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TGF-β and BMP7 interactions in tumour progression and bone metastasis

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Abstract

The skeleton is the second most frequent site of metastasis. However, only a restricted number of solid cancers, especially those of the breast and prostate, are responsible for the majority of the bone metastases. Metastatic bone disease is a major cause of morbidity, characterised by severe pain and high incidence of skeletal and haematopoietic complications (fractures, spinal cord compression and bone marrow aplasia) requiring hospitalisation. Despite the frequency of skeletal metastases, the molecular mechanisms for their propensity to colonise bone are poorly understood and treatment options are often unsatisfactory. TGF-β and the signalling pathway it controls appears to play major roles in the pathogenesis of many carcinomas, both in their early stages, when TGF-β acts to arrest growth of many cell types, and later in cancer progression when it contributes, paradoxically, to the phenotype of tumour invasiveness. Here we discuss some novel insights of the TGF-β superfamily—including BMPs and their antagonists—in the formation of bone metastasis. Increasing evidence suggests that the TGF-β superfamily is involved in bone homing, tumour dormancy, and development of micrometastases into overt bone metastases. The established role of TGF-β/BMPs and their antagonists in epithelial plasticity during embryonic development closely resembles neoplastic processes at the primary site as well as in (bone) metastasis. For instance, the tumour-stroma interactions occurring in the tissue of cancer origin, including epithelium-to-mesenchyme transition (EMT), bear similarities with the role of bone matrix-derived TGF-β in skeletal metastasis formation.

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References

  1. Seoane J (2006) Escaping from the TGFbeta anti-proliferative control. Carcinogenesis 27:2148–2156

    Article  PubMed  CAS  Google Scholar 

  2. Thiery JP (2002) Epithelial-mesenchymal transitions in tumour progression. Nat Rev Cancer 2:442–454

    Article  PubMed  CAS  Google Scholar 

  3. Vincent-Salomon A, Thiery JP (2003) Host microenvironment in breast cancer development: epithelial-mesenchymal transition in breast cancer development. Breast Cancer Res 5:101–106

    Article  PubMed  CAS  Google Scholar 

  4. Thiery JP (2003) Epithelial-mesenchymal transitions in development and pathologies. Curr Opin Cell Biol 15:740–746

    Article  PubMed  CAS  Google Scholar 

  5. Urist MR (1965) Bone: formation by autoinduction. Science 150:893–899

    Article  PubMed  CAS  Google Scholar 

  6. Chen D, Zhao M, Mundy GR (2004) Bone morphogenetic proteins. Growth Factors 22:233–241

    Article  PubMed  CAS  Google Scholar 

  7. Reddi AH (1998) Role of morphogenetic proteins in skeletal tissue engineering and regeneration. Nat Biotechnol 16:247–252

    Article  PubMed  CAS  Google Scholar 

  8. Graff JM (1997) Embryonic patterning: to BMP or not to BMP, that is the question. Cell 89:171–174

    Article  PubMed  CAS  Google Scholar 

  9. Wozney JM, Rosen V (1998) Bone morphogenetic protein and bone morphogenetic protein gene family in bone formation and repair. Clin Orthop Relat Res 346 26–37

    Article  PubMed  Google Scholar 

  10. Avsian-Kretchmer O, Hsueh AJ (2004) Comparative genomic analysis of the eight-membered ring cystine knot-containing bone morphogenetic protein antagonists. Mol Endocrinol 18:1–12

    Article  PubMed  CAS  Google Scholar 

  11. Brunet LJ, McMahon JA, McMahon AP et al (1998) Noggin, cartilage morphogenesis, and joint formation in the mammalian skeleton. Science 280:1455–1457

    Article  PubMed  CAS  Google Scholar 

  12. Schwaninger R, Rentsch CA, Wetterwald A et al (2007) Lack of noggin expression by cancer cells is a determinant of the osteoblast response in bone metastases. Am J Pathol 170:160–175

    Article  PubMed  CAS  Google Scholar 

  13. Savagner P, Boyer B, Valles AM et al (1994) Modulations of the epithelial phenotype during embryogenesis and cancer progression. Cancer Treat Res 71:229–249

