Skip to main content

Pathobiology of Osteolytic and Osteoblastic Bone Metastases

  • Chapter
Metastatic Bone Disease

Abstract

Some of the most common cancer types have a propensity to metastasize to bone. When cancer metastasizes to bone, it causes osteolysis and abnormal new bone formation. The phenotypes of deregulated bone resorption and new bone formation are the two extremes of the spectrum, but bone metastases are usually heterogeneous and patients will present with both osteolytic and osteoblastic lesions at the histologic examination. The molecular basis of this preferential growth of cancer cells in the bone microenvironment has been an area of active investigation. Although the precise molecular mechanisms underlying this process remain to be elucidated, it is now being recognized that the unique characteristics of the bone niche provide homing signals to cancer cells and create a microenvironment conducive for the cancer cells to colonize. Concomitantly, cancer cells release several regulatory factors that result in abnormal bone destruction and/or formation. This complex bidirectional interplay between tumor cells and bone microenvironment establishes a “vicious cycle” that leads to a selective growth advantage for the cancer cells. The molecular insights gained on the underpinnings of bone metastasis in recent years have also provided us with paths to design innovative approaches for therapeutic intervention.

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

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 79.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 99.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Abbreviations

1,25-(OH)2D3 :

1,25-Dihydroxyvitamin D3

BMP:

Bone morphogenetic protein

cAMP:

Cyclic adenosine monophosphate

CaSR:

Extracellular calcium-sensing receptors

CBFA1:

Core binding factor A1

CCL2:

Chemokine (C-C motif) ligand 2

CHO:

Chinese hamster ovary

CTGF:

Connective tissue growth factor

CXCL12:

Chemokine (C-X-C motif) ligand 12

CXCR4:

Chemokine (C-X-C motif) receptor 4

DKK1:

Dickkopfs 1

ET-1:

Endothelin 1

ETAR:

Endothelin A receptor

FGF:

Fibroblast growth factor

HPC:

Hematopoietic progenitor cell

HSC:

Hematopoietic stem cell

IFNγ:

Interferon γ

IGF:

Insulin-like growth factor

IL:

Interleukin

JNK:

Jun N-terminal kinase

LRP:

Lipoprotein receptor-related protein

MAPK:

Mitogen-activated protein kinase

M-CSF:

Macrophage colony-stimulating factor

MDSC:

Myeloid-derived suppressor cell

MMP:

Matrix metalloproteinase

NFk-B:

Nuclear factor kappa B

OPG:

Osteoprotegerin

OPN:

Osteopontin

PDGF:

Platelet-derived growth factor

PGE2:

Prostaglandin G2

PGF:

Placental growth factor

PKA:

Protein kinase A

PKC:

Protein kinase C

PLC:

Phospholipase C

PPARγ:

Peroxisome proliferator-activated receptor γ

PSA:

Prostate-specific antigen

PTH:

Parathyroid hormone

PTHrP:

Parathyroid hormone-related protein

RANK:

Receptor activator of nuclear factor kappa B

RANKL:

Receptor activator of nuclear factor kappa B ligand

RUNX-2:

Runt-related transcription factor 2

SDF-1:

Stromal cell-derived factor 1

sFRP:

Secreted frizzled-related protein

SMAD:

Mothers against decapentaplegic homolog

TGFβ:

Transforming growth factor β

VCAM1:

Vascular cellular adhesion molecule 1

VEGFA:

Vascular endothelial growth factor A

VEGFR1:

Vascular endothelial growth factor receptor 1

WIF-1:

Wnt inhibitory factor 1

References

  1. Roudier MP, Morrissey C, True LD, Higano CS, Vessella RL, Ott SM. Histopathological assessment of prostate cancer bone osteoblastic metastases. J Urol. 2008;180(3):1154–60.

    Article  PubMed Central  PubMed  Google Scholar 

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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  3. Yoneda T. Mechanisms of preferential metastasis of breast cancer to bone—(Review). Int J Oncol. 1996;9(1):103–9.

    CAS  PubMed  Google Scholar 

  4. Hauschka PV, Mavrakos AE, Iafrati MD, Doleman SE, Klagsbrun M. Growth factors in bone matrix. Isolation of multiple types by affinity chromatography on heparin-Sepharose. J Biol Chem. 1986;261(27):12665–74.

    CAS  PubMed  Google Scholar 

  5. Mohan S, Baylink DJ. Bone growth factors. Clin Orthop Relat Res. 1991;263:30–48.

    PubMed  Google Scholar 

  6. Pfeilschifter J, Mundy GR. Modulation of type beta transforming growth factor activity in bone cultures by osteotropic hormones. Proc Natl Acad Sci U S A. 1987;84(7):2024–8.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  7. Bussard KM, Gay CV, Mastro AM. The bone microenvironment in metastasis; what is special about bone? Cancer Metastasis Rev. 2008;27(1):41–55.

    Article  PubMed  Google Scholar 

  8. Goldring SR, Goldring MB. Eating bone or adding it: the Wnt pathway decides. Nat Med. 2007;13(2):133–4.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  10. Komori T, Yagi H, Nomura S, Yamaguchi A, Sasaki K, Deguchi K, et al. Targeted disruption of Cbfa1 results in a complete lack of bone formation owing to maturational arrest of osteoblasts. Cell. 1997;89(5):755–64.

    Article  CAS  PubMed  Google Scholar 

  11. Otto F, Thornell AP, Crompton T, Denzel A, Gilmour KC, Rosewell IR, et al. Cbfa1, a candidate gene for cleidocranial dysplasia syndrome, is essential for osteoblast differentiation and bone development. Cell. 1997;89(5):765–71.

    Article  CAS  PubMed  Google Scholar 

  12. Mohammad KS, Chen CG, Balooch G, Stebbins E, McKenna CR, Davis H, et al. Pharmacologic inhibition of the TGF-beta type I receptor kinase has anabolic and anti-catabolic effects on bone. PLoS One. 2009;4(4), e5275.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  13. Tang Y, Wu X, Lei W, Pang L, Wan C, Shi Z, et al. TGF-beta1-induced migration of bone mesenchymal stem cells couples bone resorption with formation. Nat Med. 2009;15(7):757–65.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  14. Bennett CN, Longo KA, Wright WS, Suva LJ, Lane TF, Hankenson KD, et al. Regulation of osteoblastogenesis and bone mass by Wnt10b. Proc Natl Acad Sci U S A. 2005;102(9):3324–9.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  15. Hu H, Hilton MJ, Tu X, Yu K, Ornitz DM, Long F. Sequential roles of Hedgehog and Wnt signaling in osteoblast development. Development. 2005;132(1):49–60.

