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A humanized tissue-engineered in vivo model to dissect interactions between human prostate cancer cells and human bone

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Abstract

Currently used xenograft models for prostate cancer bone metastasis lack the adequate tissue composition necessary to study the interactions between human prostate cancer cells and the human bone microenvironment. We introduce a tissue engineering approach to explore the interactions between human tumor cells and a humanized bone microenvironment. Scaffolds, seeded with human primary osteoblasts in conjunction with BMP7, were implanted into immunodeficient mice to form humanized tissue engineered bone constructs (hTEBCs) which consequently resulted in the generation of highly vascularized and viable humanized bone. At 12 weeks, PC3 and LNCaP cells were injected into the hTEBCs. Seven weeks later the mice were euthanized. Micro-CT, histology, TRAP, PTHrP and osteocalcin staining results reflected the different characteristics of the two cell lines regarding their phenotypic growth pattern within bone. Microvessel density, as assessed by vWF staining, showed that tumor vessel density was significantly higher in LNCaP injected hTEBC implants than in those injected with PC3 cells (p < 0.001). Interestingly, PC3 cells showed morphological features of epithelial and mesenchymal phenotypes suggesting a cellular plasticity within this microenvironment. Taken together, a highly reproducible humanized model was established which is successful in generating LNCaP and PC3 tumors within a complex humanized bone microenvironment. This model simulates the conditions seen clinically more closely than any other model described in the literature to date and hence represents a powerful experimental platform that can be used in future work to investigate specific biological questions relevant to bone metastasis.

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Acknowledgments

The work presented by the authors is supported by the Prostate Cancer Foundation of Australia, the National Health & Medical Research Council (NHMRC) Fellowship Grant, the Australian Research Council and the German Research Foundation (DFG HO 5068/1-1). We thank Baxter Healthcare International and Olympus Biotech for providing fibrin glue and rhBMP-7, respectively.

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Australian Prostate Cancer Research Centre, Translational Research Institute, Queensland University of Technology, 37 Kent Street, Woolloongabba, QLD, 4102, Australia

    Parisa Hesami & Judith A. Clements

  2. Regenerative Medicine Group, Institute of Health and Biomedical Innovation, Queensland University of Technology, 60 Musk Avenue, Kelvin Grove, QLD, 4049, Australia

    Parisa Hesami, Boris M. Holzapfel, Shirly Sieh, Laure Thibaudeau & Dietmar W. Hutmacher

  3. Orthopedic Center for Musculoskeletal Research, University of Wuerzburg, Brettreichstr. 11, 97072, Würzburg, Germany

    Boris M. Holzapfel

  4. Group of Cellular Machines, Biotec TU Dresden, Am Tatzberg 47-49, 01307, Dresden, Germany

    Anna Taubenberger

  5. Department of Pathology, University of Washington, Box 357470, Seattle, WA, 98195, USA

    Martine Roudier

  6. Vancouver Prostate Centre, Department of Medicine, University of British Columbia, 2660 Oak Street, Vancouver, BC, V6H 3Z6, Canada

    Ladan Fazli

  7. Skeletal Biology Program, School of Biomedical Sciences, Queensland University of Technology, 60 Musk Avenue, Kelvin Grove, QLD, 4059, Australia

    Laura S. Gregory

  8. George W Woodruff School of Mechanical Engineering, Georgia Institute of Technology, 801 Ferst Drive Northwest, Atlanta, GA, 30332, USA

    Dietmar W. Hutmacher

  9. Cancer Program, Institute of Health and Biomedical Innovation, Queensland University of Technology, 60 Musk Avenue, Kelvin Grove, QLD, 4059, Australia

    Judith A. Clements

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  1. Parisa Hesami
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  8. Laura S. Gregory
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  9. Dietmar W. Hutmacher
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  10. Judith A. Clements
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Corresponding authors

Correspondence to Dietmar W. Hutmacher or Judith A. Clements.

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Hesami, P., Holzapfel, B.M., Taubenberger, A. et al. A humanized tissue-engineered in vivo model to dissect interactions between human prostate cancer cells and human bone. Clin Exp Metastasis 31, 435–446 (2014). https://doi.org/10.1007/s10585-014-9638-5

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  • DOI: https://doi.org/10.1007/s10585-014-9638-5

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