    PubMed  CAS  Google Scholar 

  14. Hay ED (1995) An overview of epithelio-mesenchymal transformation. Acta Anat (Basel) 154:8–20

    CAS  Google Scholar 

  15. Bae SN, Arand G, Azzam H et al (1993) Molecular and cellular analysis of basement membrane invasion by human breast cancer cells in Matrigel-based in vitro assays. Breast Cancer Res Treat 24:241–255

    Article  PubMed  CAS  Google Scholar 

  16. Weinberg RA (2007) The biology of cancer, 1st edn. Garland Science, Taylor & Francis Group

  17. Dahl U, Sjodin A, Larue L et al (2002) Genetic dissection of cadherin function during nephrogenesis. Mol Cell Biol 22:1474–1487

    Article  PubMed  CAS  Google Scholar 

  18. Vukicevic S, Kopp JB, Luyten FP et al (1996) Induction of nephrogenic mesenchyme by osteogenic protein 1 (bone morphogenetic protein 7). Proc Natl Acad Sci USA 93:9021–9026

    Article  PubMed  CAS  Google Scholar 

  19. Luo G, Hofmann C, Bronckers AL et al (1995) BMP-7 is an inducer of nephrogenesis, and is also required for eye development and skeletal patterning. Genes Dev 9:2808–2820

    Article  PubMed  CAS  Google Scholar 

  20. Kalluri R, Neilson EG (2003) Epithelial-mesenchymal transition and its implications for fibrosis. J Clin Invest 112:1776–1784

    PubMed  CAS  Google Scholar 

  21. Alliston T, Choy L, Ducy P et al (2001) TGF-beta-induced repression of CBFA1 by Smad3 decreases cbfa1 and osteocalcin expression and inhibits osteoblast differentiation. EMBO J 20:2254–2272

    Article  PubMed  CAS  Google Scholar 

  22. Haraguchi R, Mo R, Hui C et al (2001) Unique functions of Sonic hedgehog signaling during external genitalia development. Development 128:4241–4250

    PubMed  CAS  Google Scholar 

  23. Muller T, Bain G, Wang X et al (2002) Regulation of epithelial cell migration and tumor formation by beta-catenin signaling. Exp Cell Res 280:119

    Article  PubMed  CAS  Google Scholar 

  24. Chuong CM, Patel N, Lin J et al (2000) Sonic hedgehog signaling pathway in vertebrate epithelial appendage morphogenesis: perspectives in development and evolution. Cell Mol Life Sci 57:1672–1681

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  26. Barasch J (2001) Genes and proteins involved in mesenchymal to epithelial transition. Curr Opin Nephrol Hypertens 10:429–436

    Article  PubMed  CAS  Google Scholar 

  27. Boyer B, Valles AM, Edme N (2000) Induction and regulation of epithelial-mesenchymal transitions. Biochem Pharmacol 60:1091–1099

    Article  PubMed  CAS  Google Scholar 

  28. Savagner P (2001) Leaving the neighborhood: molecular mechanisms involved during epithelial-mesenchymal transition. Bioessays 23:912–923

    Article  PubMed  CAS  Google Scholar 

  29. Kang Y, Massague J (2004) Epithelial-mesenchymal transitions: twist in development and metastasis. Cell 118:277–279

    Article  PubMed  CAS  Google Scholar 

  30. Bhowmick NA, Chytil A, Plieth D et al (2004) TGF-beta signaling in fibroblasts modulates the oncogenic potential of adjacent epithelia. Science 303:848–851

    Article  PubMed  CAS  Google Scholar 

  31. Tang B, Vu M, Booker T et al (2003) TGF-beta switches from tumor suppressor to prometastatic factor in a model of breast cancer progression. J Clin Invest 112:1116–1124

