Skip to main content

Advertisement

SpringerLink
Log in

Hallmarks of Bone Metastasis

  • Review
  • Published:
Calcified Tissue International Aims and scope Submit manuscript

Abstract

Breast cancer bone metastasis develops as the result of a series of complex interactions between tumor cells, bone marrow cells, and resident bone cells. The net effect of these interactions are the disruption of normal bone homeostasis, often with significantly increased osteoclast and osteoblast activity, which has provided a rational target for controlling tumor progression, with little or no emphasis on tumor eradication. Indeed, the clinical course of metastatic breast cancer is relatively long, with patients likely to experience sequential skeletal-related events (SREs), often over lengthy periods of time, even up to decades. These SREs include bone pain, fractures, and spinal cord compression, all of which may profoundly impair a patient’s quality-of-life. Our understanding of the contributions of the host bone and bone marrow cells to the control of tumor progression has grown over the years, yet the focus of virtually all available treatments remains on the control of resident bone cells, primarily osteoclasts. In this perspective, our focus is to move away from the current emphasis on the control of bone cells and focus our attention on the hallmarks of bone metastatic tumor cells and how these differ from primary tumor cells and normal host cells. In our opinion, there remains a largely unmet medical need to develop and utilize therapies that impede metastatic tumor cells while sparing normal host bone and bone marrow cells. This perspective examines the impact of metastatic tumor cells on the bone microenvironment and proposes potential new directions for uncovering the important mechanisms driving metastatic progression in bone based on the hallmarks of bone metastasis.

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
Fig. 3

Similar content being viewed by others

References

  1. Suva LJ, Gaddy D, Perrien DS, Thomas RL, Findlay DM (2005) Regulation of bone mass by mechanical loading: microarchitecture and genetics. Curr Osteoporos Rep 3:46–51

    Article  PubMed  Google Scholar 

  2. Reagan MR, Rosen CJ (2016) Navigating the bone marrow niche: translational insights and cancer-driven dysfunction. Nat Rev Rheumatol 12:154–168

    Article  CAS  PubMed  Google Scholar 

  3. Yin T, Li L (2006) The stem cell niches in bone. J Clin Invest 116:1195–1201

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Roodman GD (2004) Mechanisms of bone metastasis. N Engl J Med 350:1655–1664

    Article  CAS  PubMed  Google Scholar 

  5. Weilbaecher KN, Guise TA, McCauley LK (2011) Cancer to bone: a fatal attraction. Nat Rev Cancer 11:411–425

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Zhou HS, Carter BZ, Andreeff M (2016) Bone marrow niche-mediated survival of leukemia stem cells in acute myeloid leukemia: Yin and Yang. Cancer Biol Med 13:248–259

    Article  PubMed  PubMed Central  Google Scholar 

  7. Quail DF, Joyce JA (2013) Microenvironmental regulation of tumor progression and metastasis. Nat Med 19:1423–1437

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Makhoul I, Montgomery CO, Gaddy D, Suva LJ (2016) The best of both worlds—managing the cancer, saving the bone. Nat Rev Endocrinol 12:29–42

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  10. Guise TA et al (1996) Evidence for a causal role of parathyroid hormone-related protein in the pathogenesis of human breast cancer-mediated osteolysis. J Clin Invest 98:1544–1549

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Suva LJ et al (1987) A parathyroid hormone-related protein implicated in malignant hypercalcemia: cloning and expression. Science 237:893–896

    Article  CAS  PubMed  Google Scholar 

  12. Mundy GR, Edwards JR (2008) PTH-related peptide (PTHrP) in hypercalcemia. J Am Soc Nephrol 19:672–675

    Article  CAS  PubMed  Google Scholar 

  13. Hanahan D, Weinberg RA (2000) The hallmarks of cancer. Cell 100:57–70

    Article  CAS  PubMed  Google Scholar 

  14. Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144:646–674

    Article  CAS  PubMed  Google Scholar 

  15. Coleman RE et al (2013) Possible survival benefits from zoledronic acid treatment in patients with bone metastases from solid tumours and poor prognostic features-An exploratory analysis of placebo-controlled trials. J Bone Oncol 2:70–76

