, Therapeutic targets for bone metastases in breast cancer. Breast Cancer Res. 13, 207 (2011)

    PubMed  PubMed Central  Google Scholar 

  37. Y.X. Sun, M. Fang, J. Wang, C.R. Cooper, K.J. Pienta, R.S. Taichman, Expression and activation of alpha v beta 3 integrins by SDF-1/CXC12 increases the aggressiveness of prostate cancer cells. Prostate 67, 61–73 (2007)

    CAS  PubMed  Google Scholar 

  38. P.I. Croucher, M.M. McDonald, T.J. Martin, Bone metastasis: The importance of the neighbourhood. Nat. Rev. Cancer 16, 373–386 (2016)

    CAS  PubMed  Google Scholar 

  39. M. Croset, C. Kan, P. Clézardin, Tumour-derived miRNAs and bone metastasis. Bonekey Rep. 4, 688 (2015)

    CAS  PubMed  PubMed Central  Google Scholar 

  40. H. Taipaleenmäki, G. Browne, J. Akech, J. Zustin, A.J. van Wijnen, J.L. Stein, E. Hesse, G.S. Stein, J.B. Lian, Targeting of Runx2 by miR-135 and miR-203 impairs progression of breast cancer and metastatic bone disease. Cancer Res. 75, 1433–1444 (2015)

    PubMed  PubMed Central  Google Scholar 

  41. G. Carlinfante, D. Vassiliou, O. Svensson, M. Wendel, D. Heinegard, G. Andersson, Differential expression of osteopontin and bone sialoprotein in bone metastasis of breast and prostate carcinoma. Clin. Exp. Metastasis 20, 437–444 (2003)

    CAS  PubMed  Google Scholar 

  42. A. Bellahcene, V. Castronovo, K.U. Ogbureke, L.W. Fisher, N.S. Fedarko, Small integrin-binding ligand N-linked glycoproteins (SIBLINGs): Multifunctional proteins in cancer. Nat. Rev. Cancer 8, 212–226 (2008)

    CAS  PubMed  PubMed Central  Google Scholar 

  43. B.T. Li, M.H. Wong, N. Pavlakis, Treatment and prevention of bone metastases from breast cancer: A comprehensive review of evidence for clinical practice. J. Clin. Med. 3, 1–24 (2014)

    PubMed  PubMed Central  Google Scholar 

  44. P. Clezardin, A. Teti, Bone metastasis: Pathogenesis and therapeutic implications. Clin. Exp. Metastasis 24, 599–608 (2007)

    CAS  PubMed  Google Scholar 

  45. D.L. Lacey, W.J. Boyle, W.S. Simonet, P.J. Kostenuik, W.C. Dougall, J.K. Sullivan, J. San Martin, R. Dansey, Bench to bedside: Elucidation of the OPG–RANK–RANKL pathway and the development of denosumab. Nat. Rev. Drug Discov. 11, 401–419 (2012)

    CAS  PubMed  Google Scholar 

  46. R.E. Coleman, Bone cancer in 2011: Prevention and treatment of bone metastases. Nat. Rev. Clin. Oncol. 9, 76–78 (2012)

    CAS  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  48. J.B. Nelson, K. Fizazi, K. Miller, C. Higano, J.W. Moul, H. Akaza, T. Morris, S. McIntosh, K. Pemberton, M. Gleave, Phase 3, randomized, placebo-controlled study of zibotentan (ZD4054) in patients with castration-resistant prostate cancer metastatic to bone. Cancer 118, 5709–5718 (2011)

    Google Scholar 

  49. D. Dreau, A. Karaa, C. Culberson, H. Wyan, I.H. McKillop, M.G. Clemens, Bosentan inhibits tumor vascularization and bone metastasis in an immunocompetent skin-fold chamber model of breast carcinoma cell metastasis. Clin. Exp. Metastasis 23, 41–53 (2006)

    CAS  PubMed  Google Scholar 

  50. M. Petrillo, G. Scambia, G. Ferrandina, Novel targets for VEGF-independent antiangiogenic drugs. Expert Opin. Investig. Drugs 21, 451–472 (2012)

    CAS  PubMed  Google Scholar 

  51. F. Rossari, C. Zucchinetti, G. Buda, E. Orciuolo, Tumor dormancy as an alternative step in the development of chemoresistance and metastasis - clinical implications. Cell. Oncol. 43, 155–176 (2020)

  52. S. Ehata, A. Hanyu, M. Fujime, Y. Katsuno, E. Fukunaga, K. Goto, Y. Ishikawa, K. Nomura, H. Yokoo, T. Shimizu, E. Ogata, K. Miyazono, K. Shimizu, T. Imamura, 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 (2007)