    PubMed  CAS  Google Scholar 

  32. Paget S (1889) The distribution of secondary growths in cancer of the breast. Lancet 1:571–573

    Article  Google Scholar 

  33. Liotta LA, Kohn EC (2001) The microenvironment of the tumour-host interface. Nature 411:375–379

    Article  PubMed  CAS  Google Scholar 

  34. Fidler IJ (2002) The organ microenvironment and cancer metastasis. Differentiation 70:498–505

    Article  PubMed  Google Scholar 

  35. Cecchini MG, Wetterwald A, van der Pluijm G et al (2005) Molecular and biological mechanisms of bone metastasis. EAU Update Series 3:214

    Article  Google Scholar 

  36. Coleman RE, Rubens RD (1987) 3(Amino-1,1-hydroxypropylidene) bisphosphonate (APD) for hypercalcaemia of breast cancer. Br J Cancer 56:465–469

    PubMed  CAS  Google Scholar 

  37. Powles T, Paterson S, Kanis JA et al (2002) Randomized, placebo-controlled trial of clodronate in patients with primary operable breast cancer. J Clin Oncol 20:3219–3224

    Article  PubMed  CAS  Google Scholar 

  38. Elte JW, Bijvoet OL, Cleton FJ et al (1986) Osteolytic bone metastases in breast carcinoma pathogenesis, morbidity and bisphosphonate treatment. Eur J Cancer Clin Oncol 22:493–500

    Article  PubMed  CAS  Google Scholar 

  39. van Holten-Verzantvoort AT, Bijvoet OL, Cleton FJ et al (1987) Reduced morbidity from skeletal metastases in breast cancer patients during long-term bisphosphonate (APD) treatment. Lancet 2:983–985

    Article  PubMed  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  41. Eaton CL, Coleman RE (2003) Pathophysiology of bone metastases from prostate cancer and the role of bisphosphonates in treatment. Cancer Treat Rev 29:189–198

    Article  PubMed  CAS  Google Scholar 

  42. Buijs JT, Henriquez NV, van der Horst G et al (2007) Bone morphogenetic protein 7 in the development and treatment of bone metastases from breast cancer. Cancer Res 67:8742–8751

    Article  PubMed  CAS  Google Scholar 

  43. Buijs JT, Rentsch CA, van der Horst G et al (2007) 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 171(3):1047–1057

    Article  PubMed  CAS  Google Scholar 

  44. van der Pluijm G, Que I, Sijmons B et al (2005) Interference with the microenvironmental support impairs the de novo formation of bone metastases in vivo. Cancer Res 65:7682–7690

    PubMed  Google Scholar 

  45. Hattner R, Epker BN, Frost HM (1965) Suggested sequential mode of control of changes in cell behaviour in adult bone remodelling. Nature 206:489–490

    Article  PubMed  CAS  Google Scholar 

  46. Eriksen EF, Axelrod DW, Melsen F (1994) Bone histomorphometry. Raven Press, New York, pp 3–12

    Google Scholar 

  47. Mundy GR, Chen D, Oyajobi BO (2003) Bone remodelling. In: Favus M (ed) Primer on the metabolic bone diseases and disorders of mineral metabolism, 5th edn. American Society for Bone and Mineral Research, Washington, pp 46–58

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

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  50. Mundy GR, Yoneda T (1996) Mechanisms of bone metastasis. In: Singh G (ed) Bone metastasis—mechanisms and pathophysiology. Springer, Heidelberg, pp 1–16

    Google Scholar 

  51. Yin JJ, Selander K, Chirgwin JM 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  PubMed  CAS  Google Scholar 

  52. Guise TA, Yin JJ, Taylor SD 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  PubMed  CAS  Google Scholar 

  53. Thomas RJ, Guise TA, Yin JJ (1999) Breast cancer cells interact with osteoblasts to support osteoclast formation. Endocrinology 140:4451–4458

    Article  PubMed  CAS  Google Scholar 

  54. Guise TA, Chirgwin JM (2003) Transforming growth factor-beta in osteolytic breast cancer bone metastases. Clin Orthop Relat Res 415(Suppl):S32–S38

