Skip to main content

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

  • Short Communication
  • Published:

Prostate cancer specific integrin αvβ3 modulates bone metastatic growth and tissue remodeling

Oncogene volume 26, pages 6238–6243 (2007)Cite this article

Abstract

The management of pain and morbidity due to the spreading and growth of cancer within bone remains to be a paramount problem in clinical care. Cancer cells actively transform bone, however, the molecular requirements and mechanisms of this process remain unclear. This study shows that functional modulation of the αvβ3 integrin receptor in prostate cancer cells is required for progression within bone and determines tumor-induced bone tissue transformation. Using histology and quantitative microCT analysis, we show that αvβ3 integrin is required not only for tumor growth within the bone but for tumor-induced bone gain, a response resembling bone lesions in prostate cancer patients. Expression of normal, fully functional αvβ3 enabled tumor growth in bone (incidence: 4/4), whereas αvβ3 (−), inactive or constitutively active mutants of αvβ3 did not (incidence: 0/4, 0/6 and 1/7, respectively) within a 35-day-period. This response appeared to be bone-specific in comparison to the subcutis where tumor incidence was greater than 60% for all groups. Interestingly, bone residing prostate cancer cells expressing normal or dis-regulated αvβ3 (either inactive of constitutively active), but not those lacking β3 promoted bone gain or afforded protection from bone loss in the presence or absence of histologically detectable tumor 35 days following implantation. As bone is replete with ligands for β3 integrin, we next demonstrated that αvβ3 integrin activation on tumor cells is essential for the recognition of key bone-specific matrix proteins. As a result, prostate cancer cells expressing fully functional but not dis-regulated αvβ3 integrin are able to control their own adherence and migration to bone matrix, functions that facilitate tumor growth and control bone lesion development.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3

Similar content being viewed by others

References

  • Bakewell SJ, Nestor P, Prasad S, Tomasson MH, Dowland N, Mehrotra M et al. (2003). Platelet and osteoclast beta3 integrins are critical for bone metastasis. Proc Natl Acad Sci USA 100: 14205–14210.

    Article  CAS  Google Scholar 

  • Byzova TV, Kim W, Midura RJ, Plow EF . (2000). Activation of integrin alpha(V)beta(3) regulates cell adhesion and migration to bone sialoprotein. Exp Cell Res 254: 299–308.

    Article  CAS  Google Scholar 

  • Chen YP, Djaffar I, Pidard D, Steiner B, Cieutat AM, Caen JP et al. (1992). Ser-752–>Pro mutation in the cytoplasmic domain of integrin beta 3 subunit and defective activation of platelet integrin alpha IIb beta 3 (glycoprotein IIb-IIIa) in a variant of Glanzmann thrombasthenia. Proc Natl Acad Sci USA 89: 10169–10173.

    Article  CAS  Google Scholar 

  • De S, Chen J, Narizhneva NV, Heston W, Brainard J, Sage EH et al. (2003). Molecular pathway for cancer metastasis to bone. J Biol Chem 278: 39044–39050.

    Article  CAS  Google Scholar 

  • De S, Razorenova O, McCabe NP, O'Toole T, Qin J, Byzova TV . (2005). VEGF-integrin interplay controls tumor growth and vascularization. Proc Natl Acad Sci USA 102: 7589–7594.

    Article  CAS  Google Scholar 

  • Felding-Habermann B, O'Toole TE, Smith JW, Fransvea E, Ruggeri ZM, Ginsberg MH et al. (2001). Integrin activation controls metastasis in human breast cancer. Proc Natl Acad Sci USA 98: 1853–1858.

    Article  CAS  Google Scholar 

  • Feng X, Novack DV, Faccio R, Ory DS, Aya K, Boyer MI et al. (2001). A Glanzmann's mutation in beta 3 integrin specifically impairs osteoclast function. J Clin Invest 107: 1137–1144.

    Article  CAS  Google Scholar 

  • Ginsberg MH, Du X, Plow EF . (1992). Inside-out integrin signalling. Curr Opin Cell Biol 4: 766–771.

    Article  CAS  Google Scholar 

  • Hughes PE, Diaz-Gonzalez F, Leong L, Wu C, McDonald JA, Shattil SJ et al. (1996). Breaking the integrin hinge. A defined structural constraint regulates integrin signaling. J Biol Chem 271: 6571–6574.

    Article  CAS  Google Scholar 

  • Jacobs SC . (1983). Spread of prostatic cancer to bone. Urology 21: 337–344.

    Article  CAS  Google Scholar 

  • Kanamori M, Vanden Berg SR, Bergers G, Berger MS, Pieper RO . (2004). Integrin beta3 overexpression suppresses tumor growth in a human model of gliomagenesis: implications for the role of beta3 overexpression in glioblastoma multiforme. Cancer Res 64: 2751–2758.

