Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.


Bone marrow niches in the regulation of bone metastasis


The bone marrow has been widely recognised to host a unique microenvironment that facilitates tumour colonisation. Bone metastasis frequently occurs in the late stages of malignant diseases such as breast, prostate and lung cancers. The biology of bone metastasis is determined by tumour-cell-intrinsic traits as well as their interaction with the microenvironment. The bone marrow is a dynamic organ in which various stages of haematopoiesis, osteogenesis, osteolysis and different kinds of immune response are precisely regulated. These different cellular components constitute specialised tissue microenvironments—niches—that play critical roles in controlling tumour cell colonisation, including initial seeding, dormancy and outgrowth. In this review, we will dissect the dynamic nature of the interactions between tumour cells and bone niches. By targeting certain steps of tumour progression and crosstalk with the bone niches, the development of potential therapeutic approaches for the clinical treatment of bone metastasis might be feasible.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Fig. 1: The normal bone marrow niche.
Fig. 2: The perivascular and endosteal niches in bone metastasis.
Fig. 3: Other cells in the bone metastatic niche.


  1. 1.

    Wan, L., Pantel, K. & Kang, Y. Tumor metastasis: moving new biological insights into the clinic. Nat. Med. 19, 1450–1464 (2013).

    CAS  PubMed  Google Scholar 

  2. 2.

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

    CAS  PubMed  Google Scholar 

  3. 3.

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

    CAS  PubMed  Google Scholar 

  4. 4.

    Lambert, A. W., Pattabiraman, D. R. & Weinberg, R. A. Emerging biological principles of metastasis. Cell 168, 670–691 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. 5.

    Coleman, R. E. Metastatic bone disease: clinical features, pathophysiology and treatment strategies. Cancer Treat Rev. 27, 165–176 (2001).

    CAS  PubMed  Google Scholar 

  6. 6.

    Macedo, F., Ladeira, K., Pinho, F., Saraiva, N., Bonito, N., Pinto, L. et al. Bone metastases: an overview. Oncol. Rev. 11, 321–321 (2017).

    PubMed  PubMed Central  Google Scholar 

  7. 7.

    Kimura, T. Multidisciplinary approach for bone metastasis: a review. Cancers (Basel) 10, 156 (2018).

  8. 8.

    Guzik, G. Results of the treatment of bone metastases with modular prosthetic replacement—analysis of 67 patients. J. Orthop. Surg. Res. 11, 20 (2016).

    PubMed  PubMed Central  Google Scholar 

  9. 9.

    Guise, T. A., Kozlow, W. M., Heras-Herzig, A., Padalecki, S. S., Yin, J. J. & Chirgwin, J. M. Molecular mechanisms of breast cancer metastases to bone. Clin. Breast Cancer 5(Suppl), S46–S53 (2005).

    CAS  PubMed  Google Scholar 

  10. 10.

    Pan, H., Gray, R., Braybrooke, J., Davies, C., Taylor, C., McGale, P. et al. 20-Year risks of breast-cancer recurrence after stopping endocrine therapy at 5 years. N. Engl. J. Med. 377, 1836–1846 (2017).

    PubMed  PubMed Central  Google Scholar 

  11. 11.

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

    CAS  PubMed  Google Scholar 

  12. 12.

    Obenauf, A. C. & Massague, J. Surviving at a distance: organ-specific metastasis. Trends Cancer 1, 76–91 (2015).

    PubMed  PubMed Central  Google Scholar 

  13. 13.

    Ghajar, C. M. Metastasis prevention by targeting the dormant niche. Nat. Rev. Cancer 15, 238–247 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. 14.

    Zaidi, M. Skeletal remodeling in health and disease. Nat. Med. 13, 791–801 (2007).

    CAS  PubMed  Google Scholar 

  15. 15.

    Karsenty, G. & Wagner, E. F. Reaching a genetic and molecular understanding of skeletal development. Dev. Cell 2, 389–406 (2002).

    CAS  PubMed  Google Scholar 

  16. 16.

    Harada, S. & Rodan, G. A. Control of osteoblast function and regulation of bone mass. Nature 423, 349–355 (2003).

    CAS  PubMed  Google Scholar 

  17. 17.

    Franz-Odendaal, T. A., Hall, B. K. & Witten, P. E. Buried alive: how osteoblasts become osteocytes. Dev. Dyn. 235, 176–190 (2006).

    CAS  PubMed  Google Scholar 

  18. 18.

    Frost, H. M. In vivo osteocyte death. J. Bone Joint Surg. Am. 42, 138–143 (1960).

    PubMed  Google Scholar 

  19. 19.

    Ikeda, K. & Takeshita, S. The role of osteoclast differentiation and function in skeletal homeostasis. J. Biochem. 159, 1–8 (2016).

    CAS  PubMed  Google Scholar 

  20. 20.