    Article  PubMed  PubMed Central  Google Scholar 

  16. Chambers AF, Groom AC, MacDonald IC (2002) Dissemination and growth of cancer cells in metastatic sites. Nat Rev Cancer 2:563–572

    Article  CAS  PubMed  Google Scholar 

  17. Pantel K, Alix-Panabieres C, Riethdorf S (2009) Cancer micrometastases. Nat Rev Clin Oncol 6:339–351

    Article  CAS  PubMed  Google Scholar 

  18. Pantel K, Brakenhoff RH (2004) Dissecting the metastatic cascade. Nat Rev Cancer 4:448–456

    Article  CAS  PubMed  Google Scholar 

  19. Pantel K, Riethdorf S (2009) Pathology: are circulating tumor cells predictive of overall survival? Nat Rev Clin Oncol 6:190–191

    Article  PubMed  Google Scholar 

  20. Klein CA (2009) Parallel progression of primary tumours and metastases. Nat Rev Cancer 9:302–312

    Article  CAS  PubMed  Google Scholar 

  21. Price TT et al (2016) Dormant breast cancer micrometastases reside in specific bone marrow niches that regulate their transit to and from bone. Sci Transl Med 8:340ra373

    Article  Google Scholar 

  22. Zhang XH, Giuliano M, Trivedi MV, Schiff R, Osborne CK (2013) Metastasis dormancy in estrogen receptor-positive breast cancer. Clin Cancer Res 19:6389–6397

    Article  CAS  PubMed  Google Scholar 

  23. Croucher PI, McDonald MM, Martin TJ (2016) Bone metastasis: the importance of the neighbourhood. Nat Rev Cancer 16:373–386

    Article  CAS  PubMed  Google Scholar 

  24. Alvarez-Cubero MJ et al (2016) Dormant circulating tumor cells in prostate cancer: therapeutic, clinical and biological implications. Curr Drug Targets 17:693–701

    Article  CAS  PubMed  Google Scholar 

  25. Dasgupta A, Lim AR, Ghajar CM (2017) Circulating and disseminated tumor cells: harbingers or initiators of metastasis? Mol Oncol 11:40–61

    Article  PubMed  PubMed Central  Google Scholar 

  26. Gomis RR, Alarcon C, Nadal C, Van Poznak C, Massague J (2006) C/EBPbeta at the core of the TGFbeta cytostatic response and its evasion in metastatic breast cancer cells. Cancer Cell 10:203–214

    Article  CAS  PubMed  Google Scholar 

  27. Tomasetti C, Vogelstein B (2015) Cancer risk: role of environment-response. Science 347:729–731

    Article  CAS  PubMed  Google Scholar 

  28. Smith HA, Kang Y (2013) The metastasis-promoting roles of tumor-associated immune cells. J Mol Med (Berl) 91:411–429

    Article  CAS  Google Scholar 

  29. Ghajar CM et al (2013) The perivascular niche regulates breast tumour dormancy. Nat Cell Biol 15:807–817

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Giuliano AE et al (2011) Association of occult metastases in sentinel lymph nodes and bone marrow with survival among women with early-stage invasive breast cancer. JAMA 306:385–393

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Giuliano AE et al (2010) Locoregional recurrence after sentinel lymph node dissection with or without axillary dissection in patients with sentinel lymph node metastases: the American College of Surgeons Oncology Group Z0011 randomized trial. Ann Surg 252:426–432 discussion 432–423

    PubMed  PubMed Central  Google Scholar 

  32. Viehl CT et al (2011) Prognostic impact and therapeutic implications of sentinel lymph node micro-metastases in early-stage breast cancer patients. J Surg Oncol 103:531–533

    Article  PubMed  Google Scholar 

  33. Karpanen T et al (2001) Vascular endothelial growth factor C promotes tumor lymphangiogenesis and intralymphatic tumor growth. Cancer Res 61:1786–1790

    CAS  PubMed  Google Scholar 

  34. Thomas R et al (1999) Breast cancer cells interact with osteoblasts to support osteoclast formation. Endocrinology 140:4451–4458