    Article  CAS  PubMed  Google Scholar 

  16. Milat F, Ng KW. Is Wnt signalling the final common pathway leading to bone formation? Mol Cell Endocrinol. 2009;310(1–2):52–62.

    Article  CAS  PubMed  Google Scholar 

  17. Williams BO, Insogna KL. Where Wnts went: the exploding field of Lrp5 and Lrp6 signaling in bone. J Bone Miner Res. 2009;24(2):171–8.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  18. Binnerts ME, Kim KA, Bright JM, Patel SM, Tran K, Zhou M, et al. R-Spondin1 regulates Wnt signaling by inhibiting internalization of LRP6. Proc Natl Acad Sci U S A. 2007;104(37):14700–5.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  19. Dougall WC, Glaccum M, Charrier K, Rohrbach K, Brasel K, De Smedt T, et al. RANK is essential for osteoclast and lymph node development. Genes Dev. 1999;13(18):2412–24.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  20. Lacey DL, Timms E, Tan HL, Kelley MJ, Dunstan CR, Burgess T, et al. Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell. 1998;93(2):165–76.

    Article  CAS  PubMed  Google Scholar 

  21. Baud'huin M, Renault R, Charrier C, Riet A, Moreau A, Brion R, et al. Interleukin-34 is expressed by giant cell tumours of bone and plays a key role in RANKL-induced osteoclastogenesis. J Pathol. 2010;221(1):77–86.

    Article  PubMed  CAS  Google Scholar 

  22. Horton MA, Dorey EL, Nesbitt SA, Samanen J, Ali FE, Stadel JM, et al. Modulation of vitronectin receptor-mediated osteoclast adhesion by Arg-Gly-Asp peptide analogs: a structure-function analysis. J Bone Miner Res. 1993;8(2):239–47.

    Article  CAS  PubMed  Google Scholar 

  23. Mundy GR, Guise TA. Hormonal control of calcium homeostasis. Clin Chem. 1999;45(8 Pt 2):1347–52.

    CAS  PubMed  Google Scholar 

  24. Dvorak MM, Siddiqua A, Ward DT, Carter DH, Dallas SL, Nemeth EF, et al. Physiological changes in extracellular calcium concentration directly control osteoblast function in the absence of calciotropic hormones. Proc Natl Acad Sci U S A. 2004;101(14):5140–5.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  25. Berger CE, Rathod H, Gillespie JI, Horrocks BR, Datta HK. Scanning electrochemical microscopy at the surface of bone-resorbing osteoclasts: evidence for steady-state disposal and intracellular functional compartmentalization of calcium. J Bone Miner Res. 2001;16(11):2092–102.

    Article  CAS  PubMed  Google Scholar 

  26. Chattopadhyay N. Effects of calcium-sensing receptor on the secretion of parathyroid hormone-related peptide and its impact on humoral hypercalcemia of malignancy. Am J Physiol Endocrinol Metab. 2006;290(5):E761–70.

    Article  CAS  PubMed  Google Scholar 

  27. VanHouten J, Dann P, McGeoch G, Brown EM, Krapcho K, Neville M, et al. The calcium-sensing receptor regulates mammary gland parathyroid hormone-related protein production and calcium transport. J Clin Invest. 2004;113(4):598–608.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  28. Ardeshirpour L, Dann P, Pollak M, Wysolmerski J, VanHouten J. The calcium-sensing receptor regulates PTHrP production and calcium transport in the lactating mammary gland. Bone. 2006;38(6):787–93.

    Article  CAS  PubMed  Google Scholar 

  29. Moallem E, Kilav R, Silver J, Naveh-Many T. RNA-protein binding and post-transcriptional regulation of parathyroid hormone gene expression by calcium and phosphate. J Biol Chem. 1998;273(9):5253–9.

    Article  CAS  PubMed  Google Scholar 

  30. Okazaki T, Igarashi T, Kronenberg HM. 5'-flanking region of the parathyroid hormone gene mediates negative regulation by 1,25-(OH)2 vitamin D3. J Biol Chem. 1988;263(5):2203–8.

    CAS  PubMed  Google Scholar 

  31. Silver J, Naveh-Many T, Mayer H, Schmelzer HJ, Popovtzer MM. Regulation by vitamin D metabolites of parathyroid hormone gene transcription in vivo in the rat. J Clin Invest. 1986;78(5):1296–301.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  32. Tatsumi S, Segawa H, Morita K, Haga H, Kouda T, Yamamoto H, et al. Molecular cloning and hormonal regulation of PiT-1, a sodium-dependent phosphate cotransporter from rat parathyroid glands. Endocrinology. 1998;139(4):1692–9.

    CAS  PubMed  Google Scholar 

  33. Juppner H, Abou-Samra AB, Freeman M, Kong XF, Schipani E, Richards J, et al. A G protein-linked receptor for parathyroid hormone and parathyroid hormone-related peptide. Science. 1991;254(5034):1024–6.

    Article  CAS  PubMed  Google Scholar 

  34. Mahon MJ, Donowitz M, Yun CC, Segre GV. Na(+)/H(+) exchanger regulatory factor 2 directs parathyroid hormone 1 receptor signalling. Nature. 2002;417(6891):858–61.

    Article  CAS  PubMed  Google Scholar 

  35. Swarthout JT, D'Alonzo RC, Selvamurugan N, Partridge NC. Parathyroid hormone-dependent signaling pathways regulating genes in bone cells. Gene. 2002;282(1–2):1–17.

    Article  CAS  PubMed  Google Scholar 

  36. Bell NH. Vitamin D-endocrine system. J Clin Invest. 1985;76(1):1–6.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  37. Kawashima H, Kraut JA, Kurokawa K. Metabolic acidosis suppresses 25-hydroxyvitamin in D3-1alpha-hydroxylase in the rat kidney. Distinct site and mechanism of action. J Clin Invest. 1982;70(1):135–40.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  38. Norman AW, Roth J, Orci L. The vitamin D endocrine system: steroid metabolism, hormone receptors, and biological response (calcium binding proteins). Endocr Rev. 1982;3(4):331–66.

    Article  CAS  PubMed  Google Scholar 

  39. Brenza HL, DeLuca HF. Regulation of 25-hydroxyvitamin D3 1alpha-hydroxylase gene expression by parathyroid hormone and 1,25-dihydroxyvitamin D3. Arch Biochem Biophys. 2000;381(1):143–52.

    Article  CAS  PubMed  Google Scholar 

  40. Portale AA, Halloran BP, Morris Jr RC. Physiologic regulation of the serum concentration of 1,25-dihydroxyvitamin D by phosphorus in normal men. J Clin Invest. 1989;83(5):1494–9.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  41. Takeyama K, Kitanaka S, Sato T, Kobori M, Yanagisawa J, Kato S. 25-hydroxyvitamin D3 1alpha-hydroxylase and vitamin D synthesis. Science. 1997;277(5333):1827–30.