    Article  CAS  Google Scholar 

  • Keller ET, Brown J . (2004). Prostate cancer bone metastases promote both osteolytic and osteoblastic activity. J Cell Biochem 91: 718–729.

    Article  CAS  Google Scholar 

  • Kitagawa Y, Dai J, Zhang J, Keller JM, Nor J, Yao Z et al. (2005). Vascular endothelial growth factor contributes to prostate cancer-mediated osteoblastic activity. Cancer Res 65: 10921–10929.

    Article  CAS  Google Scholar 

  • Latson L KB, Bryan J, Stredney D, Davros W, Midura R, Apte S et al. (2003). X-ray microcomputed tomography system: novel applications in bone imaging. Proceedings of the 25th International Conference of the IEEE Engineering in Medicine and Biology Society 2: 1058–1061.

    Google Scholar 

  • Li W, Metcalf DG, Gorelik R, Li R, Mitra N, Nanda V et al. (2005). A push-pull mechanism for regulating integrin function. Proc Natl Acad Sci USA 102: 1424–1429.

    Article  CAS  Google Scholar 

  • Nemeth JA, Cher ML, Zhou Z, Mullins C, Bhagat S, Trikha M . (2003). Inhibition of alpha(v)beta3 integrin reduces angiogenesis, bone turnover, and tumor cell proliferation in experimental prostate cancer bone metastases. Clin Exp Metastasis 20: 413–420.

    Article  CAS  Google Scholar 

  • Pecheur I, Peyruchaud O, Serre CM, Guglielmi J, Voland C, Bourre F et al. (2002). Integrin alpha(v)beta3 expression confers on tumor cells a greater propensity to metastasize to bone. FASEB J 16: 1266–1268.

    Article  CAS  Google Scholar 

  • Ruiz C, Liu CY, Sun QH, Sigaud-Fiks M, Fressinaud E, Muller JY et al. (2001). A point mutation in the cysteine-rich domain of glycoprotein (GP) IIIa results in the expression of a GPIIb-IIIa (alphaIIbbeta3) integrin receptor locked in a high-affinity state and a Glanzmann thrombasthenia-like phenotype. Blood 98: 2432–2441.

    Article  CAS  Google Scholar 

  • Saad F, Clarke N, Colombel M . (2006). Natural history and treatment of bone complications in prostate cancer. Eur Urol 49: 429–440.

    Article  CAS  Google Scholar 

  • Schwartz MA, Ginsberg MH . (2002). Networks and crosstalk: integrin signalling spreads. Nat Cell Biol 4: E65–E68.

    Article  CAS  Google Scholar 

  • Sloan EK, Pouliot N, Stanley KM, Chia J, Moseley JM, Hards DK et al. (2006). Tumor-specific expression of αvβ3 integrin promotes spontaneous metastasis of breast cancer to bone. Breast Cancer Res 8: R20.

    Article  Google Scholar 

  • Stewart DA, Cooper CR, Sikes RA . (2004). Changes in extracellular matrix (ECM) and ECM-associated proteins in the metastatic progression of prostate cancer. Reprod Biol Endocrinol 2: 2.

    Article  Google Scholar 

  • Takayama S, Ishii S, Ikeda T, Masamura S, Doi M, Kitajima M . (2005). The relationship between bone metastasis from human breast cancer and integrin alpha(v)beta3 expression. Anticancer Res 25: 79–83.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Dr Sara Seidelmann for critical review of this manuscript. This work was supported by the following grants: DK060933 to TV Byzova. NP McCabe is the recipient of a Ruth L Kirschstein Research Service Award (NRSA) Individual Fellowship (CA1172462); Cleveland Clinic Musculoskeletal Core Center funded in part by NIAMS Core Center Grant 1P30 AR-050953.

Author information

Authors and Affiliations

  1. Department of Molecular Cardiology, Joseph J Jacobs Center for Thrombosis and Vascular Biology, Cleveland Clinic Foundation, Cleveland, OH, USA

    N P McCabe, S De & T V Byzova

  2. Department of Biomedical Engineering, Cleveland Clinic Foundation, Cleveland, OH, USA

    A Vasanji

  3. Department of Anatomic Pathology, Cleveland Clinic Foundation, Cleveland, OH, USA

    J Brainard

Authors
  1. N P McCabe
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. S De
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. A Vasanji
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. J Brainard
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. T V Byzova
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to T V Byzova.

Additional information

Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

McCabe, N., De, S., Vasanji, A. et al. Prostate cancer specific integrin αvβ3 modulates bone metastatic growth and tissue remodeling. Oncogene 26, 6238–6243 (2007). https://doi.org/10.1038/sj.onc.1210429

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1210429

Keywords

This article is cited by

Search

Advanced search

Quick links