    Chitu, V. & Stanley, E. R. Colony-stimulating factor-1 in immunity and inflammation. Curr. Opin. Immunol. 18, 39–48 (2006).

    CAS  PubMed  Google Scholar 

  21. 21.

    Gow, D. J., Sester, D. P. & Hume, D. A. CSF-1, IGF-1, and the control of postnatal growth and development. J. Leukoc. Biol. 88, 475–481 (2010).

    CAS  PubMed  Google Scholar 

  22. 22.

    Haider, M. T., Smit, D. J. & Taipaleenmaki, H. The endosteal niche in breast cancer bone metastasis. Front. Oncol. 10, 335 (2020).

    PubMed  PubMed Central  Google Scholar 

  23. 23.

    Shen, Y. & Nilsson, S. K. Bone, microenvironment and hematopoiesis. Curr. Opin. Hematol. 19, 250–255 (2012).

    CAS  PubMed  Google Scholar 

  24. 24.

    Frenette, P. S., Pinho, S., Lucas, D. & Scheiermann, C. Mesenchymal stem cell: keystone of the hematopoietic stem cell niche and a stepping-stone for regenerative medicine. Annu. Rev. Immunol. 31, 285–316 (2013).

    PubMed  Google Scholar 

  25. 25.

    Morrison, S. J. & Scadden, D. T. The bone marrow niche for haematopoietic stem cells. Nature 505, 327–334 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. 26.

    Clevers, H. The cancer stem cell: premises, promises and challenges. Nat. Med. 17, 313–319 (2011).

    CAS  PubMed  Google Scholar 

  27. 27.

    Hsu, Y. C. & Fuchs, E. A family business: stem cell progeny join the niche to regulate homeostasis. Nat. Rev. Mol. Cell Biol. 13, 103–114 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. 28.

    Moore, K. A. & Lemischka, I. R. Stem cells and their niches. Science 311, 1880–1885 (2006).

    CAS  PubMed  Google Scholar 

  29. 29.

    Morrison, S. J. & Spradling, A. C. Stem cells and niches: mechanisms that promote stem cell maintenance throughout life. Cell 132, 598–611 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. 30.

    Mendez-Ferrer, S., Michurina, T. V., Ferraro, F., Mazloom, A. R., Macarthur, B. D., Lira, S. A. et al. Mesenchymal and haematopoietic stem cells form a unique bone marrow niche. Nature 466, 829–834 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. 31.

    Yu, V. W. & Scadden, D. T. Heterogeneity of the bone marrow niche. Curr. Opin. Hematol. 23, 331–338 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. 32.

    Birbrair, A. & Frenette, P. S. Niche heterogeneity in the bone marrow. Ann. N. Y. Acad. Sci. 1370, 82–96 (2016).

    PubMed  PubMed Central  Google Scholar 

  33. 33.

    Katsimbri, P. The biology of normal bone remodelling. Eur. J. Cancer Care (Engl.) 26, e12740 (2017).

  34. 34.

    Feng, X. & McDonald, J. M. Disorders of bone remodeling. Annu. Rev. Pathol. 6, 121–145 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. 35.

    Pinho, S., Lacombe, J., Hanoun, M., Mizoguchi, T., Bruns, I., Kunisaki, Y. et al. PDGFRalpha and CD51 mark human nestin+ sphere-forming mesenchymal stem cells capable of hematopoietic progenitor cell expansion. J. Exp. Med. 210, 1351–1367 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. 36.

    Greenbaum, A., Hsu, Y. M., Day, R. B., Schuettpelz, L. G., Christopher, M. J., Borgerding, J. N. et al. CXCL12 in early mesenchymal progenitors is required for haematopoietic stem-cell maintenance. Nature 495, 227–230 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. 37.

    Ding, L., Saunders, T. L., Enikolopov, G. & Morrison, S. J. Endothelial and perivascular cells maintain haematopoietic stem cells. Nature 481, 457–462 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. 38.

    Park, D., Spencer, J. A., Koh, B. I., Kobayashi, T., Fujisaki, J., Clemens, T. L. et al. Endogenous bone marrow MSCs are dynamic, fate-restricted participants in bone maintenance and regeneration. Cell Stem Cell 10, 259–272 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. 39.

    Ding, L. & Morrison, S. J. Haematopoietic stem cells and early lymphoid progenitors occupy distinct bone marrow niches. Nature 495, 231–235 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. 40.

    Sacchetti, B., Funari, A., Michienzi, S., Di Cesare, S., Piersanti, S., Saggio, I. et al. Self-renewing osteoprogenitors in bone marrow sinusoids can organize a hematopoietic microenvironment. Cell 131, 324–336 (2007).

    CAS  PubMed  Google Scholar 

  41. 41.