    Article  CAS  PubMed  Google Scholar 

  42. Barbour GL, Coburn JW, Slatopolsky E, Norman AW, Horst RL. Hypercalcemia in an anephric patient with sarcoidosis: evidence for extrarenal generation of 1,25-dihydroxyvitamin D. N Engl J Med. 1981;305(8):440–3.

    Article  CAS  PubMed  Google Scholar 

  43. Gkonos PJ, London R, Hendler ED. Hypercalcemia and elevated 1,25-dihydroxyvitamin D levels in a patient with end-stage renal disease and active tuberculosis. N Engl J Med. 1984;311(26):1683–5.

    Article  CAS  PubMed  Google Scholar 

  44. Zerwekh JE, Breslau NA. Human placental production of 1 alpha,25-dihydroxyvitamin D3: biochemical characterization and production in normal subjects and patients with pseudohypoparathyroidism. J Clin Endocrinol Metab. 1986;62(1):192–6.

    Article  CAS  PubMed  Google Scholar 

  45. Holtrop ME, Cox KA, Clark MB, Holick MF, Anast CS. 1,25-dihydroxycholecalciferol stimulates osteoclasts in rat bones in the absence of parathyroid hormone. Endocrinology. 1981;108(6):2293–301.

    Article  CAS  PubMed  Google Scholar 

  46. Suda T, Takahashi N, Martin TJ. Modulation of osteoclast differentiation. Endocr Rev. 1992;13(1):66–80.

    CAS  PubMed  Google Scholar 

  47. Takahashi N, Yamana H, Yoshiki S, Roodman GD, Mundy GR, Jones SJ, et al. Osteoclast-like cell formation and its regulation by osteotropic hormones in mouse bone marrow cultures. Endocrinology. 1988;122(4):1373–82.

    Article  CAS  PubMed  Google Scholar 

  48. Friedman J, Au WY, Raisz LG. Responses of fetal rat bone to thyrocalcitonin in tissue culture. Endocrinology. 1968;82(1):149–56.

    Article  CAS  PubMed  Google Scholar 

  49. Chambers TJ, Magnus CJ. Calcitonin alters behaviour of isolated osteoclasts. J Pathol. 1982;136(1):27–39.

    Article  CAS  PubMed  Google Scholar 

  50. Heersche JN, Marcus R, Aurbach GD. Calcitonin and the formation of 3',5'-AMP in bone and kidney. Endocrinology. 1974;94(1):241–7.

    Article  CAS  PubMed  Google Scholar 

  51. Moonga BS, Alam AS, Bevis PJ, Avaldi F, Soncini R, Huang CL, et al. Regulation of cytosolic free calcium in isolated rat osteoclasts by calcitonin. J Endocrinol. 1992;132(2):241–9.

    Article  CAS  PubMed  Google Scholar 

  52. Clines GA, Guise TA. Hypercalcaemia of malignancy and basic research on mechanisms responsible for osteolytic and osteoblastic metastasis to bone. Endocr Relat Cancer. 2005;12(3):549–83.

    Article  CAS  PubMed  Google Scholar 

  53. Mundy GR, Martin TJ. The hypercalcemia of malignancy: pathogenesis and management. Metabolism. 1982;31(12):1247–77.

    Article  CAS  PubMed  Google Scholar 

  54. Moseley JM, Kubota M, Diefenbach-Jagger H, Wettenhall RE, Kemp BE, Suva LJ, et al. Parathyroid hormone-related protein purified from a human lung cancer cell line. Proc Natl Acad Sci U S A. 1987;84(14):5048–52.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  55. Burtis WJ, Brady TG, Orloff JJ, Ersbak JB, Warrell Jr RP, Olson BR, et al. Immunochemical characterization of circulating parathyroid hormone-related protein in patients with humoral hypercalcemia of cancer. N Engl J Med. 1990;322(16):1106–12.

    Article  CAS  PubMed  Google Scholar 

  56. Danks JA, Ebeling PR, Hayman J, Chou ST, Moseley JM, Dunlop J, et al. Parathyroid hormone-related protein: immunohistochemical localization in cancers and in normal skin. J Bone Miner Res. 1989;4(2):273–8.

    Article  CAS  PubMed  Google Scholar 

  57. Asa SL, Henderson J, Goltzman D, Drucker DJ. Parathyroid hormone-like peptide in normal and neoplastic human endocrine tissues. J Clin Endocrinol Metab. 1990;71(5):1112–8.

    Article  CAS  PubMed  Google Scholar 

  58. Luparello C, Ginty AF, Gallagher JA, Pucci-Minafra I, Minafra S. Transforming growth factor-beta 1, beta 2, and beta 3, urokinase and parathyroid hormone-related peptide expression in 8701-BC breast cancer cells and clones. Differentiation. 1993;55(1):73–80.

    Article  CAS  PubMed  Google Scholar 

  59. Luparello C, Burtis WJ, Raue F, Birch MA, Gallagher JA. Parathyroid hormone-related peptide and 8701-BC breast cancer cell growth and invasion in vitro: evidence for growth-inhibiting and invasion-promoting effects. Mol Cell Endocrinol. 1995;111(2):225–32.

    Article  CAS  PubMed  Google Scholar 

  60. Li H, Seitz PK, Selvanayagam P, Rajaraman S, Cooper CW. Effect of endogenously produced parathyroid hormone-related peptide on growth of a human hepatoma cell line (Hep G2). Endocrinology. 1996;137(6):2367–74.

    CAS  PubMed  Google Scholar 

  61. Chen HL, Demiralp B, Schneider A, Koh AJ, Silve C, Wang CY, et al. Parathyroid hormone and parathyroid hormone-related protein exert both pro- and anti-apoptotic effects in mesenchymal cells. J Biol Chem. 2002;277(22):19374–81.

    Article  CAS  PubMed  Google Scholar 

  62. Rosenthal N, Insogna KL, Godsall JW, Smaldone L, Waldron JA, Stewart AF. Elevations in circulating 1,25-dihydroxyvitamin D in three patients with lymphoma-associated hypercalcemia. J Clin Endocrinol Metab. 1985;60(1):29–33.

    Article  CAS  PubMed  Google Scholar 

  63. Seymour JF, Kantarjian HM. Hypercalcemia in acute lymphoblastic leukemia. Leuk Res. 1994;18(3):231–2.

    Article  CAS  PubMed  Google Scholar 

  64. Kremer R, Shustik C, Tabak T, Papavasiliou V, Goltzman D. Parathyroid-hormone-related peptide in hematologic malignancies. Am J Med. 1996;100(4):406–11.