    CAS  PubMed  Google Scholar 

  53. T. Koreckij, H. Nguyen, L.G. Brown, E.Y. Yu, R.L. Vessella, E. Corey, Dasatinib inhibits the growth of prostate cancer in bone and provides additional protection from osteolysis. Br. J. Cancer 101, 263–268 (2009)

    CAS  PubMed  PubMed Central  Google Scholar 

  54. F. Saad, A. Lipton, SRC kinase inhibition: Targeting bone metastases and tumor growth in prostate and breast cancer. Cancer Treat. Rev. 36, 177–184 (2010)

    CAS  PubMed  Google Scholar 

  55. L.J. Lombardo, F.Y. Lee, P. Chen, D. Norris, J.C. Barrish, K. Behnia, S. Castaneda, L.A. Cornelius, J. Das, A.M. Doweyko, C. Fairchild, J.T. Hunt, I. Inigo, K. Johnston, A. Kamath, D. Kan, H. Klei, P. Marathe, S. Pang, R. Peterson, S. Pitt, G.L. Schieven, R.J. Schmidt, J. Tokarski, M.L. Wen, J. Wityak, R.M. Borzilleri, Discovery of N-(2-chloro-6-methyl-phenyl)-2-(6-(4-(2-hydroxyethyl)-piperazin-1-yl)-2-methylpyrimidin-4-ylamino) thiazole-5-carboxamide (BMS-354825), a dual Src/Abl kinase inhibitor with potent antitumor activity in preclinical. J. Med. Chem. 47, 6658–6661 (2004)

    CAS  PubMed  Google Scholar 

  56. X.H. Zhang, Q. Wang, W. Gerald, C.A. Hudis, L. Norton, M. Smid, J.A. Foekens, J. Massagué, Latent bone metastasis in breast cancer tied to Src-dependent survival signals. Cancer Cell 16, 67–78 (2009)

    CAS  PubMed  PubMed Central  Google Scholar 

  57. T.J. de Vries, M.G. Mullender, M.A. van Duin, C.M. Semeins, N. James, T.P. Green, V. Everts, J. Klein-Nulend, The Src inhibitor AZD0530 reversibly inhibits the formation and activity of human osteoclasts. Mol. Cancer Res. 7, 476–488 (2009)

    PubMed  Google Scholar 

  58. P. Clëzardin, Integrins in bone metastasis formation and potential therapeutic implications. Curr. Cancer Drug Targets 9, 801–806 (2009)

    PubMed  Google Scholar 

  59. Y. Zhao, R. Bachelier, I. Treilleux, P. Pujuguet, O. Peyruchaud, R. Baron, P. Clément-Lacroix, P. Clezardin, Tumor alphavbeta integrin is a therapeutic target for breast cancer bone metastases. Cancer Res. 67, 5821–5830 (2007)

    CAS  PubMed  Google Scholar 

  60. M.D. Jones, J.C. Liu, T.K. Barthel, S. Hussain, E. Lovria, D. Cheng, J.A. Schoonmaker, S. Mulay, D.C. Ayers, M.L. Bouxsein, G.S. Stein, S. Mukherjee, J.B. Lian, A proteasome inhibitor, bortezomib, inhibits breast cancer growth and reduces osteolysis by downregulating metastatic genes. Clin. Cancer Res. 16, 4978–4989 (2010)

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Funding

This work was supported by the National Natural Science Foundation of China (Grant No.81774221), The Capital Health Research and Development of Special (No.2018–2-1113), the Basic-Clinical Cooperation Program from Capital Medical University (No.17JL14), the Research Foundation of Beijing Friendship Hospital, Capital Medical University (No.yyqdkt2016–4) and the Beijing Municipal 215 High-level Health Person Foundation Project (No.2014-3-004).

Author information

Authors and Affiliations

  1. Cancer Center, Beijing Friendship Hospital, Capital Medical University, No.95 Yong An Road, Xi Cheng District, Beijing, 100050, China

    Xiaoting Ma & Jing Yu

Authors
  1. Xiaoting Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jing Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Xiaoting Ma wrote the manuscript, collected materials, and consulted the literature; Jing Yu revised the paper and provided funding.

Corresponding author

Correspondence to Jing Yu.

Ethics declarations

Conflict of interest

On behalf of all authors, the corresponding author states that there is no conflict of interest.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ma, X., Yu, J. Role of the bone microenvironment in bone metastasis of malignant tumors - therapeutic implications. Cell Oncol. 43, 751–761 (2020). https://doi.org/10.1007/s13402-020-00512-w

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13402-020-00512-w

Keywords

Search

Navigation