    Agarwal, P., Isringhausen, S., Li, H., Paterson, A. J., He, J., Gomariz, A. et al. Mesenchymal niche-specific expression of Cxcl12 controls quiescence of treatment-resistant leukemia stem cells. Cell Stem Cell 24, 769–784 e766 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. 42.

    Asada, N., Kunisaki, Y., Pierce, H., Wang, Z., Fernandez, N. F., Birbrair, A. et al. Differential cytokine contributions of perivascular haematopoietic stem cell niches. Nat Cell Biol 19, 214–223 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. 43.

    Kang, Y., Siegel, P. M., Shu, W., Drobnjak, M., Kakonen, S. M., Cordon-Cardo, C. et al. A multigenic program mediating breast cancer metastasis to bone. Cancer Cell 3, 537–549 (2003).

    CAS  PubMed  Google Scholar 

  44. 44.

    Chatterjee, S., Behnam Azad, B. & Nimmagadda, S. The intricate role of CXCR4 in cancer. Adv. Cancer Res. 124, 31–82 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. 45.

    Shiozawa, Y., Havens, A. M., Pienta, K. J. & Taichman, R. S. The bone marrow niche: habitat to hematopoietic and mesenchymal stem cells, and unwitting host to molecular parasites. Leukemia 22, 941–950 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. 46.

    Chen, F., Lin, X., Xu, P., Zhang, Z., Chen, Y., Wang, C. et al. Nuclear export of smads by RanBP3L regulates bone morphogenetic protein signaling and mesenchymal stem cell differentiation. Mol. Cell Biol. 35, 1700–1711 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. 47.

    Ambrosi, T. H., Longaker, M. T. & Chan, C. K. F. A revised perspective of skeletal stem cell biology. Front. Cell Dev. Biol. 7, 189 (2019).

    PubMed  PubMed Central  Google Scholar 

  48. 48.

    Acar, M., Kocherlakota, K. S., Murphy, M. M., Peyer, J. G., Oguro, H., Inra, C. N. et al. Deep imaging of bone marrow shows non-dividing stem cells are mainly perisinusoidal. Nature 526, 126–130 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. 49.

    Crane, G. M., Jeffery, E. & Morrison, S. J. Adult haematopoietic stem cell niches. Nat. Rev. Immunol. 17, 573–590 (2017).

    CAS  PubMed  Google Scholar 

  50. 50.

    Asada, N., Takeishi, S. & Frenette, P. S. Complexity of bone marrow hematopoietic stem cell niche. Int. J. Hematol. 106, 45–54 (2017).

    PubMed  Google Scholar 

  51. 51.

    Sun, Y. X., Schneider, A., Jung, Y., Wang, J., Dai, J., Wang, J. et al. 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 (2005).

    CAS  PubMed  Google Scholar 

  52. 52.

    Nervi, B., Ramirez, P., Rettig, M. P., Uy, G. L., Holt, M. S., Ritchey, J. K. et al. Chemosensitization of acute myeloid leukemia (AML) following mobilization by the CXCR4 antagonist AMD3100. Blood 113, 6206–6214 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. 53.

    Shain, K. H., Yarde, D. N., Meads, M. B., Huang, M., Jove, R., Hazlehurst, L. A. et al. Beta1 integrin adhesion enhances IL-6-mediated STAT3 signaling in myeloma cells: implications for microenvironment influence on tumor survival and proliferation. Cancer Res. 69, 1009–1015 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. 54.

    Ara, T., Song, L., Shimada, H., Keshelava, N., Russell, H. V., Metelitsa, L. S. et al. Interleukin-6 in the bone marrow microenvironment promotes the growth and survival of neuroblastoma cells. Cancer Res. 69, 329–337 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. 55.

    Brocke-Heidrich, K., Kretzschmar, A. K., Pfeifer, G., Henze, C., Loffler, D., Koczan, D. et al. Interleukin-6-dependent gene expression profiles in multiple myeloma INA-6 cells reveal a Bcl-2 family-independent survival pathway closely associated with Stat3 activation. Blood 103, 242–251 (2004).

    CAS  PubMed  Google Scholar 

  56. 56.

    Ono, M., Kosaka, N., Tominaga, N., Yoshioka, Y., Takeshita, F., Takahashi, R. U. et al. Exosomes from bone marrow mesenchymal stem cells contain a microRNA that promotes dormancy in metastatic breast cancer cells. Sci. Signal 7, ra63 (2014).

    PubMed  Google Scholar 

  57. 57.

    Ramasamy, S. K. Structure and functions of blood vessels and vascular niches in bone. Stem Cells Int. 2017, 5046953 (2017).

    PubMed  PubMed Central  Google Scholar 

  58. 58.

    Hendriks, M. & Ramasamy, S. K. Blood vessels and vascular niches in bone development and physiological remodeling. Front. Cell Dev. Biol. 8, 602278–602278 (2020).

    PubMed  PubMed Central  Google Scholar 

  59. 59.