    Article  CAS  PubMed  Google Scholar 

  65. Ikeda K, Ohno H, Hane M, Yokoi H, Okada M, Honma T, et al. Development of a sensitive two-site immunoradiometric assay for parathyroid hormone-related peptide: evidence for elevated levels in plasma from patients with adult T-cell leukemia/lymphoma and B-cell lymphoma. J Clin Endocrinol Metab. 1994;79(5):1322–7.

    CAS  PubMed  Google Scholar 

  66. Sabatini M, Boyce B, Aufdemorte T, Bonewald L, Mundy GR. Infusions of recombinant human interleukins 1 alpha and 1 beta cause hypercalcemia in normal mice. Proc Natl Acad Sci U S A. 1988;85(14):5235–9.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  67. Guise TA, Garrett IR, Bonewald LF, Mundy GR. Interleukin-1 receptor antagonist inhibits the hypercalcemia mediated by interleukin-1. J Bone Miner Res. 1993;8(5):583–7.

    Article  CAS  PubMed  Google Scholar 

  68. Weissglas M, Schamhart D, Lowik C, Papapoulos S, Vos P, Kurth KH. Hypercalcemia and cosecretion of interleukin-6 and parathyroid hormone related peptide by a human renal cell carcinoma implanted into nude mice. J Urol. 1995;153(3 Pt 1):854–7.

    CAS  PubMed  Google Scholar 

  69. Black K, Garrett IR, Mundy GR. Chinese hamster ovarian cells transfected with the murine interleukin-6 gene cause hypercalcemia as well as cachexia, leukocytosis and thrombocytosis in tumor-bearing nude mice. Endocrinology. 1991;128(5):2657–9.

    Article  CAS  PubMed  Google Scholar 

  70. Ueno M, Ban S, Nakanoma T, Tsukamoto T, Nonaka S, Hirata R, et al. Hypercalcemia in a patient with renal cell carcinoma producing parathyroid hormone-related protein and interleukin-6. Int J Urol. 2000;7(6):239–42.

    Article  CAS  PubMed  Google Scholar 

  71. Yates AJ, Boyce BF, Favarato G, Aufdemorte TB, Marcelli C, Kester MB, et al. Expression of human transforming growth factor alpha by Chinese hamster ovarian tumors in nude mice causes hypercalcemia and increased osteoclastic bone resorption. J Bone Miner Res. 1992;7(7):847–53.

    Article  CAS  PubMed  Google Scholar 

  72. Johnson RA, Boyce BF, Mundy GR, Roodman GD. Tumors producing human tumor necrosis factor induced hypercalcemia and osteoclastic bone resorption in nude mice. Endocrinology. 1989;124(3):1424–7.

    Article  CAS  PubMed  Google Scholar 

  73. Hulter HN, Halloran BP, Toto RD, Peterson JC. Long-term control of plasma calcitriol concentration in dogs and humans. Dominant role of plasma calcium concentration in experimental hyperparathyroidism. J Clin Invest. 1985;76(2):695–702.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  75. Batson OV. The function of the vertebral veins and their role in the spread of metastases. Ann Surg. 1940;112(1):138–49.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  76. Paget S. The distribution of secondary growths in cancer of the breast. 1889. Cancer Metastasis Rev. 1989;8(2):98–101.

    CAS  PubMed  Google Scholar 

  77. Chirgwin JM, Guise TA. Molecular mechanisms of tumor-bone interactions in osteolytic metastases. Crit Rev Eukaryot Gene Expr. 2000;10(2):159–78.

    Article  CAS  PubMed  Google Scholar 

  78. Psaila B, Lyden D. The metastatic niche: adapting the foreign soil. Nat Rev Cancer. 2009;9(4):285–93.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  79. Oskarsson T, Batlle E, Massague J. Metastatic stem cells: sources, niches, and vital pathways. Cell Stem Cell. 2014;14(3):306–21.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  80. Kaplan RN, Riba RD, Zacharoulis S, Bramley AH, Vincent L, Costa C, et al. VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche. Nature. 2005;438(7069):820–7.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  81. Hiratsuka S, Watanabe A, Sakurai Y, Akashi-Takamura S, Ishibashi S, Miyake K, et al. The S100A8-serum amyloid A3-TLR4 paracrine cascade establishes a pre-metastatic phase. Nat Cell Biol. 2008;10(11):1349–55.

    Article  CAS  PubMed  Google Scholar 

  82. Sawant A, Deshane J, Jules J, Lee CM, Harris BA, Feng X, et al. Myeloid-derived suppressor cells function as novel osteoclast progenitors enhancing bone loss in breast cancer. Cancer Res. 2013;73(2):672–82.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  83. Purhonen S, Palm J, Rossi D, Kaskenpaa N, Rajantie I, Yla-Herttuala S, et al. Bone marrow-derived circulating endothelial precursors do not contribute to vascular endothelium and are not needed for tumor growth. Proc Natl Acad Sci U S A. 2008;105(18):6620–5.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  84. Guise TA. Breast cancer bone metastases: it's all about the neighborhood. Cell. 2013;154(5):957–9.

    Article  CAS  PubMed  Google Scholar 

  85. Zhang XH, Jin X, Malladi S, Zou Y, Wen YH, Brogi E, et al. Selection of bone metastasis seeds by mesenchymal signals in the primary tumor stroma. Cell. 2013;154(5):1060–73.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  86. Kelly T, Suva LJ, Huang Y, Macleod V, Miao HQ, Walker RC, et al. Expression of heparanase by primary breast tumors promotes bone resorption in the absence of detectable bone metastases. Cancer Res. 2005;65(13):5778–84.

    Article  CAS  PubMed  Google Scholar 

  87. Anborgh PH, Mutrie JC, Tuck AB, Chambers AF. Role of the metastasis-promoting protein osteopontin in the tumour microenvironment. J Cell Mol Med. 2010;14(8):2037–44.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  88. Lynch CC, Hikosaka A, Acuff HB, Martin MD, Kawai N, Singh RK, et al. MMP-7 promotes prostate cancer-induced osteolysis via the solubilization of RANKL. Cancer Cell. 2005;7(5):485–96.

    Article  CAS  PubMed  Google Scholar 

  89. McAllister SS, Gifford AM, Greiner AL, Kelleher SP, Saelzler MP, Ince TA, et al. Systemic endocrine instigation of indolent tumor growth requires osteopontin. Cell. 2008;133(6):994–1005.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  90. Pazolli E, Luo X, Brehm S, Carbery K, Chung JJ, Prior JL, et al. Senescent stromal-derived osteopontin promotes preneoplastic cell growth. Cancer Res. 2009;69(3):1230–9.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  91. Guise TA, Mohammad KS, Clines G, Stebbins EG, Wong DH, Higgins LS, et al. Basic mechanisms responsible for osteolytic and osteoblastic bone metastases. Clin Cancer Res. 2006;12(20 Pt 2):6213s–6s.