    Google Scholar 

  55. Deckers M, van Dinther M, Buijs J et al (2006) The tumor suppressor Smad4 is required for transforming growth factor beta-induced epithelial to mesenchymal transition and bone metastasis of breast cancer cells. Cancer Res 66:2202–2209

    Article  PubMed  CAS  Google Scholar 

  56. Kang Y, He W, Tulley S et al (2005) Breast cancer bone metastasis mediated by the Smad tumor suppressor pathway. Proc Natl Acad Sci USA 102:13909–13914

    Article  PubMed  CAS  Google Scholar 

  57. Javelaud D, Mohammad KS, McKenna CR et al (2007) Stable overexpression of Smad7 in human melanoma cells impairs bone metastasis. Cancer Res 67:2317–2324

    Article  PubMed  CAS  Google Scholar 

  58. Bryden AA, Freemont AJ, Clarke NW et al (1999) Paradoxical expression of E-cadherin in prostatic bone metastases. BJU Int 84:1032–1034

    Article  PubMed  CAS  Google Scholar 

  59. Bryden AA, Hoyland JA, Freemont A et al (2002) E-cadherin and beta-catenin are down-regulated in prostatic bone metastases. BJU Int 89:400–403

    Article  PubMed  CAS  Google Scholar 

  60. Christiansen JJ, Rajasekaran AK (2006) Reassessing epithelial to mesenchymal transition as a prerequisite for carcinoma invasion and metastasis. Cancer Res 66:8319–8326

    Article  PubMed  CAS  Google Scholar 

  61. Wetterwald A, van der Pluijm G, Que I et al (2002) Optical imaging of cancer metastasis to bone marrow: a mouse model of minimal residual disease. Am J Pathol 160:1143–1153

    PubMed  Google Scholar 

  62. Piccirillo SG, Reynolds BA, Zanetti N et al (2006) Bone morphogenetic proteins inhibit the tumorigenic potential of human brain tumour-initiating cells. Nature 444:761–765

    Article  PubMed  CAS  Google Scholar 

  63. Al-Hajj M, Wicha MS, Benito-Hernandez A et al (2003) Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci USA 100:3983–3988

    Article  PubMed  CAS  Google Scholar 

  64. Al-Hajj M, Clarke MF (2004) Self-renewal and solid tumor stem cells. Oncogene 23:7274–7282

    Article  PubMed  CAS  Google Scholar 

  65. Collins AT, Berry PA, Hyde C et al (2005) Prospective identification of tumorigenic prostate cancer stem cells. Cancer Res 65:10946–10951

    Article  PubMed  CAS  Google Scholar 

  66. Maitland NJ, Collins A (2005) A tumour stem cell hypothesis for the origins of prostate cancer. BJU Int 96:1219–1223

    Article  PubMed  CAS  Google Scholar 

  67. Collins AT, Maitland NJ (2006) Prostate cancer stem cells. Eur J Cancer 42:1213–1218

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

This work was grant supported by European Sixth Framework Programme, MetaBre, LSHC-CT-2004-503049 and BRECOSM LSHC-CT-2004-50322 and Dutch Cancer Society (NKI-2001-2481, RUL-2001-2485 and UL-2004-3028).

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Authors and Affiliations

  1. Department of Endocrinology, Leiden University Medical Centre, Leiden, The Netherlands

    Jeroen T. Buijs, Niek V. Henriquez & Gabri van der Pluijm

  2. Department of Urology, Leiden University Medical Centre, J3-100, P.O. Box 9600, 2333 ZA, Leiden, The Netherlands

    Jeroen T. Buijs, Petra G. M. van Overveld, Geertje van der Horst & Gabri van der Pluijm

  3. Department of Molecular Cell Biology, Leiden University Medical Centre, Leiden, The Netherlands

    Peter ten Dijke

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  1. Jeroen T. Buijs
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Correspondence to Gabri van der Pluijm.

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Buijs, J.T., Henriquez, N.V., van Overveld, P.G. et al. TGF-β and BMP7 interactions in tumour progression and bone metastasis. Clin Exp Metastasis 24, 609–617 (2007). https://doi.org/10.1007/s10585-007-9118-2

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