    Lafage-Proust, M. H., Roche, B., Langer, M., Cleret, D., Vanden Bossche, A., Olivier, T. et al. Assessment of bone vascularization and its role in bone remodeling. Bonekey Rep 4, 662 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. 60.

    Augustin, H. G. & Koh, G. Y. Organotypic vasculature: from descriptive heterogeneity to functional pathophysiology. Science 357, eaal2379 (2017).

  61. 61.

    Sanger, N., Effenberger, K. E., Riethdorf, S., Van Haasteren, V., Gauwerky, J., Wiegratz, I. et al. Disseminated tumor cells in the bone marrow of patients with ductal carcinoma in situ. Int. J. Cancer 129, 2522–2526 (2011).

    PubMed  Google Scholar 

  62. 62.

    Melchior, S. W., Corey, E., Ellis, W. J., Ross, A. A., Layton, T. J., Oswin, M. M. et al. Early tumor cell dissemination in patients with clinically localized carcinoma of the prostate. Clin. Cancer Res. 3, 249–256 (1997).

    CAS  PubMed  Google Scholar 

  63. 63.

    Walz, G., Aruffo, A., Kolanus, W., Bevilacqua, M. & Seed, B. Recognition by ELAM-1 of the sialyl-Lex determinant on myeloid and tumor cells. Science 250, 1132–1135 (1990).

    CAS  PubMed  Google Scholar 

  64. 64.

    Gunasinghe, N. P., Wells, A., Thompson, E. W. & Hugo, H. J. Mesenchymal-epithelial transition (MET) as a mechanism for metastatic colonisation in breast cancer. Cancer Metastasis Rev. 31, 469–478 (2012).

    CAS  PubMed  Google Scholar 

  65. 65.

    Esposito, M., Mondal, N., Greco, T. M., Wei, Y., Spadazzi, C., Lin, S. C. et al. Bone vascular niche E-selectin induces mesenchymal-epithelial transition and Wnt activation in cancer cells to promote bone metastasis. Nat. Cell Biol. 21, 627–639 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. 66.

    Carlson, P., Dasgupta, A., Grzelak, C. A., Kim, J., Barrett, A., Coleman, I. M. et al. Targeting the perivascular niche sensitizes disseminated tumour cells to chemotherapy. Nat. Cell Biol. 21, 238–250 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. 67.

    Yagiz, K. & Rittling, S. R. Both cell-surface and secreted CSF-1 expressed by tumor cells metastatic to bone can contribute to osteoclast activation. Exp Cell Res. 315, 2442–2452 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. 68.

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

    CAS  PubMed  PubMed Central  Google Scholar 

  69. 69.

    Kang, Y. Dissecting tumor-stromal interactions in breast cancer bone metastasis. Endocrinol. Metab. (Seoul) 31, 206–212 (2016).

    CAS  Google Scholar 

  70. 70.

    Ell, B. & Kang, Y. SnapShot: Bone Metastasis. Cell 151, 690–690 e691 (2012).

    CAS  PubMed  Google Scholar 

  71. 71.

    Roodman, G. D. Mechanisms of bone metastasis. N. Engl. J. Med. 350, 1655–1664 (2004).

    CAS  Google Scholar 

  72. 72.

    Yin, J. J., Selander, K., Chirgwin, J. M., Dallas, M., Grubbs, B. G., Wieser, R. et al. TGF-beta signaling blockade inhibits PTHrP secretion by breast cancer cells and bone metastases development. J. Clin. Invest. 103, 197–206 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. 73.

    Sethi, N., Dai, X., Winter, C. G. & Kang, Y. Tumor-derived JAGGED1 promotes osteolytic bone metastasis of breast cancer by engaging notch signaling in bone cells. Cancer Cell 19, 192–205 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. 74.

    Boyle, W. J., Simonet, W. S. & Lacey, D. L. Osteoclast differentiation and activation. Nature 423, 337–342 (2003).

    CAS  PubMed  Google Scholar 

  75. 75.

    Iotsova, V., Caamano, J., Loy, J., Yang, Y., Lewin, A. & Bravo, R. Osteopetrosis in mice lacking NF-kappaB1 and NF-kappaB2. Nat. Med. 3, 1285–1289 (1997).

    CAS  PubMed  Google Scholar 

  76. 76.

    Lacey, D. L., Timms, E., Tan, H. L., Kelley, M. J., Dunstan, C. R., Burgess, T. et al. Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell 93, 165–176 (1998).

    CAS  Google Scholar 

  77. 77.

    Lu, X., Mu, E., Wei, Y., Riethdorf, S., Yang, Q., Yuan, M. et al. VCAM-1 promotes osteolytic expansion of indolent bone micrometastasis of breast cancer by engaging alpha4beta1-positive osteoclast progenitors. Cancer Cell 20, 701–714 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. 78.