    Article  CAS  PubMed  Google Scholar 

  92. Guise TA, Yin JJ, Taylor SD, Kumagai Y, Dallas M, Boyce BF, et al. Evidence for a causal role of parathyroid hormone-related protein in the pathogenesis of human breast cancer-mediated osteolysis. J Clin Invest. 1996;98(7):1544–9.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  93. Li X, Loberg R, Liao J, Ying C, Snyder LA, Pienta KJ, et al. A destructive cascade mediated by CCL2 facilitates prostate cancer growth in bone. Cancer Res. 2009;69(4):1685–92.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  94. Yano S, Macleod RJ, Chattopadhyay N, Tfelt-Hansen J, Kifor O, Butters RR, et al. Calcium-sensing receptor activation stimulates parathyroid hormone-related protein secretion in prostate cancer cells: role of epidermal growth factor receptor transactivation. Bone. 2004;35(3):664–72.

    Article  CAS  PubMed  Google Scholar 

  95. Sanders JL, Chattopadhyay N, Kifor O, Yamaguchi T, Butters RR, Brown EM. Extracellular calcium-sensing receptor expression and its potential role in regulating parathyroid hormone-related peptide secretion in human breast cancer cell lines. Endocrinology. 2000;141(12):4357–64.

    CAS  PubMed  Google Scholar 

  96. Liao J, McCauley LK. Skeletal metastasis: established and emerging roles of parathyroid hormone related protein (PTHrP). Cancer Metastasis Rev. 2006;25(4):559–71.

    Article  CAS  PubMed  Google Scholar 

  97. McCauley LK, Martin TJ. Twenty-five years of PTHrP progress: from cancer hormone to multifunctional cytokine. J Bone Miner Res. 2012;27(6):1231–9.

    Article  CAS  PubMed  Google Scholar 

  98. Yoneda T, Hiraga T. Crosstalk between cancer cells and bone microenvironment in bone metastasis. Biochem Biophys Res Commun. 2005;328(3):679–87.

    Article  CAS  PubMed  Google Scholar 

  99. Clines GA, Guise TA. Molecular mechanisms and treatment of bone metastasis. Expert Rev Mol Med. 2008;10, e7.

    Article  PubMed  Google Scholar 

  100. Kang Y, Siegel PM, Shu W, Drobnjak M, Kakonen SM, Cordon-Cardo C, et al. A multigenic program mediating breast cancer metastasis to bone. Cancer Cell. 2003;3(6):537–49.

    Article  CAS  PubMed  Google Scholar 

  101. Lehr JE, Pienta KJ. Preferential adhesion of prostate cancer cells to a human bone marrow endothelial cell line. J Natl Cancer Inst. 1998;90(2):118–23.

    Article  CAS  PubMed  Google Scholar 

  102. Yoneda T. Cellular and molecular basis of preferential metastasis of breast cancer to bone. J Orthop Sci. 2000;5(1):75–81.

    Article  CAS  PubMed  Google Scholar 

  103. Brenner S, Whiting-Theobald N, Kawai T, Linton GF, Rudikoff AG, Choi U, et al. CXCR4-transgene expression significantly improves marrow engraftment of cultured hematopoietic stem cells. Stem Cells. 2004;22(7):1128–33.

    Article  CAS  PubMed  Google Scholar 

  104. Calvi LM, Adams GB, Weibrecht KW, Weber JM, Olson DP, Knight MC, et al. Osteoblastic cells regulate the haematopoietic stem cell niche. Nature. 2003;425(6960):841–6.

    Article  CAS  PubMed  Google Scholar 

  105. Christopher MJ, Liu F, Hilton MJ, Long F, Link DC. Suppression of CXCL12 production by bone marrow osteoblasts is a common and critical pathway for cytokine-induced mobilization. Blood. 2009;114(7):1331–9.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  106. Hidalgo A, Peired AJ, Weiss LA, Katayama Y, Frenette PS. The integrin alphaMbeta2 anchors hematopoietic progenitors in the bone marrow during enforced mobilization. Blood. 2004;104(4):993–1001.

    Article  CAS  PubMed  Google Scholar 

  107. Kahn J, Byk T, Jansson-Sjostrand L, Petit I, Shivtiel S, Nagler A, et al. Overexpression of CXCR4 on human CD34+ progenitors increases their proliferation, migration, and NOD/SCID repopulation. Blood. 2004;103(8):2942–9.

    Article  CAS  PubMed  Google Scholar 

  108. Mendez-Ferrer S, Michurina TV, Ferraro F, Mazloom AR, Macarthur BD, Lira SA, et al. Mesenchymal and haematopoietic stem cells form a unique bone marrow niche. Nature. 2010;466(7308):829–34.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  109. Papayannopoulou T. Mechanisms of stem-/progenitor-cell mobilization: the anti-VLA-4 paradigm. Semin Hematol. 2000;37(1 Suppl 2):11–8.

    Article  CAS  PubMed  Google Scholar 

  110. Stier S, Ko Y, Forkert R, Lutz C, Neuhaus T, Grunewald E, et al. Osteopontin is a hematopoietic stem cell niche component that negatively regulates stem cell pool size. J Exp Med. 2005;201(11):1781–91.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  111. Zhang J, Niu C, Ye L, Huang H, He X, Tong WG, et al. Identification of the haematopoietic stem cell niche and control of the niche size. Nature. 2003;425(6960):836–41.

    Article  CAS  PubMed  Google Scholar 

  112. Kollet O, Dar A, Shivtiel S, Kalinkovich A, Lapid K, Sztainberg Y, et al. Osteoclasts degrade endosteal components and promote mobilization of hematopoietic progenitor cells. Nat Med. 2006;12(6):657–64.

    Article  CAS  PubMed  Google Scholar 

  113. Mendez-Ferrer S, Frenette PS. Hematopoietic stem cell trafficking: regulated adhesion and attraction to bone marrow microenvironment. Ann N Y Acad Sci. 2007;1116:392–413.

    Article  CAS  PubMed  Google Scholar 

  114. Shiozawa Y, Pedersen EA, Havens AM, Jung Y, Mishra A, Joseph J, 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  PubMed Central  CAS  PubMed  Google Scholar 

  115. Muller A, Homey B, Soto H, Ge N, Catron D, Buchanan ME, et al. Involvement of chemokine receptors in breast cancer metastasis. Nature. 2001;410(6824):50–6.

    Article  CAS  PubMed  Google Scholar 

  116. Sun YX, Fang M, Wang J, Cooper CR, Pienta KJ, Taichman RS. Expression and activation of alpha v beta 3 integrins by SDF-1/CXC12 increases the aggressiveness of prostate cancer cells. Prostate. 2007;67(1):61–73.