    Article  CAS  PubMed  Google Scholar 

  35. Johnson RW et al (2016) Induction of LIFR confers a dormancy phenotype in breast cancer cells disseminated to the bone marrow. Nat Cell Biol 18:1078–1089

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Wang H et al (2015) The osteogenic niche promotes early-stage bone colonization of disseminated breast cancer cells. Cancer Cell 27:193–210

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. Hoar FJ, Chaudhri S, Wadley MS, Stonelake PS (2003) Co-expression of vascular endothelial growth factor C (VEGF-C) and c-erbB2 in human breast carcinoma. Eur J Cancer 39:1698–1703

    Article  CAS  PubMed  Google Scholar 

  38. Park HR, Min K, Kim HS, Jung WW, Park YK (2008) Expression of vascular endothelial growth factor-C and its receptor in osteosarcomas. Pathol Res Pract 204:575–582

    Article  CAS  PubMed  Google Scholar 

  39. Tzeng HE, Chang AC, Tsai CH, Wang SW, Tang CH (2016) Basic fibroblast growth factor promotes VEGF-C-dependent lymphangiogenesis via inhibition of miR-381 in human chondrosarcoma cells. Oncotarget 7:38566–38578

    Article  PubMed  PubMed Central  Google Scholar 

  40. Huang CY et al (2016) Adiponectin promotes VEGF-C-dependent lymphangiogenesis by inhibiting miR-27b through a CaMKII/AMPK/p38 signaling pathway in human chondrosarcoma cells. Clin Sci (Lond) 130:1523–1533

    Article  CAS  Google Scholar 

  41. Yang WH et al (2016) Leptin promotes VEGF-C production and induces lymphangiogenesis by suppressing miR-27b in human chondrosarcoma cells. Sci Rep 6:28647

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Martin TJ (2002) Manipulating the environment of cancer cells in bone: a novel therapeutic approach. J Clin Invest 110:1399–1401

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Paszek MJ, Weaver VM (2004) The tension mounts: mechanics meets morphogenesis and malignancy. J Mammary Gland Biol Neoplasia 9:325–342

    Article  PubMed  Google Scholar 

  44. Kwakwa KA, Sterling JA (2017) Integrin alphavbeta3 signaling in tumor-induced bone disease. Cancers (Basel) 9:84

    Article  Google Scholar 

  45. Kwakwa KA, Vanderburgh JP, Guelcher SA, Sterling JA (2017) Engineering 3D models of tumors and bone to understand tumor-induced bone disease and improve treatments. Curr Osteoporos Rep 15:247–254

    Article  PubMed  Google Scholar 

  46. Ruppender NS et al (2010) Matrix rigidity induces osteolytic gene expression of metastatic breast cancer cells. PLoS ONE 5:e15451

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  47. Johnson RW et al (2014) Wnt signaling induces gene expression of factors associated with bone destruction in lung and breast cancer. Clin Exp Metastasis 31:945–959

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Page JM et al (2015) Matrix rigidity regulates the transition of tumor cells to a bone-destructive phenotype through integrin beta3 and TGF-beta receptor type II. Biomaterials 64:33–44

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Amend SR, Pienta KJ (2015) Ecology meets cancer biology: the cancer swamp promotes the lethal cancer phenotype. Oncotarget 6:9669–9678

    Article  PubMed  PubMed Central  Google Scholar 

  50. Johnson RW, Sowder ME, Giaccia AJ (2017) Hypoxia and bone metastatic disease. Curr Osteoporos Rep 15:231–238

    Article  PubMed  Google Scholar 

  51. Spencer JA et al (2014) Direct measurement of local oxygen concentration in the bone marrow of live animals. Nature 508:269–273

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Chow DC, Wenning LA, Miller WM, Papoutsakis ET (2001) Modeling pO(2) distributions in the bone marrow hematopoietic compartment. II. Modified Kroghian models. Biophys J 81:685–696

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Harrison JS, Rameshwar P, Chang V, Bandari P (2002) Oxygen saturation in the bone marrow of healthy volunteers. Blood 99:394

    Article  CAS  PubMed  Google Scholar 

  54. Bendre MS et al (2002) Expression of interleukin 8 and not parathyroid hormone-related protein by human breast cancer cells correlates with bone metastasis in vivo. Cancer Res 62:5571–5579

    CAS  PubMed  Google Scholar 

  55. Chou SC, Azuma Y, Varia MA, Raleigh JA (2004) Evidence that involucrin, a marker for differentiation, is oxygen regulated in human squamous cell carcinomas. Br J Cancer 90:728–735

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Gross MW, Karbach U, Groebe K, Franko AJ, Mueller-Klieser W (1995) Calibration of misonidazole labeling by simultaneous measurement of oxygen tension and labeling density in multicellular spheroids. Int J Cancer 61:567–573

    Article  CAS  PubMed  Google Scholar 

  57. Dupuy F et al (2015) PDK1-dependent metabolic reprogramming dictates metastatic potential in breast cancer. Cell Metab 22:577–589

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  59. Lawson MA et al (2015) Osteoclasts control reactivation of dormant myeloma cells by remodelling the endosteal niche. Nat Commun 6:8983

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Kalluri R, Weinberg RA (2009) The basics of epithelial-mesenchymal transition. J Clin Invest 119:1420–1428

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Junankar S et al (2015) Real-time intravital imaging establishes tumor-associated macrophages as the extraskeletal target of bisphosphonate action in cancer. Cancer Discov 5:35–42

    Article  CAS  PubMed  Google Scholar 

  62. Mori G, D’Amelio P, Faccio R, Brunetti G (2015) Bone-immune cell crosstalk: bone diseases. J Immunol Res 2015:108451

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  63. Roato I (2013) Interaction among cells of bone, immune system, and solid tumors leads to bone metastases. Clin Dev Immunol 2013:315024

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  64. Lin WW, Karin M (2007) A cytokine-mediated link between innate immunity, inflammation, and cancer. J Clin Invest 117:1175–1183

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Lau YS et al (2007) RANKL-dependent and RANKL-independent mechanisms of macrophage-osteoclast differentiation in breast cancer. Breast Cancer Res Treat 105:7–16

    Article  CAS  PubMed  Google Scholar 

  66. Balkwill F, Mantovani A (2001) Inflammation and cancer: back to Virchow? Lancet 357:539–545

    Article  CAS  PubMed  Google Scholar 

  67. Fournier PG, Chirgwin JM, Guise TA (2006) New insights into the role of T cells in the vicious cycle of bone metastases. Curr Opin Rheumatol 18:396–404

    Article  CAS  PubMed  Google Scholar 

  68. Kamalakar A et al (2017) PTHrP(12-48) modulates the bone marrow microenvironment and suppresses human osteoclast differentiation and lifespan. J Bone Miner Res 32:1421–1431

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Leblanc R, Peyruchaud O (2016) The role of platelets and megakaryocytes in bone metastasis. J Bone Oncol 5:109–111

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Palumbo C, Ferretti M, Marotti G (2004) Osteocyte dendrogenesis in static and dynamic bone formation: an ultrastructural study. Anat Rec A 278:474–480

    Article  Google Scholar 

  72. Nakashima T et al (2011) Evidence for osteocyte regulation of bone homeostasis through RANKL expression. Nat Med 17:1231–1234

    Article  CAS  PubMed  Google Scholar 

  73. Xiong J et al (2011) Matrix-embedded cells control osteoclast formation. Nat Med 17:1235–1241

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Giuliani N et al (2012) Increased osteocyte death in multiple myeloma patients: role in myeloma-induced osteoclast formation. Leukemia 26:1391–1401

    Article  CAS  PubMed  Google Scholar 

  75. Suva LJ, Washam C, Nicholas RW, Griffin RJ (2011) Bone metastasis: mechanisms and therapeutic opportunities. Nat Rev Endocrinol 7:208–218

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Gkotzamanidou M et al (2012) Sclerostin: a possible target for the management of cancer-induced bone disease. Expert Opin Ther Targets 16:761–769

    Article  CAS  PubMed  Google Scholar 

  77. Mendoza-Villanueva D, Zeef L, Shore P (2011) Metastatic breast cancer cells inhibit osteoblast differentiation through the Runx2/CBFbeta-dependent expression of the Wnt antagonist, sclerostin. Breast Cancer Res 13:R106

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Wilson C, Coleman R (2016) Adjuvant bone-targeted therapies for postmenopausal breast cancer. JAMA Oncol 2:423–424

    Article  PubMed  Google Scholar 

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

    Article  CAS  Google Scholar 

  80. Taipaleenmaki H et al (2016) Antagonizing miR-218-5p attenuates Wnt signaling and reduces metastatic bone disease of triple negative breast cancer cells. Oncotarget 7:79032–79046

    Article  PubMed  PubMed Central  Google Scholar 

  81. Hassan MQ et al (2012) miR-218 directs a Wnt signaling circuit to promote differentiation of osteoblasts and osteomimicry of metastatic cancer cells. J Biol Chem 287:42084–42092

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Yin JJ et al (1999) TGF-beta signaling blockade inhibits PTHrP secretion by breast cancer cells and bone metastases development. J Clin Invest 103:197–206

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Biswas S et al (2011) Anti-transforming growth factor ss antibody treatment rescues bone loss and prevents breast cancer metastasis to bone. PLoS ONE 6:e27090

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Johnson RW et al (2011) TGF-beta promotion of Gli2-induced expression of parathyroid hormone-related protein, an important osteolytic factor in bone metastasis, is independent of canonical Hedgehog signaling. Cancer Res 71:822–831

    Article  CAS  PubMed  Google Scholar 

  85. Sterling JA et al (2006) The hedgehog signaling molecule Gli2 induces parathyroid hormone-related peptide expression and osteolysis in metastatic human breast cancer cells. Cancer Res 66:7548–7553

    Article  CAS  PubMed  Google Scholar 

  86. Heller E et al (2012) Hedgehog signaling inhibition blocks growth of resistant tumors through effects on tumor microenvironment. Cancer Res 72:897–907

    Article  CAS  PubMed  Google Scholar 

  87. Taipale J, Beachy PA (2001) The Hedgehog and Wnt signalling pathways in cancer. Nature 411:349–354

    Article  CAS  PubMed  Google Scholar 

  88. Mohammad KS et al (2011) TGF-beta-RI kinase inhibitor SD-208 reduces the development and progression of melanoma bone metastases. Cancer Res 71:175–184

    Article  CAS  PubMed  Google Scholar 

  89. Cannonier SA, Gonzales CB, Ely K, Guelcher SA, Sterling JA (2016) Hedgehog and TGFbeta signaling converge on Gli2 to control bony invasion and bone destruction in oral squamous cell carcinoma. Oncotarget 7:76062–76075

    Article  PubMed  PubMed Central  Google Scholar 

  90. Johnson RW, Schipani E, Giaccia AJ (2015) HIF targets in bone remodeling and metastatic disease. Pharmacol Ther 150:169–177

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Bendre MS 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

    Article  CAS  PubMed  Google Scholar 

  92. Zheng Y et al (2014) Targeting IL-6 and RANKL signaling inhibits prostate cancer growth in bone. Clin Exp Metastasis 31:921–933

    Article  CAS  PubMed  Google Scholar 

  93. Luo X et al (2016) Stromal-initiated changes in the bone promote metastatic niche development. Cell Rep 14:82–92

    Article  CAS  PubMed  Google Scholar 

  94. Williams SC (2013) First IL-6-blocking drug nears approval for rare blood disorder. Nat Med 19:1193

    Article  PubMed  CAS  Google Scholar 

  95. Eckschlager T, Plch J, Stiborova M, Hrabeta J (2017) Histone deacetylase inhibitors as anticancer drugs. Int J Mol Sci 18:1414

    Article  PubMed Central  Google Scholar 

  96. Pratap J et al (2010) The histone deacetylase inhibitor, vorinostat, reduces tumor growth at the metastatic bone site and associated osteolysis, but promotes normal bone loss. Mol Cancer Ther 9:3210–3220

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Larson SR et al (2014) Prostate cancer derived prostatic acid phosphatase promotes an osteoblastic response in the bone microenvironment. Clin Exp Metastasis 31:247–256

    Article  CAS  PubMed  Google Scholar 

  98. Coleman RE (1997) Skeletal complications of malignancy. Cancer 80:1588–1594

    Article  CAS  PubMed  Google Scholar 

  99. Suva LJ, Brander BE, Makhoul I (2011) Update on bone-modifying agents in metastatic breast cancer. Nat Rev Endocrinol 7:380–381

    Article  PubMed  Google Scholar 

  100. Kelly T et al (2005) Expression of heparanase by primary breast tumors promotes bone resorption in the absence of detectable bone metastases. Cancer Res 65:5778–5784

    Article  CAS  PubMed  Google Scholar 

  101. Ozdemir BC et al (2014) The molecular signature of the stroma response in prostate cancer-induced osteoblastic bone metastasis highlights expansion of hematopoietic and prostate epithelial stem cell niches. PLoS ONE 9:e114530

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  102. Kim MY et al (2009) Tumor self-seeding by circulating cancer cells. Cell 139:1315–1326

    Article  PubMed  PubMed Central  Google Scholar 

  103. Padua D et al (2008) TGFbeta primes breast tumors for lung metastasis seeding through angiopoietin-like 4. Cell 133:66–77

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Vilalta M, Rafat M, Giaccia AJ, Graves EE (2014) Recruitment of circulating breast cancer cells is stimulated by radiotherapy. Cell Rep 8:402–409

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Manolagas S (2000) Birth and death of bone cells: basic regulatory mechanisms and implications for the pathogenesis and treatment of osteoporosis. Endocr Rev 21:115–137

    CAS  PubMed  Google Scholar 

  106. Martinez LM et al (2014) Changes in the peripheral blood and bone marrow from untreated advanced breast cancer patients that are associated with the establishment of bone metastases. Clin Exp Metastasis 31:213–232

    Article  CAS  PubMed  Google Scholar 

  107. Stine KC et al (2014) Cisplatin inhibits bone healing during distraction osteogenesis. J Orthop Res 32:464–470

    Article  CAS  PubMed  Google Scholar 

  108. Stine KC et al (2016) Nutlin-3 treatment spares cisplatin-induced inhibition of bone healing while maintaining osteosarcoma toxicity. J Orthop Res 34:1716–1724

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Xiong J et al (2015) Osteocytes, not osteoblasts or lining cells, are the main source of the RANKL required for osteoclast formation in remodeling bone. PLoS ONE 10:e0138189

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  110. Bultynck G (2016) The anti-metastatic micro-environment of the bone: importance of osteocyte Cx43 hemichannels. Biochim Biophys Acta 1866:121–127

    CAS  PubMed  Google Scholar 

  111. Massague J, Batlle E, Gomis RR (2017) Understanding the molecular mechanisms driving metastasis. Mol Oncol 11:3–4

    Article  PubMed  PubMed Central  Google Scholar 

  112. Giustacchini A et al (2017) Single-cell transcriptomics uncovers distinct molecular signatures of stem cells in chronic myeloid leukemia. Nat Med 23:692–702

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by NIH R01CA166060 (LJS) and NIH R00CA194198 (RWJ). Our efforts in this area are dedicated to the memory of the late Dr. Greg Mundy whose vision and leadership provided much of the stimulus for the field to study the bone marrow microenvironment of cancer.

Competing interests

The authors Rachelle W. Johnson and Larry J. Suva declare no competing interests.

Author information

Authors and Affiliations

  1. Division of Clinical Pharmacology, Department of Medicine, Vanderbilt Center for Bone Biology, Vanderbilt University Medical Center, Nashville, TN, 37232, USA

    Rachelle W. Johnson

  2. Department of Veterinary Physiology and Pharmacology, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX, 77843, USA

    Larry J. Suva

Authors
  1. Rachelle W. Johnson
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Larry J. Suva
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Larry J. Suva.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Johnson, R.W., Suva, L.J. Hallmarks of Bone Metastasis. Calcif Tissue Int 102, 141–151 (2018). https://doi.org/10.1007/s00223-017-0362-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00223-017-0362-4

Keywords

Search

Navigation