    Zheng, H., Bae, Y., Kasimir-Bauer, S., Tang, R., Chen, J., Ren, G. et al. Therapeutic antibody targeting tumor- and osteoblastic niche-derived jagged1 sensitizes bone metastasis to chemotherapy. Cancer Cell 32, 731–747 e736 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. 79.

    Hume, D. A. & MacDonald, K. P. Therapeutic applications of macrophage colony-stimulating factor-1 (CSF-1) and antagonists of CSF-1 receptor (CSF-1R) signaling. Blood 119, 1810–1820 (2012).

    CAS  PubMed  Google Scholar 

  80. 80.

    Westendorf, J. J., Kahler, R. A. & Schroeder, T. M. Wnt signaling in osteoblasts and bone diseases. Gene 341, 19–39 (2004).

    CAS  PubMed  Google Scholar 

  81. 81.

    Hall, C. L., Bafico, A., Dai, J., Aaronson, S. A. & Keller, E. T. Prostate cancer cells promote osteoblastic bone metastases through Wnts. Cancer Res. 65, 7554–7560 (2005).

    CAS  PubMed  Google Scholar 

  82. 82.

    Ren, D., Dai, Y., Yang, Q., Zhang, X., Guo, W., Ye, L. et al. Wnt5a induces and maintains prostate cancer cells dormancy in bone. J. Exp. Med. 216, 428–449 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. 83.

    Zhuang, X., Zhang, H., Li, X., Li, X., Cong, M., Peng, F. et al. Differential effects on lung and bone metastasis of breast cancer by Wnt signalling inhibitor DKK1. Nat. Cell Biol. 19, 1274–1285 (2017).

    CAS  PubMed  Google Scholar 

  84. 84.

    Wang, H., Yu, C., Gao, X., Welte, T., Muscarella, A. M., Tian, L. et al. The osteogenic niche promotes early-stage bone colonization of disseminated breast cancer cells. Cancer Cell 27, 193–210 (2015).

    PubMed  PubMed Central  Google Scholar 

  85. 85.

    Wang, H., Tian, L., Liu, J., Goldstein, A., Bado, I., Zhang, W. et al. The osteogenic niche is a calcium reservoir of bone micrometastases and confers unexpected therapeutic vulnerability. Cancer Cell 34, 823–839 e827 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. 86.

    Devignes, C. S., Aslan, Y., Brenot, A., Devillers, A., Schepers, K., Fabre, S. et al. HIF signaling in osteoblast-lineage cells promotes systemic breast cancer growth and metastasis in mice. Proc. Natl Acad. Sci. USA 115, E992–E1001 (2018).

    CAS  PubMed  Google Scholar 

  87. 87.

    Delgado-Calle, J. & Bellido, T. Osteocytes and skeletal pathophysiology. Curr. Mol. Biol. Rep. 1, 157–167 (2015).

    PubMed  PubMed Central  Google Scholar 

  88. 88.

    Robling, A. G. & Bonewald, L. F. The Osteocyte: New Insights. Annu. Rev. Physiol 82, 485–506 (2020).

    CAS  PubMed  Google Scholar 

  89. 89.

    Sottnik, J. L., Dai, J., Zhang, H., Campbell, B. & Keller, E. T. Tumor-induced pressure in the bone microenvironment causes osteocytes to promote the growth of prostate cancer bone metastases. Cancer Res. 75, 2151–2158 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. 90.

    Delgado-Calle, J., Anderson, J., Cregor, M. D., Hiasa, M., Chirgwin, J. M., Carlesso, N. et al. Bidirectional notch signaling and osteocyte-derived factors in the bone marrow microenvironment promote tumor cell proliferation and bone destruction in multiple myeloma. Cancer Res. 76, 1089–1100 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. 91.

    Dierkes, C., Kreisel, M., Schulz, A., Steinmeyer, J., Wolff, J. C. & Fink, L. Catabolic properties of microdissected human endosteal bone lining cells. Calcif. Tissue Int. 84, 146–155 (2009).

    CAS  PubMed  Google Scholar 

  92. 92.

    Johnson, R. W. & Suva, L. J. Hallmarks of Bone Metastasis. Calcif. Tissue Int. 102, 141–151 (2018).

    CAS  PubMed  Google Scholar 

  93. 93.

    Feuerer, M., Rocha, M., Bai, L., Umansky, V., Solomayer, E. F., Bastert, G. et al. Enrichment of memory T cells and other profound immunological changes in the bone marrow from untreated breast cancer patients. Int. J. Cancer 92, 96–105 (2001).

    CAS  PubMed  Google Scholar 

  94. 94.

    Zhang, K., Kim, S., Cremasco, V., Hirbe, A. C., Collins, L., Piwnica-Worms, D. et al. CD8+ T cells regulate bone tumor burden independent of osteoclast resorption. Cancer Res. 71, 4799–4808 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. 95.

    Lode, H. N., Xiang, R., Dreier, T., Varki, N. M., Gillies, S. D. & Reisfeld, R. A. Natural killer cell-mediated eradication of neuroblastoma metastases to bone marrow by targeted interleukin-2 therapy. Blood 91, 1706–1715 (1998).

    CAS  PubMed  Google Scholar 

  96. 96.

    Bidwell, B. N., Slaney, C. Y., Withana, N. P., Forster, S., Cao, Y., Loi, S. et al. Silencing of Irf7 pathways in breast cancer cells promotes bone metastasis through immune escape. Nat. Med. 18, 1224–1231 (2012).

    CAS  PubMed  Google Scholar 

  97. 97.

    Colucci, S., Brunetti, G., Rizzi, R., Zonno, A., Mori, G., Colaianni, G. et al. T cells support osteoclastogenesis in an in vitro model derived from human multiple myeloma bone disease: the role of the OPG/TRAIL interaction. Blood 104, 3722–3730 (2004).

    CAS  PubMed  Google Scholar 

  98. 98.

    Monteiro, A. C., Leal, A. C., Goncalves-Silva, T., Mercadante, A. C., Kestelman, F., Chaves, S. B. et al. T cells induce pre-metastatic osteolytic disease and help bone metastases establishment in a mouse model of metastatic breast cancer. PLoS ONE 8, e68171 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. 99.

    Zhao, E., Wang, L., Dai, J., Kryczek, I., Wei, S., Vatan, L. et al. Regulatory T cells in the bone marrow microenvironment in patients with prostate cancer. Oncoimmunology 1, 152–161 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. 100.

    Wyckoff, J. B., Wang, Y., Lin, E. Y., Li, J. F., Goswami, S., Stanley, E. R. et al. Direct visualization of macrophage-assisted tumor cell intravasation in mammary tumors. Cancer Res. 67, 2649–2656 (2007).

    CAS  PubMed  Google Scholar 

  101. 101.

    Mendoza-Reinoso, V., McCauley, L. K. & Fournier, P. G. J. Contribution of macrophages and T cells in skeletal metastasis. Cancers (Basel) 12, 1014 (2020).

  102. 102.

    Ma, R. Y., Zhang, H., Li, X. F., Zhang, C. B., Selli, C., Tagliavini, G. et al. Monocyte-derived macrophages promote breast cancer bone metastasis outgrowth. J. Exp. Med. 217, e20191820 (2020).

  103. 103.

    Zhao, E., Xu, H., Wang, L., Kryczek, I., Wu, K., Hu, Y. et al. Bone marrow and the control of immunity. Cell Mol. Immunol. 9, 11–19 (2012).

    CAS  PubMed  Google Scholar 

  104. 104.

    Zhuang, J., Zhang, J., Lwin, S. T., Edwards, J. R., Edwards, C. M., Mundy, G. R. et al. Osteoclasts in multiple myeloma are derived from Gr-1+CD11b+myeloid-derived suppressor cells. PLoS ONE 7, e48871 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. 105.

    Sawant, A., Hensel, J. A., Chanda, D., Harris, B. A., Siegal, G. P., Maheshwari, A. et al. Depletion of plasmacytoid dendritic cells inhibits tumor growth and prevents bone metastasis of breast cancer cells. J. Immunol. 189, 4258–4265 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  106. 106.

    Qian, B., Deng, Y., Im, J. H., Muschel, R. J., Zou, Y., Li, J. et al. A distinct macrophage population mediates metastatic breast cancer cell extravasation, establishment and growth. PLoS ONE 4, e6562 (2009).

    PubMed  PubMed Central  Google Scholar 

  107. 107.

    Saji, H., Koike, M., Yamori, T., Saji, S., Seiki, M., Matsushima, K. et al. Significant correlation of monocyte chemoattractant protein-1 expression with neovascularization and progression of breast carcinoma. Cancer 92, 1085–1091 (2001).

    CAS  PubMed  Google Scholar 

  108. 108.

    Kitamura, T., Qian, B. Z., Soong, D., Cassetta, L., Noy, R., Sugano, G. et al. CCL2-induced chemokine cascade promotes breast cancer metastasis by enhancing retention of metastasis-associated macrophages. J. Exp. Med. 212, 1043–1059 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. 109.

    Silzle, T., Kreutz, M., Dobler, M. A., Brockhoff, G., Knuechel, R. & Kunz-Schughart, L. A. Tumor-associated fibroblasts recruit blood monocytes into tumor tissue. Eur. J. Immunol. 33, 1311–1320 (2003).

    CAS  PubMed  Google Scholar 

  110. 110.

    Huang, B., Lei, Z., Zhao, J., Gong, W., Liu, J., Chen, Z. et al. CCL2/CCR2 pathway mediates recruitment of myeloid suppressor cells to cancers. Cancer Lett. 252, 86–92 (2007).

    CAS  PubMed  Google Scholar 

  111. 111.

    Kirk, P. S., Koreckij, T., Nguyen, H. M., Brown, L. G., Snyder, L. A., Vessella, R. L. et al. Inhibition of CCL2 signaling in combination with docetaxel treatment has profound inhibitory effects on prostate cancer growth in bone. Int. J. Mol. Sci. 14, 10483–10496 (2013).

    PubMed  PubMed Central  Google Scholar 

  112. 112.

    Ell, B., Mercatali, L., Ibrahim, T., Campbell, N., Schwarzenbach, H., Pantel, K. et al. Tumor-induced osteoclast miRNA changes as regulators and biomarkers of osteolytic bone metastasis. Cancer Cell 24, 542–556 (2013).

    CAS  PubMed  Google Scholar 

  113. 113.

    Manthey, C. L., Johnson, D. L., Illig, C. R., Tuman, R. W., Zhou, Z., Baker, J. F. et al. JNJ-28312141, a novel orally active colony-stimulating factor-1 receptor/FMS-related receptor tyrosine kinase-3 receptor tyrosine kinase inhibitor with potential utility in solid tumors, bone metastases, and acute myeloid leukemia. Mol. Cancer Ther. 8, 3151–3161 (2009).

    CAS  PubMed  Google Scholar 

  114. 114.

    Sloan, E. K., Priceman, S. J., Cox, B. F., Yu, S., Pimentel, M. A., Tangkanangnukul, V. et al. The sympathetic nervous system induces a metastatic switch in primary breast cancer. Cancer Res. 70, 7042–7052 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. 115.

    Morris, E. V. & Edwards, C. M. The role of bone marrow adipocytes in bone metastasis. J. Bone Oncol. 5, 121–123 (2016).

    PubMed  PubMed Central  Google Scholar 

  116. 116.

    Lucotti, S. & Muschel, R. J. Platelets and Metastasis: New Implications of an Old Interplay. Front. Oncol. 10, 1350 (2020).

    PubMed  PubMed Central  Google Scholar 

  117. 117.

    Maroni, P. Megakaryocytes in bone metastasis: protection or progression? Cells 8, 134 (2019).

  118. 118.

    Jackson, W. 3rd, Sosnoski, D. M., Ohanessian, S. E., Chandler, P., Mobley, A., Meisel, K. D. et al. Role of megakaryocytes in breast cancer metastasis to bone. Cancer Res. 77, 1942–1954 (2017).

    CAS  PubMed  Google Scholar 

  119. 119.

    Li, X., Koh, A. J., Wang, Z., Soki, F. N., Park, S. I., Pienta, K. J. et al. Inhibitory effects of megakaryocytic cells in prostate cancer skeletal metastasis. J Bone Miner. Res. 26, 125–134 (2011).

    CAS  PubMed  Google Scholar 

  120. 120.

    Shirai, T., Revenko, A. S., Tibbitts, J., Ngo, A. T. P., Mitrugno, A., Healy, L. D. et al. Hepatic thrombopoietin gene silencing reduces platelet count and breast cancer progression in transgenic MMTV-PyMT mice. Blood Adv. 3, 3080–3091 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. 121.

    Psaila, B., Lyden, D. & Roberts, I. Megakaryocytes, malignancy and bone marrow vascular niches. J. Thromb. Haemost. 10, 177–188 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  122. 122.

    Smith, E. P., Specker, B. & Korach, K. S. Recent experimental and clinical findings in the skeleton associated with loss of estrogen hormone or estrogen receptor activity. J. Steroid Biochem. Mol. Biol. 118, 264–272 (2010).

    CAS  PubMed  Google Scholar 

  123. 123.

    Morrissey, C., Roudier, M. P., Dowell, A., True, L. D., Ketchanji, M., Welty, C. et al. Effects of androgen deprivation therapy and bisphosphonate treatment on bone in patients with metastatic castration-resistant prostate cancer: results from the University of Washington Rapid Autopsy Series. J Bone Miner. Res. 28, 333–340 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  124. 124.

    Nakamura, T., Imai, Y., Matsumoto, T., Sato, S., Takeuchi, K., Igarashi, K. et al. Estrogen prevents bone loss via estrogen receptor alpha and induction of Fas ligand in osteoclasts. Cell 130, 811–823 (2007).

    CAS  PubMed  Google Scholar 

  125. 125.

    Ren, G., Esposito, M. & Kang, Y. Bone metastasis and the metastatic niche. J. Mol. Med. (Berl.) 93, 1203–1212 (2015).

    CAS  Google Scholar 

  126. 126.

    Drake, M. T., Clarke, B. L. & Khosla, S. Bisphosphonates: mechanism of action and role in clinical practice. Mayo Clin. Proc. 83, 1032–1045 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  127. 127.

    Early Breast Cancer Trialists’ Collaborative, G. Adjuvant bisphosphonate treatment in early breast cancer: meta-analyses of individual patient data from randomised trials. Lancet 386, 1353–1361 (2015).

    Google Scholar 

  128. 128.

    Ottewell, P. D., Wang, N., Brown, H. K., Reeves, K. J., Fowles, C. A., Croucher, P. I. et al. Zoledronic acid has differential antitumor activity in the pre- and postmenopausal bone microenvironment in vivo. Clin. Cancer Res. 20, 2922–2932 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  129. 129.

    Lacey, D. L., Boyle, W. J., Simonet, W. S., Kostenuik, P. J., Dougall, W. C., Sullivan, J. K. et al. 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 

  130. 130.

    Fizazi, K., Carducci, M., Smith, M., Damiao, R., Brown, J., Karsh, L. et al. Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study. Lancet 377, 813–822 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  131. 131.

    Kostenuik, P. J., Nguyen, H. Q., McCabe, J., Warmington, K. S., Kurahara, C., Sun, N. et al. Denosumab, a fully human monoclonal antibody to RANKL, inhibits bone resorption and increases BMD in knock-in mice that express chimeric (murine/human) RANKL. J. Bone Miner. Res. 24, 182–195 (2009).

    CAS  PubMed  Google Scholar 

  132. 132.

    Oyajobi, B. O., Anderson, D. M., Traianedes, K., Williams, P. J., Yoneda, T. & Mundy, G. R. Therapeutic efficacy of a soluble receptor activator of nuclear factor kappaB-IgG Fc fusion protein in suppressing bone resorption and hypercalcemia in a model of humoral hypercalcemia of malignancy. Cancer Res. 61, 2572–2578 (2001).

    CAS  PubMed  Google Scholar 

  133. 133.

    Bone, H. G., McClung, M. R., Roux, C., Recker, R. R., Eisman, J. A., Verbruggen, N. et al. Odanacatib, a cathepsin-K inhibitor for osteoporosis: a two-year study in postmenopausal women with low bone density. J. Bone Miner. Res. 25, 937–947 (2010).

    PubMed  Google Scholar 

  134. 134.

    Lotinun, S., Kiviranta, R., Matsubara, T., Alzate, J. A., Neff, L., Luth, A. et al. Osteoclast-specific cathepsin K deletion stimulates S1P-dependent bone formation. J. Clin. Invest. 123, 666–681 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  135. 135.

    Id Boufker, H., Lagneaux, L., Najar, M., Piccart, M., Ghanem, G., Body, J. J. et al. The Src inhibitor dasatinib accelerates the differentiation of human bone marrow-derived mesenchymal stromal cells into osteoblasts. BMC Cancer 10, 298 (2010).

    PubMed  PubMed Central  Google Scholar 

  136. 136.

    Vandyke, K., Dewar, A. L., Diamond, P., Fitter, S., Schultz, C. G., Sims, N. A. et al. The tyrosine kinase inhibitor dasatinib dysregulates bone remodeling through inhibition of osteoclasts in vivo. J. Bone Miner. Res. 25, 1759–1770 (2010).

    CAS  PubMed  Google Scholar 

  137. 137.

    Lee, Y. C., Huang, C. F., Murshed, M., Chu, K., Araujo, J. C., Ye, X. et al. Src family kinase/abl inhibitor dasatinib suppresses proliferation and enhances differentiation of osteoblasts. Oncogene 29, 3196–3207 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  138. 138.

    Eckhardt, B. L., Francis, P. A., Parker, B. S. & Anderson, R. L. Strategies for the discovery and development of therapies for metastatic breast cancer. Nat. Rev. Drug Discov. 11, 479–497 (2012).

    CAS  PubMed  Google Scholar 

Download references


We thank the members of our laboratory for helpful discussions. We also apologise to the many investigators whose important studies could not be cited directly here owing to space limitations. Illustrations created with

Author information




F.C. and Y.H. co-wrote and revised the manuscript. Y.K. co-wrote and revised the manuscript and provided overall guidance.

Corresponding author

Correspondence to Yibin Kang.

Ethics declarations

Ethics approval and consent to participate

Not applicable.

Consent to publish

Not applicable.

Data availability

Not applicable.

Competing interests

Y.K. holds equity interest in KayoThera and Firebrand Therapeutics.

Funding information

The work in the authors’ laboratory is supported by grants from the Brewster Foundation, American Cancer Society, Susan G. Komen Foundation, Breast Cancer Research Foundation, the NIH and the U.S. Department of Defense to Y.K.

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

Verify currency and authenticity via CrossMark

Cite this article

Chen, F., Han, Y. & Kang, Y. Bone marrow niches in the regulation of bone metastasis. Br J Cancer 124, 1912–1920 (2021).

Download citation


Quick links