    Article  CAS  PubMed  Google Scholar 

  117. Sun YX, 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. 2005;20(2):318–29.

    Article  CAS  PubMed  Google Scholar 

  118. Smith MC, Luker KE, Garbow JR, Prior JL, Jackson E, Piwnica-Worms D, et al. CXCR4 regulates growth of both primary and metastatic breast cancer. Cancer Res. 2004;64(23):8604–12.

    Article  CAS  PubMed  Google Scholar 

  119. Lapteva N, Yang AG, Sanders DE, Strube RW, Chen SY. CXCR4 knockdown by small interfering RNA abrogates breast tumor growth in vivo. Cancer Gene Ther. 2005;12(1):84–9.

    Article  CAS  PubMed  Google Scholar 

  120. Sun YX, Wang J, Shelburne CE, Lopatin DE, Chinnaiyan AM, Rubin MA, 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 

  121. Orimo A, Gupta PB, Sgroi DC, Arenzana-Seisdedos F, Delaunay T, Naeem R, et al. Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion. Cell. 2005;121(3):335–48.

    Article  CAS  PubMed  Google Scholar 

  122. Chinni SR, Sivalogan S, Dong Z, Filho JC, Deng X, Bonfil RD, et al. CXCL12/CXCR4 signaling activates Akt-1 and MMP-9 expression in prostate cancer cells: the role of bone microenvironment-associated CXCL12. Prostate. 2006;66(1):32–48.

    Article  CAS  PubMed  Google Scholar 

  123. Michigami T, Shimizu N, Williams PJ, Niewolna M, Dallas SL, Mundy GR, et al. Cell-cell contact between marrow stromal cells and myeloma cells via VCAM-1 and alpha(4)beta(1)-integrin enhances production of osteoclast-stimulating activity. Blood. 2000;96(5):1953–60.

    CAS  PubMed  Google Scholar 

  124. Matsuura N, Puzon-McLaughlin W, Irie A, Morikawa Y, Kakudo K, Takada Y. Induction of experimental bone metastasis in mice by transfection of integrin alpha 4 beta 1 into tumor cells. Am J Pathol. 1996;148(1):55–61.

    PubMed Central  CAS  PubMed  Google Scholar 

  125. Korah R, Boots M, Wieder R. Integrin alpha5beta1 promotes survival of growth-arrested breast cancer cells: an in vitro paradigm for breast cancer dormancy in bone marrow. Cancer Res. 2004;64(13):4514–22.

    Article  CAS  PubMed  Google Scholar 

  126. Liesveld JL, Dipersio JF, Abboud CN. Integrins and adhesive receptors in normal and leukemic CD34+ progenitor cells: potential regulatory checkpoints for cellular traffic. Leuk Lymphoma. 1994;14(1-2):19–28.

    Article  CAS  PubMed  Google Scholar 

  127. Lang SH, Clarke NW, George NJ, Testa NG. Primary prostatic epithelial cell binding to human bone marrow stroma and the role of alpha2beta1 integrin. Clin Exp Metastasis. 1997;15(3):218–27.

    Article  CAS  PubMed  Google Scholar 

  128. Hall CL, Dubyk CW, Riesenberger TA, Shein D, Keller ET, van Golen KL. Type I collagen receptor (alpha2beta1) signaling promotes prostate cancer invasion through RhoC GTPase. Neoplasia. 2008;10(8):797–803.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  129. Hall CL, Dai J, van Golen KL, Keller ET, Long MW. Type I collagen receptor (alpha 2 beta 1) signaling promotes the growth of human prostate cancer cells within the bone. Cancer Res. 2006;66(17):8648–54.

    Article  CAS  PubMed  Google Scholar 

  130. Mori Y, Shimizu N, Dallas M, Niewolna M, Story B, Williams PJ, et al. Anti-alpha4 integrin antibody suppresses the development of multiple myeloma and associated osteoclastic osteolysis. Blood. 2004;104(7):2149–54.

    Article  CAS  PubMed  Google Scholar 

  131. Sung V, Stubbs 3rd JT, Fisher L, Aaron AD, Thompson EW. Bone sialoprotein supports breast cancer cell adhesion proliferation and migration through differential usage of the alpha(v)beta3 and alpha(v)beta5 integrins. J Cell Physiol. 1998;176(3):482–94.

    Article  CAS  PubMed  Google Scholar 

  132. Felding-Habermann B, O'Toole TE, Smith JW, Fransvea E, Ruggeri ZM, Ginsberg MH, et al. Integrin activation controls metastasis in human breast cancer. Proc Natl Acad Sci U S A. 2001;98(4):1853–8.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  133. Clezardin P. Integrins in bone metastasis formation and potential therapeutic implications. Curr Cancer Drug Targets. 2009;9(7):801–6.

    Article  CAS  PubMed  Google Scholar 

  134. Schneider JG, Amend SR, Weilbaecher KN. Integrins and bone metastasis: integrating tumor cell and stromal cell interactions. Bone. 2011;48(1):54–65.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  135. Parmo-Cabanas M, Bartolome RA, Wright N, Hidalgo A, Drager AM, Teixido J. Integrin alpha4beta1 involvement in stromal cell-derived factor-1alpha-promoted myeloma cell transendothelial migration and adhesion: role of cAMP and the actin cytoskeleton in adhesion. Exp Cell Res. 2004;294(2):571–80.

    Article  CAS  PubMed  Google Scholar 

  136. Bandyopadhyay A, Agyin JK, Wang L, Tang Y, Lei X, Story BM, et al. Inhibition of pulmonary and skeletal metastasis by a transforming growth factor-beta type I receptor kinase inhibitor. Cancer Res. 2006;66(13):6714–21.

    Article  CAS  PubMed  Google Scholar 

  137. Yin JJ, Pollock CB, Kelly K. Mechanisms of cancer metastasis to the bone. Cell Res. 2005;15(1):57–62.

    Article  CAS  PubMed  Google Scholar 

  138. Southby J, Kissin MW, Danks JA, Hayman JA, Moseley JM, Henderson MA, et al. Immunohistochemical localization of parathyroid hormone-related protein in human breast cancer. Cancer Res. 1990;50(23):7710–6.

    CAS  PubMed  Google Scholar 

  139. Powell GJ, Southby J, Danks JA, Stillwell RG, Hayman JA, Henderson MA, et al. Localization of parathyroid hormone-related protein in breast cancer metastases: increased incidence in bone compared with other sites. Cancer Res. 1991;51(11):3059–61.

    CAS  PubMed  Google Scholar 

  140. Vargas SJ, Gillespie MT, Powell GJ, Southby J, Danks JA, Moseley JM, et al. Localization of parathyroid hormone-related protein mRNA expression in breast cancer and metastatic lesions by in situ hybridization. J Bone Miner Res. 1992;7(8):971–9.

    Article  CAS  PubMed  Google Scholar 

  141. Guise TA, Mundy GR. Physiological and pathological roles of parathyroid hormone-related peptide. Curr Opin Nephrol Hypertens. 1996;5(4):307–15.

    Article  CAS  PubMed  Google Scholar 

  142. Thomas RJ, Guise TA, Yin JJ, Elliott J, Horwood NJ, Martin TJ, et al. Breast cancer cells interact with osteoblasts to support osteoclast formation. Endocrinology. 1999;140(10):4451–8.

    CAS  PubMed  Google Scholar 

  143. Yin JJ, Selander K, Chirgwin JM, Dallas M, Grubbs BG, Wieser R, et al. TGF-beta signaling blockade inhibits PTHrP secretion by breast cancer cells and bone metastases development. J Clin Invest. 1999;103(2):197–206.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  144. Massague J. TGF-beta signal transduction. Annu Rev Biochem. 1998;67:753–91.

    Article  CAS  PubMed  Google Scholar 

  145. Wieser R, Wrana JL, Massague J. GS domain mutations that constitutively activate T beta R-I, the downstream signaling component in the TGF-beta receptor complex. EMBO J. 1995;14(10):2199–208.

    PubMed Central  CAS  PubMed  Google Scholar 

  146. Kakonen SM, Selander KS, Chirgwin JM, Yin JJ, Burns S, Rankin WA, et al. Transforming growth factor-beta stimulates parathyroid hormone-related protein and osteolytic metastases via Smad and mitogen-activated protein kinase signaling pathways. J Biol Chem. 2002;277(27):24571–8.

    Article  CAS  PubMed  Google Scholar 

  147. Javed A, Barnes GL, Pratap J, Antkowiak T, Gerstenfeld LC, van Wijnen AJ, et al. Impaired intranuclear trafficking of Runx2 (AML3/CBFA1) transcription factors in breast cancer cells inhibits osteolysis in vivo. Proc Natl Acad Sci U S A. 2005;102(5):1454–9.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  148. Voorzanger-Rousselot N, Goehrig D, Journe F, Doriath V, Body JJ, Clezardin P, et al. Increased Dickkopf-1 expression in breast cancer bone metastases. Br J Cancer. 2007;97(7):964–70.

    PubMed Central  CAS  PubMed  Google Scholar 

  149. Pinzone JJ, Hall BM, Thudi NK, Vonau M, Qiang YW, Rosol TJ, et al. The role of Dickkopf-1 in bone development, homeostasis, and disease. Blood. 2009;113(3):517–25.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  150. Grano M, Mori G, Minielli V, Cantatore FP, Colucci S, Zallone AZ. Breast cancer cell line MDA-231 stimulates osteoclastogenesis and bone resorption in human osteoclasts. Biochem Biophys Res Commun. 2000;270(3):1097–100.

    Article  CAS  PubMed  Google Scholar 

  151. Wani MR, Fuller K, Kim NS, Choi Y, Chambers T. Prostaglandin E2 cooperates with TRANCE in osteoclast induction from hemopoietic precursors: synergistic activation of differentiation, cell spreading, and fusion. Endocrinology. 1999;140(4):1927–35.

    Article  CAS  PubMed  Google Scholar 

  152. Kakonen SM, Mundy GR. Mechanisms of osteolytic bone metastases in breast carcinoma. Cancer. 2003;97(3 Suppl):834–9.

    Article  PubMed  Google Scholar 

  153. Sethi N, Dai X, Winter CG, Kang Y. Tumor-derived JAGGED1 promotes osteolytic bone metastasis of breast cancer by engaging notch signaling in bone cells. Cancer Cell. 2011;19(2):192–205.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  154. Coenegrachts L, Maes C, Torrekens S, Van Looveren R, Mazzone M, Guise TA, et al. Anti-placental growth factor reduces bone metastasis by blocking tumor cell engraftment and osteoclast differentiation. Cancer Res. 2010;70(16):6537–47.

    Article  CAS  PubMed  Google Scholar 

  155. Sachdev D, Yee D. The IGF system and breast cancer. Endocr Relat Cancer. 2001;8(3):197–209.

    Article  CAS  PubMed  Google Scholar 

  156. Yoneda T, Williams PJ, Hiraga T, Niewolna M, Nishimura R. A bone-seeking clone exhibits different biological properties from the MDA-MB-231 parental human breast cancer cells and a brain-seeking clone in vivo and in vitro. J Bone Miner Res. 2001;16(8):1486–95.

    Article  CAS  PubMed  Google Scholar 

  157. 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. 2013;24(4):542–56.

    Article  CAS  PubMed  Google Scholar 

  158. Waning DL, Mohammad KS, Guise TA. Cancer-associated osteoclast differentiation takes a good look in the miR(NA)ror. Cancer Cell. 2013;24(4):407–9.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  159. Charhon SA, Chapuy MC, Delvin EE, Valentin-Opran A, Edouard CM, Meunier PJ. Histomorphometric analysis of sclerotic bone metastases from prostatic carcinoma special reference to osteomalacia. Cancer. 1983;51(5):918–24.

    Article  CAS  PubMed  Google Scholar 

  160. Koutsilieris M. Skeletal metastases in advanced prostate cancer: cell biology and therapy. Crit Rev Oncol Hematol. 1995;18(1):51–64.

    Article  CAS  PubMed  Google Scholar 

  161. Saad F, Gleason DM, Murray R, Tchekmedyian S, Venner P, Lacombe L, 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 

  162. Guise TA, Yin JJ, Mohammad KS. Role of endothelin-1 in osteoblastic bone metastases. Cancer. 2003;97(3 Suppl):779–84.

    Article  PubMed  Google Scholar 

  163. Yin JJ, Mohammad KS, Kakonen SM, Harris S, Wu-Wong JR, Wessale JL, et al. A causal role for endothelin-1 in the pathogenesis of osteoblastic bone metastases. Proc Natl Acad Sci U S A. 2003;100(19):10954–9.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  164. Rosenbaum E, Carducci MA. Pharmacotherapy of hormone refractory prostate cancer: new developments and challenges. Expert Opin Pharmacother. 2003;4(6):875–87.

    Article  CAS  PubMed  Google Scholar 

  165. Nelson JB, Nabulsi AA, Vogelzang NJ, Breul J, Zonnenberg BA, Daliani DD, et al. Suppression of prostate cancer induced bone remodeling by the endothelin receptor A antagonist atrasentan. J Urol. 2003;169(3):1143–9.

    Article  CAS  PubMed  Google Scholar 

  166. Carducci MA, Saad F, Abrahamsson PA, Dearnaley DP, Schulman CC, North SA, et al. A phase 3 randomized controlled trial of the efficacy and safety of atrasentan in men with metastatic hormone-refractory prostate cancer. Cancer. 2007;110(9):1959–66.

    Article  CAS  PubMed  Google Scholar 

  167. Quinn DI, Tangen CM, Hussain M, Lara Jr PN, Goldkorn A, Moinpour CM, et al. Docetaxel and atrasentan versus docetaxel and placebo for men with advanced castration-resistant prostate cancer (SWOG S0421): a randomised phase 3 trial. Lancet Oncol. 2013;14(9):893–900.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  168. Atrasentan of no benefit to men with metastatic prostate cancer. BoneKEy Reports. 2014;3: 503.

    Google Scholar 

  169. Clines GA, Mohammad KS, Bao Y, Stephens OW, Suva LJ, Shaughnessy Jr JD, et al. Dickkopf homolog 1 mediates endothelin-1-stimulated new bone formation. Mol Endocrinol. 2007;21(2):486–98.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  170. Hall CL, Bafico A, Dai J, Aaronson SA, Keller ET. Prostate cancer cells promote osteoblastic bone metastases through Wnts. Cancer Res. 2005;65(17):7554–60.

    CAS  PubMed  Google Scholar 

  171. Chen G, Shukeir N, Potti A, Sircar K, Aprikian A, Goltzman D, et al. Up-regulation of Wnt-1 and beta-catenin production in patients with advanced metastatic prostate carcinoma: potential pathogenetic and prognostic implications. Cancer. 2004;101(6):1345–56.

    Article  CAS  PubMed  Google Scholar 

  172. Cumming AP, Hopmans SN, Vukmirovic-Popovic S, Duivenvoorden WC. PSA affects prostate cancer cell invasion in vitro and induces an osteoblastic phenotype in bone in vivo. Prostate Cancer Prostatic Dis. 2011;14(4):286–94.

    Article  CAS  PubMed  Google Scholar 

  173. Cramer SD, Chen Z, Peehl DM. Prostate specific antigen cleaves parathyroid hormone-related protein in the PTH-like domain: inactivation of PTHrP-stimulated cAMP accumulation in mouse osteoblasts. J Urol. 1996;156(2 Pt 1):526–31.

    CAS  PubMed  Google Scholar 

  174. Iwamura M, Hellman J, Cockett AT, Lilja H, Gershagen S. Alteration of the hormonal bioactivity of parathyroid hormone-related protein (PTHrP) as a result of limited proteolysis by prostate-specific antigen. Urology. 1996;48(2):317–25.

    Article  CAS  PubMed  Google Scholar 

  175. Schluter KD, Katzer C, Piper HM. A N-terminal PTHrP peptide fragment void of a PTH/PTHrP-receptor binding domain activates cardiac ET(A) receptors. Br J Pharmacol. 2001;132(2):427–32.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  176. Black MH, Diamandis EP. The diagnostic and prognostic utility of prostate-specific antigen for diseases of the breast. Breast Cancer Res Treat. 2000;59(1):1–14.

    Article  CAS  PubMed  Google Scholar 

  177. Fielder PJ, Rosenfeld RG, Graves HC, Grandbois K, Maack CA, Sawamura S, et al. Biochemical analysis of prostate specific antigen-proteolyzed insulin-like growth factor binding protein-3. Growth Regul. 1994;4(4):164–72.

    CAS  PubMed  Google Scholar 

  178. Killian CS, Corral DA, Kawinski E, Constantine RI. Mitogenic response of osteoblast cells to prostate-specific antigen suggests an activation of latent TGF-beta and a proteolytic modulation of cell adhesion receptors. Biochem Biophys Res Commun. 1993;192(2):940–7.

    Article  CAS  PubMed  Google Scholar 

  179. Achbarou A, Kaiser S, Tremblay G, Ste-Marie LG, Brodt P, Goltzman D, et al. Urokinase overproduction results in increased skeletal metastasis by prostate cancer cells in vivo. Cancer Res. 1994;54(9):2372–7.

    CAS  PubMed  Google Scholar 

  180. Buijs JT, Rentsch CA, van der Horst G, van Overveld PG, Wetterwald A, Schwaninger R, et al. BMP7, a putative regulator of epithelial homeostasis in the human prostate, is a potent inhibitor of prostate cancer bone metastasis in vivo. Am J Pathol. 2007;171(3):1047–57.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  181. Safadi FF, Xu J, Smock SL, Kanaan RA, Selim AH, Odgren PR, et al. Expression of connective tissue growth factor in bone: its role in osteoblast proliferation and differentiation in vitro and bone formation in vivo. J Cell Physiol. 2003;196(1):51–62.

    Article  CAS  PubMed  Google Scholar 

  182. Cornish J, Naot D. Amylin and adrenomedullin: novel regulators of bone growth. Curr Pharm Des. 2002;8(23):2009–21.

    Article  CAS  PubMed  Google Scholar 

  183. Casimiro S, Guise TA, Chirgwin J. The critical role of the bone microenvironment in cancer metastases. Mol Cell Endocrinol. 2009;310(1-2):71–81.

    Article  CAS  PubMed  Google Scholar 

  184. Orr W, Varani J, Gondex MK, Ward PA, Mundy GR. Chemotactic responses of tumor cells to products of resorbing bone. Science. 1979;203(4376):176–9.

    Article  CAS  PubMed  Google Scholar 

  185. Doerr ME, Jones JI. The roles of integrins and extracellular matrix proteins in the insulin-like growth factor I-stimulated chemotaxis of human breast cancer cells. J Biol Chem. 1996;271(5):2443–7.

    Article  CAS  PubMed  Google Scholar 

  186. Tavazoie SF, Alarcon C, Oskarsson T, Padua D, Wang Q, Bos PD, et al. Endogenous human microRNAs that suppress breast cancer metastasis. Nature. 2008;451(7175):147–52.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  187. Browne G, Taipaleenmaki H, Stein GS, Stein JL, Lian JB. MicroRNAs in the control of metastatic bone disease. Trends Endocrinol Metab. 2014;25(6):320–7.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Theresa A. Guise MD .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2016 Springer Science+Business Media New York

About this chapter

Cite this chapter

Chiechi, A., Guise, T.A. (2016). Pathobiology of Osteolytic and Osteoblastic Bone Metastases. In: Randall, R. (eds) Metastatic Bone Disease. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-5662-9_2

Download citation

  • DOI: https://doi.org/10.1007/978-1-4614-5662-9_2

  • Publisher Name: Springer, New York, NY

  • Print ISBN: 978-1-4614-5661-2

  • Online ISBN: 978-1-4614-5662-9

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics