Cancer and Metastasis Reviews

, Volume 32, Issue 1–2, pp 129–145 | Cite as

Humanised xenograft models of bone metastasis revisited: novel insights into species-specific mechanisms of cancer cell osteotropism

  • Boris Michael HolzapfelEmail author
  • Laure Thibaudeau
  • Parisa Hesami
  • Anna Taubenberger
  • Nina Pauline Holzapfel
  • Susanne Mayer-Wagner
  • Carl Power
  • Judith Clements
  • Pamela Russell
  • Dietmar Werner Hutmacher


The determinants and key mechanisms of cancer cell osteotropism have not been identified, mainly due to the lack of reproducible animal models representing the biological, genetic and clinical features seen in humans. An ideal model should be capable of recapitulating as many steps of the metastatic cascade as possible, thus facilitating the development of prognostic markers and novel therapeutic strategies. Most animal models of bone metastasis still have to be derived experimentally as most syngeneic and transgeneic approaches do not provide a robust skeletal phenotype and do not recapitulate the biological processes seen in humans. The xenotransplantation of human cancer cells or tumour tissue into immunocompromised murine hosts provides the possibility to simulate early and late stages of the human disease. Human bone or tissue-engineered human bone constructs can be implanted into the animal to recapitulate more subtle, species-specific aspects of the mutual interaction between human cancer cells and the human bone microenvironment. Moreover, the replication of the entire “organ” bone makes it possible to analyse the interaction between cancer cells and the haematopoietic niche and to confer at least a partial human immunity to the murine host. This process of humanisation is facilitated by novel immunocompromised mouse strains that allow a high engraftment rate of human cells or tissue. These humanised xenograft models provide an important research tool to study human biological processes of bone metastasis.


Bone metastasis Xenograft model Humanised Bone graft Haematopoiesis 



The work presented by the authors is supported by the German Research Foundation (DFG HO 5068/1-1), the Australian Research Council (Future Fellowship Program) and the Prostate Cancer Foundation of Australia.

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

10555_2013_9437_MOESM1_ESM.pdf (38 kb)
ESM 1 (PDF 37.6 kb)
10555_2013_9437_MOESM2_ESM.pdf (38 kb)
ESM 2 (PDF 38.0 kb)


  1. 1.
    Brown, J. E., Neville-Webbe, H., & Coleman, R. E. (2004). The role of bisphosphonates in breast and prostate cancers. Endocrine-Related Cancer, 11, 207–224.PubMedCrossRefGoogle Scholar
  2. 2.
    Fizazi, K., Albiges, L., Massard, C., et al. (2012). Novel and bone-targeted agents for CRPC. Annals of Oncology, 23(Suppl 10), x264–x267. doi: 10.1093/annonc/mds353.PubMedCrossRefGoogle Scholar
  3. 3.
    Mackiewicz-Wysocka, M., Pankowska, M., & Wysocki, P. J. (2012). Progress in the treatment of bone metastases in cancer patients. Expert Opinion on Investigational Drugs, 21, 785–795. doi: 10.1517/13543784.2012.679928.PubMedCrossRefGoogle Scholar
  4. 4.
    Wong, M. H., Stockler, M. R., & Pavlakis, N. (2012). Bisphosphonates and other bone agents for breast cancer. Cochrane Database of Systematic Reviews, 2, CD003474. doi: 10.1002/14651858.CD003474.pub3.Google Scholar
  5. 5.
    Hutmacher, D. W. (2010). Biomaterials offer cancer research the third dimension. Nature Materials, 9, 90–93. doi: 10.1038/nmat2619.PubMedCrossRefGoogle Scholar
  6. 6.
    Rosol, T. J., Tannehill-Gregg, S. H., LeRoy, B. E., et al. (2003). Animal models of bone metastasis. Cancer, 97, 748–757. doi: 10.1002/cncr.11150.PubMedCrossRefGoogle Scholar
  7. 7.
    Welch, D. R. (1997). Technical considerations for studying cancer metastasis in vivo. Clinical & Experimental Metastasis, 15, 272–306.CrossRefGoogle Scholar
  8. 8.
    Goldstein, R. H., Weinberg, R. A., & Rosenblatt, M. (2010). Of mice and (wo)men: mouse models of breast cancer metastasis to bone. Journal of Bone and Mineral Research, 25, 431–436. doi: 10.1002/jbmr.68.PubMedCrossRefGoogle Scholar
  9. 9.
    Singh, A. S., & Figg, W. D. (2005). In vivo models of prostate cancer metastasis to bone. Journal of Urology, 174, 820–826. doi: 10.1097/01.ju.0000169133.82167.aa.PubMedCrossRefGoogle Scholar
  10. 10.
    Richmond, A., & Su, Y. (2008). Mouse xenograft models vs GEM models for human cancer therapeutics. Disease Models & Mechanisms, 1, 78–82. doi: 10.1242/dmm.000976.CrossRefGoogle Scholar
  11. 11.
    Kuperwasser, C., Dessain, S., Bierbaum, B. E., et al. (2005). A mouse model of human breast cancer metastasis to human bone. Cancer Research, 65, 6130–6138. doi: 10.1158/0008-5472.CAN-04-1408.PubMedCrossRefGoogle Scholar
  12. 12.
    Nemeth, J. A., Harb, J. F., Barroso, U., Jr., et al. (1999). Severe combined immunodeficient-hu model of human prostate cancer metastasis to human bone. Cancer Research, 59, 1987–1993.PubMedGoogle Scholar
  13. 13.
    Yonou, H., Yokose, T., Kamijo, T., et al. (2001). Establishment of a novel species- and tissue-specific metastasis model of human prostate cancer in humanized non-obese diabetic/severe combined immunodeficient mice engrafted with human adult lung and bone. Cancer Research, 61, 2177–2182.PubMedGoogle Scholar
  14. 14.
    Xia, T. S., Wang, G. Z., Ding, Q., et al. (2012). Bone metastasis in a novel breast cancer mouse model containing human breast and human bone. Breast Cancer Research and Treatment, 132, 471–486. doi: 10.1007/s10549-011-1496-0.PubMedCrossRefGoogle Scholar
  15. 15.
    Kuperwasser, C., Chavarria, T., Wu, M., et al. (2004). Reconstruction of functionally normal and malignant human breast tissues in mice. Proceedings of the National Academy of Sciences of the United States of America, 101, 4966–4971. doi: 10.1073/pnas.0401064101.PubMedCrossRefGoogle Scholar
  16. 16.
    Ganick, D. J., Sarnwick, R. D., Shahidi, N. T., et al. (1980). Inability of intravenously injected monocellular suspensions of human bone marrow to establish in the nude mouse. International Archives of Allergy and Applied Immunology, 62, 330–333.PubMedCrossRefGoogle Scholar
  17. 17.
    Shultz, L. D., Ishikawa, F., & Greiner, D. L. (2007). Humanized mice in translational biomedical research. Nature Reviews Immunology, 7, 118–130. doi: 10.1038/nri2017.PubMedCrossRefGoogle Scholar
  18. 18.
    Bosma, G. C., Custer, R. P., & Bosma, M. J. (1983). A severe combined immunodeficiency mutation in the mouse. Nature, 301, 527–530.PubMedCrossRefGoogle Scholar
  19. 19.
    Kyoizumi, S., Baum, C. M., Kaneshima, H., et al. (1992). Implantation and maintenance of functional human bone marrow in SCID-hu mice. Blood, 79, 1704–1711.PubMedGoogle Scholar
  20. 20.
    Greiner, D. L., Hesselton, R. A., & Shultz, L. D. (1998). SCID mouse models of human stem cell engraftment. Stem Cells, 16, 166–177. doi: 10.1002/stem.160166.PubMedCrossRefGoogle Scholar
  21. 21.
    Shultz, L. D., Schweitzer, P. A., Christianson, S. W., et al. (1995). Multiple defects in innate and adaptive immunologic function in NOD/LtSz-scid mice. Journal of Immunology, 154, 180–191.Google Scholar
  22. 22.
    Boynton, E., Aubin, J., Gross, A., et al. (1996). Human osteoblasts survive and deposit new bone when human bone is implanted in SCID mouse. Bone, 18, 321–326.PubMedCrossRefGoogle Scholar
  23. 23.
    Christianson, S. W., Greiner, D. L., Schweitzer, I. B., et al. (1996). Role of natural killer cells on engraftment of human lymphoid cells and on metastasis of human T-lymphoblastoid leukemia cells in C57BL/6J-scid mice and in C57BL/6J-scid bg mice. Cellular Immunology, 171, 186–199. doi: 10.1006/cimm.1996.0193.PubMedGoogle Scholar
  24. 24.
    Prochazka, M., Gaskins, H. R., Shultz, L. D., et al. (1992). The nonobese diabetic scid mouse: model for spontaneous thymomagenesis associated with immunodeficiency. Proceedings of the National Academy of Sciences of the United States of America, 89, 3290–3294.PubMedCrossRefGoogle Scholar
  25. 25.
    Meyerrose, T. E., Herrbrich, P., Hess, D. A., et al. (2003). Immune-deficient mouse models for analysis of human stem cells. Biotechniques, 35, 1262–1272.PubMedGoogle Scholar
  26. 26.
    Nakamura, Y., Ito, M., Yamamoto, T., et al. (2005). Engraftment of NOD/SCID/gammac(null) mice with multilineage neoplastic cells from patients with juvenile myelomonocytic leukaemia. British Journal of Haematology, 130, 51–57. doi: 10.1111/j.1365-2141.2005.05578.x.PubMedCrossRefGoogle Scholar
  27. 27.
    Shultz, L. D., Lyons, B. L., Burzenski, L. M., et al. (2005). Human lymphoid and myeloid cell development in NOD/LtSz-scid IL2R gamma null mice engrafted with mobilized human hemopoietic stem cells. Journal of Immunology, 174, 6477–6489.Google Scholar
  28. 28.
    Ishikawa, F., Yasukawa, M., Lyons, B., et al. (2005). Development of functional human blood and immune systems in NOD/SCID/IL2 receptor gamma chain(null) mice. Blood, 106, 1565–1573. doi: 10.1182/blood-2005-02-0516.PubMedCrossRefGoogle Scholar
  29. 29.
    Ito, R., Takahashi, T., Katano, I., et al. (2012). Current advances in humanized mouse models. Cellular and molecular immunology, 9, 208–214. doi: 10.1038/cmi.2012.2.PubMedCrossRefGoogle Scholar
  30. 30.
    Shultz, L. D., Saito, Y., Najima, Y., et al. (2010). Generation of functional human T-cell subsets with HLA-restricted immune responses in HLA class I expressing NOD/SCID/IL2r gamma(null) humanized mice. Proceedings of the National Academy of Sciences of the United States of America, 107, 13022–13027. doi: 10.1073/pnas.1000475107.PubMedCrossRefGoogle Scholar
  31. 31.
    Shtivelman, E., & Namikawa, R. (1995). Species-specific metastasis of human tumor cells in the severe combined immunodeficiency mouse engrafted with human tissue. Proceedings of the National Academy of Sciences of the United States of America, 92, 4661–4665.PubMedCrossRefGoogle Scholar
  32. 32.
    Banerjee, S., Hussain, M., Wang, Z., et al. (2007). In vitro and in vivo molecular evidence for better therapeutic efficacy of ABT-627 and taxotere combination in prostate cancer. Cancer Research, 67, 3818–3826. doi: 10.1158/0008-5472.CAN-06-3879.PubMedCrossRefGoogle Scholar
  33. 33.
    Deng, X., He, G., Levine, A., et al. (2008). Adenovirus-mediated expression of TIMP-1 and TIMP-2 in bone inhibits osteolytic degradation by human prostate cancer. International Journal of Cancer, 122, 209–218. doi: 10.1002/ijc.23053.CrossRefGoogle Scholar
  34. 34.
    Nie, D., Nemeth, J., Qiao, Y., et al. (2003). Increased metastatic potential in human prostate carcinoma cells by overexpression of arachidonate 12-lipoxygenase. Clinical & Experimental Metastasis, 20, 657–663. doi: 10.1023/A:1027302408187.CrossRefGoogle Scholar
  35. 35.
    Carbonell, F., Calvo, W., & Fliedner, T. M. (1982). Cellular composition of human fetal bone marrow. Histologic study in methacrylate sections. Acta Anatomica (Basel), 113, 371–375.CrossRefGoogle Scholar
  36. 36.
    LeBien, T. W., Wormann, B., Villablanca, J. G., et al. (1990). Multiparameter flow cytometric analysis of human fetal bone marrow B cells. Leukemia, 4, 354–358.PubMedGoogle Scholar
  37. 37.
    Villablanca, J. G., Anderson, J. M., Moseley, M., et al. (1990). Differentiation of normal human pre-B cells in vitro. The Journal of Experimental Medicine, 172, 325–334.PubMedCrossRefGoogle Scholar
  38. 38.
    Christensen, R. D., Harper, T. E., & Rothstein, G. (1986). Granulocyte-macrophage progenitor cells in term and preterm neonates. Journal of Pediatrics, 109, 1047–1051.PubMedCrossRefGoogle Scholar
  39. 39.
    Emerson, S. G., Thomas, S., Ferrara, J. L., et al. (1989). Developmental regulation of erythropoiesis by hematopoietic growth factors: analysis on populations of BFU-E from bone marrow, peripheral blood, and fetal liver. Blood, 74, 49–55.PubMedGoogle Scholar
  40. 40.
    Ikuta, K., Kina, T., MacNeil, I., et al. (1990). A developmental switch in thymic lymphocyte maturation potential occurs at the level of hematopoietic stem cells. Cell, 62, 863–874.PubMedCrossRefGoogle Scholar
  41. 41.
    Goya, M., Miyamoto, S., Nagai, K., et al. (2004). Growth inhibition of human prostate cancer cells in human adult bone implanted into nonobese diabetic/severe combined immunodeficient mice by a ligand-specific antibody to human insulin-like growth factors. Cancer Research, 64, 6252–6258. doi: 10.1158/0008-5472.CAN-04-0919.PubMedCrossRefGoogle Scholar
  42. 42.
    Ling, L. J., Wang, S., Liu, X. A., et al. (2008). A novel mouse model of human breast cancer stem-like cells with high CD44 + CD24-/lower phenotype metastasis to human bone. Chinese Medical Journal, 121, 1980–1986.PubMedGoogle Scholar
  43. 43.
    Sangai, T., Fujimoto, H., Miyamoto, S., et al. (2008). Roles of osteoclasts and bone-derived IGFs in the survival and growth of human breast cancer cells in human adult bone implanted into nonobese diabetic/severe combined immunodeficient mice. Clinical & Experimental Metastasis, 25, 401–410. doi: 10.1007/s10585-008-9144-8.CrossRefGoogle Scholar
  44. 44.
    Yang, W., Lam, P., Kitching, R., et al. (2007). Breast cancer metastasis in a human bone NOD/SCID mouse model. Cancer Biology & Therapy, 6, 1289–1294.Google Scholar
  45. 45.
    Yonou, H., Ochiai, A., Goya, M., et al. (2004). Intraosseous growth of human prostate cancer in implanted adult human bone: relationship of prostate cancer cells to osteoclasts in osteoblastic metastatic lesions. Prostate, 58, 406–413. doi: 10.1002/pros.10349.PubMedCrossRefGoogle Scholar
  46. 46.
    Lam, P., Yang, W., Amemiya, Y., et al. (2009). A human bone NOD/SCID mouse model to distinguish metastatic potential in primary breast cancers. Cancer Biology & Therapy, 8, 1010–1017.CrossRefGoogle Scholar
  47. 47.
    Liu, S., Goldstein, R. H., Scepansky, E. M., et al. (2009). Inhibition of rho-associated kinase signaling prevents breast cancer metastasis to human bone. Cancer Research, 69, 8742–8751. doi: 10.1158/0008-5472.CAN-09-1541.PubMedCrossRefGoogle Scholar
  48. 48.
    Amemiya, Y., Yang, W., Benatar, T., et al. (2011). Insulin like growth factor binding protein-7 reduces growth of human breast cancer cells and xenografted tumors. Breast Cancer Research and Treatment, 126, 373–384. doi: 10.1007/s10549-010-0921-0.PubMedCrossRefGoogle Scholar
  49. 49.
    Murphy, W. J., Kumar, V., & Bennett, M. (1987). Rejection of bone marrow allografts by mice with severe combined immune deficiency (SCID). Evidence that natural killer cells can mediate the specificity of marrow graft rejection. The Journal of Experimental Medicine, 165, 1212–1217.PubMedCrossRefGoogle Scholar
  50. 50.
    Heike, Y., Ohira, T., Takahashi, M., et al. (1995). Long-term human hematopoiesis in SCID-hu mice bearing transplanted fragments of adult bone and bone marrow cells. Blood, 86, 524–530.PubMedGoogle Scholar
  51. 51.
    Sandhu, J. S., Clark, B. R., Boynton, E. L., et al. (1996). Human hematopoiesis in SCID mice implanted with human adult cancellous bone. Blood, 88, 1973–1982.PubMedGoogle Scholar
  52. 52.
    Hubin, F., Humblet, C., Belaid, Z., et al. (2004). Maintenance of functional human cancellous bone and human hematopoiesis in NOD/SCID mice. Cell Transplantation, 13, 823–831.PubMedCrossRefGoogle Scholar
  53. 53.
    Kaplan, R. N., Rafii, S., & Lyden, D. (2006). Preparing the "soil": the premetastatic niche. Cancer Research, 66, 11089–11093. doi: 10.1158/0008-5472.CAN-06-2407.PubMedCrossRefGoogle Scholar
  54. 54.
    Kaplan, R. N., Riba, R. D., Zacharoulis, S., et al. (2005). VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche. Nature, 438, 820–827. doi: 10.1038/nature04186.PubMedCrossRefGoogle Scholar
  55. 55.
    Shiozawa, Y., Pedersen, E. A., Havens, A. M., et al. (2011). Human prostate cancer metastases target the hematopoietic stem cell niche to establish footholds in mouse bone marrow. The Journal of Clinical Investigation, 121, 1298–1312. doi: 10.1172/JCI43414.PubMedCrossRefGoogle Scholar
  56. 56.
    Kahn, D., Weiner, G. J., Ben-Haim, S., et al. (1994). Positron emission tomographic measurement of bone marrow blood flow to the pelvis and lumbar vertebrae in young normal adults. Blood, 83, 958–963.PubMedGoogle Scholar
  57. 57.
    Roodman, G. D. (2004). Mechanisms of bone metastasis. The New England Journal of Medicine, 350, 1655–1664. doi: 10.1056/NEJMra030831.PubMedCrossRefGoogle Scholar
  58. 58.
    Bianco, P. (2011). Bone and the hematopoietic niche: a tale of two stem cells. Blood, 117, 5281–5288. doi: 10.1182/blood-2011-01-315069.PubMedCrossRefGoogle Scholar
  59. 59.
    Xia, T. S., Wang, J., Yin, H., et al. (2010). Human tissue-specific microenvironment: an essential requirement for mouse models of breast cancer. Oncology Reports, 24, 203–211.PubMedGoogle Scholar
  60. 60.
    Waitches, G., Zawin, J. K., & Poznanski, A. K. (1994). Sequence and rate of bone marrow conversion in the femora of children as seen on MR imaging: are accepted standards accurate? AJR. American Journal of Roentgenology, 162, 1399–1406.PubMedCrossRefGoogle Scholar
  61. 61.
    Atkinson, H. R. (1962). Bone marrow distribution as a factor in estimating radiation to the blood-forming organ: a survey of present knowledge. Journal of the College of Radiologists of Australasia, 6, 149–154.PubMedCrossRefGoogle Scholar
  62. 62.
    Ellis, R. E. (1961). The distribution of active bone marrow in the adult. Physics in Medicine and Biology, 5, 255–258.PubMedCrossRefGoogle Scholar
  63. 63.
    Hayman, J. A., Callahan, J. W., Herschtal, A., et al. (2011). Distribution of proliferating bone marrow in adult cancer patients determined using FLT-PET imaging. International Journal of Radiation Oncology, Biology, Physics, 79, 847–852. doi: 10.1016/j.ijrobp.2009.11.040.PubMedCrossRefGoogle Scholar
  64. 64.
    Laor, T., & Jaramillo, D. (2009). MR imaging insights into skeletal maturation: what is normal? Radiology, 250, 28–38. doi: 10.1148/radiol.2501071322.PubMedCrossRefGoogle Scholar
  65. 65.
    Hutmacher, D. W., Loessner, D., Rizzi, S., et al. (2010). Can tissue engineering concepts advance tumor biology research? Trends in Biotechnology, 28, 125–133. doi: 10.1016/j.tibtech.2009.12.001.PubMedCrossRefGoogle Scholar
  66. 66.
    Moreau, J. E., Anderson, K., Mauney, J. R., et al. (2007). Tissue-engineered bone serves as a target for metastasis of human breast cancer in a mouse model. Cancer Research, 67, 10304–10308. doi: 10.1158/0008-5472.CAN-07-2483.PubMedCrossRefGoogle Scholar
  67. 67.
    Schuster, J., Zhang, J., & Longo, M. (2006). A novel human osteoblast-derived severe combined immunodeficiency mouse model of bone metastasis. Journal of Neurosurgery: Spine, 4, 388–391. doi: 10.3171/spi.2006.4.5.388.PubMedCrossRefGoogle Scholar
  68. 68.
    Hutmacher, D. W., Horch, R. E., Loessner, D., et al. (2009). Translating tissue engineering technology platforms into cancer research. Journal of Cellular and Molecular Medicine, 13, 1417–1427. doi: 10.1111/j.1582-4934.2009.00853.x.PubMedCrossRefGoogle Scholar
  69. 69.
    Goldstein, R. H., Reagan, M. R., Anderson, K., et al. (2010). Human bone marrow-derived MSCs can home to orthotopic breast cancer tumors and promote bone metastasis. Cancer Research, 70, 10044–10050. doi: 10.1158/0008-5472.CAN-10-1254.PubMedCrossRefGoogle Scholar
  70. 70.
    Moreau, J., Anderson, K. M., Mauney, J. R., et al. (2007). Studies of osteotropism on both sides of the breast cancer–bone interaction. Annals of the New York Academy of Sciences, 1117, 328–344. doi: 10.1196/annals.1402.003.PubMedCrossRefGoogle Scholar
  71. 71.
    Yu, H., VandeVord, P. J., Mao, L., et al. (2009). Improved tissue-engineered bone regeneration by endothelial cell mediated vascularization. Biomaterials, 30, 508–517. doi: 10.1016/j.biomaterials.2008.09.047.PubMedCrossRefGoogle Scholar
  72. 72.
    Holzapfel, B. M., Reichert, J. C., Schantz, J. T., et al. (2012). How smart do biomaterials need to be? A translational science and clinical point of view. Adv Drug Deliv Rev. doi: 10.1016/j.addr.2012.07.009.PubMedGoogle Scholar
  73. 73.
    Hutmacher, D. W., Schantz, J. T., Lam, C. X., et al. (2007). State of the art and future directions of scaffold-based bone engineering from a biomaterials perspective. Journal of Tissue Engineering and Regenerative Medicine, 1, 245–260. doi: 10.1002/term.24.PubMedCrossRefGoogle Scholar
  74. 74.
    Probst, F. A., Hutmacher, D. W., Muller, D. F., et al. (2010). Calvarial reconstruction by customized bioactive implant. Handchirurgie, Mikrochirurgie, Plastische Chirurgie, 42, 369–373. doi: 10.1055/s-0030-1248310.PubMedCrossRefGoogle Scholar
  75. 75.
    Reichert, J. C., Cipitria, A., Epari, D. R., et al. (2012). A tissue engineering solution for segmental defect regeneration in load-bearing long bones. Science Translational Medicine, 4, 141ra193. doi: 10.1126/scitranslmed.3003720.CrossRefGoogle Scholar
  76. 76.
    Reichert, J. C., Epari, D. R., Wullschleger, M. E., et al. (2010). Establishment of a preclinical ovine model for tibial segmental bone defect repair by applying bone tissue engineering strategies. Tissue Engineering. Part B, Reviews, 16, 93–104. doi: 10.1089/ten.TEB.2009.0455.PubMedCrossRefGoogle Scholar
  77. 77.
    Fidler, I. J. (2003). The pathogenesis of cancer metastasis: the 'seed and soil' hypothesis revisited. Nature Reviews. Cancer, 3, 453–458. doi: 10.1038/nrc1098.PubMedCrossRefGoogle Scholar
  78. 78.
    Zeidman, I., & Buss, J. M. (1952). Transpulmonary passage of tumor cell emboli. Cancer Research, 12, 731–733.PubMedGoogle Scholar
  79. 79.
    Fidler, I. J. (2001). Seed and soil revisited: contribution of the organ microenvironment to cancer metastasis. Surgical Oncology Clinics of North America, 10, 257–269. vii-viiii.PubMedGoogle Scholar
  80. 80.
    Halperin, E. C., Schmidt-Ulrich, R. K., Perez, C. A., & Brady, L. W. (2004). The discipline of radiation oncology. In C. A. Perez, L. W. Brady, E. C. Halperin, & R. K. Schmidt-Ulrich (Eds.), Hrsg. Principles and Practice of Radiation Oncology (4th ed., pp. 1–95). Philadelphia: Lippincott Williams & Wilkins.Google Scholar
  81. 81.
    Paget, S. (1889). The distribution of secondary growths in cancer of the breast. Lancet, 1, 571–573.CrossRefGoogle Scholar
  82. 82.
    Bauerle, T., Adwan, H., Kiessling, F., et al. (2005). Characterization of a rat model with site-specific bone metastasis induced by MDA-MB-231 breast cancer cells and its application to the effects of an antibody against bone sialoprotein. International Journal of Cancer, 115, 177–186. doi: 10.1002/ijc.20840.CrossRefGoogle Scholar
  83. 83.
    Bauerle, T., Peterschmitt, J., Hilbig, H., et al. (2006). Treatment of bone metastasis induced by MDA-MB-231 breast cancer cells with an antibody against bone sialoprotein. International Journal of Oncology, 28, 573–583.PubMedGoogle Scholar
  84. 84.
    Neudert, M., Fischer, C., Krempien, B., et al. (2003). Site-specific human breast cancer (MDA-MB-231) metastases in nude rats: model characterisation and in vivo effects of ibandronate on tumour growth. International Journal of Cancer, 107, 468–477. doi: 10.1002/ijc.11397.CrossRefGoogle Scholar
  85. 85.
    Halpern, J., Lynch, C. C., Fleming, J., et al. (2006). The application of a murine bone bioreactor as a model of tumor: bone interaction. Clinical & Experimental Metastasis, 23, 345–356. doi: 10.1007/s10585-006-9044-8.CrossRefGoogle Scholar
  86. 86.
    Tamura, H., Ishii, S., Ikeda, T., et al. (1999). The relationship between urinary pyridinoline, deoxypyridinoline and bone metastasis in a rat breast cancer model. Breast Cancer, 6, 23–28.PubMedCrossRefGoogle Scholar
  87. 87.
    Tamura, H., Ishii, S., Ikeda, T., et al. (1996). Therapeutic efficacy of pamidronate in combination with chemotherapy to bone metastasis of breast cancer in a rat model. Surgical Oncology, 5, 141–147.PubMedCrossRefGoogle Scholar
  88. 88.
    Mayevski, A. (1978). Ischemia in the brain: the effects of carotid artery ligation and decapitation on the energy state of the awake and anesthetized rat. Brain Research, 140, 217–230.CrossRefGoogle Scholar
  89. 89.
    Yoneda, T., Williams, P. J., Hiraga, T., et al. (2001). 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. Journal of Bone and Mineral Research, 16, 1486–1495. doi: 10.1359/jbmr.2001.16.8.1486.PubMedCrossRefGoogle Scholar
  90. 90.
    Goodale, D., Phay, C., Postenka, C. O., et al. (2009). Characterization of tumor cell dissemination patterns in preclinical models of cancer metastasis using flow cytometry and laser scanning cytometry. Cytometry. Part A, 75, 344–355. doi: 10.1002/cyto.a.20657.CrossRefGoogle Scholar
  91. 91.
    Havens, A. M., Pedersen, E. A., Shiozawa, Y., et al. (2008). An in vivo mouse model for human prostate cancer metastasis. Neoplasia, 10, 371–380.PubMedGoogle Scholar
  92. 92.
    Thalmann, G. N., Anezinis, P. E., Chang, S. M., et al. (1994). Androgen-independent cancer progression and bone metastasis in the LNCaP model of human prostate cancer. Cancer Research, 54, 2577–2581.PubMedGoogle Scholar
  93. 93.
    Tsingotjidou, A. S., Ahluwalia, R., Zhang, X., et al. (2003). A metastatic human prostate cancer model using intraprostatic implantation of tumor produced by PC-3 neolacZ transfected cells. International Journal of Oncology, 23, 1569–1574.PubMedGoogle Scholar
  94. 94.
    Al Nakouzi, N., Bawa, O., Le Pape, A., et al. (2012). The IGR-CaP1 xenograft model recapitulates mixed osteolytic/blastic bone lesions observed in metastatic prostate cancer. Neoplasia, 14, 376–387.PubMedGoogle Scholar
  95. 95.
    An, Z., Wang, X., Geller, J., et al. (1998). Surgical orthotopic implantation allows high lung and lymph node metastatic expression of human prostate carcinoma cell line PC-3 in nude mice. Prostate, 34, 169–174.PubMedCrossRefGoogle Scholar
  96. 96.
    Rembrink, K., Romijn, J. C., van der Kwast, T. H., et al. (1997). Orthotopic implantation of human prostate cancer cell lines: a clinically relevant animal model for metastatic prostate cancer. Prostate, 31, 168–174.PubMedCrossRefGoogle Scholar
  97. 97.
    Nemeth, J. A., Yousif, R., Herzog, M., et al. (2002). Matrix metalloproteinase activity, bone matrix turnover, and tumor cell proliferation in prostate cancer bone metastasis. Journal of the National Cancer Institute, 94, 17–25.PubMedCrossRefGoogle Scholar
  98. 98.
    Yonou, H., Kanomata, N., Goya, M., et al. (2003). Osteoprotegerin/osteoclastogenesis inhibitory factor decreases human prostate cancer burden in human adult bone implanted into nonobese diabetic/severe combined immunodeficient mice. Cancer Research, 63, 2096–2102.PubMedGoogle Scholar
  99. 99.
    Sutton, E. J., Henning, T. D., Pichler, B. J., et al. (2008). Cell tracking with optical imaging. European Radiology, 18, 2021–2032. doi: 10.1007/s00330-008-0984-z.PubMedCrossRefGoogle Scholar
  100. 100.
    Butler, T. P., & Gullino, P. M. (1975). Quantitation of cell shedding into efferent blood of mammary adenocarcinoma. Cancer Research, 35, 512–516.PubMedGoogle Scholar
  101. 101.
    Weiss, L. (1990). Metastatic inefficiency. Advances in Cancer Research, 54, 159–211.PubMedCrossRefGoogle Scholar
  102. 102.
    Welch, D. R. (2006). Do we need to redefine a cancer metastasis and staging definitions? Breast Disease, 26, 3–12.PubMedGoogle Scholar
  103. 103.
    Tentler, J. J., Tan, A. C., Weekes, C. D., et al. (2012). Patient-derived tumour xenografts as models for oncology drug development. Nature Reviews. Clinical Oncology, 9, 338–350. doi: 10.1038/nrclinonc.2012.61.PubMedCrossRefGoogle Scholar
  104. 104.
    Daniel, V. C., Marchionni, L., Hierman, J. S., et al. (2009). A primary xenograft model of small-cell lung cancer reveals irreversible changes in gene expression imposed by culture in vitro. Cancer Research, 69, 3364–3373. doi: 10.1158/0008-5472.CAN-08-4210.PubMedCrossRefGoogle Scholar
  105. 105.
    Hillen, F., & Griffioen, A. W. (2007). Tumour vascularization: sprouting angiogenesis and beyond. Cancer Metastasis Reviews, 26, 489–502. doi: 10.1007/s10555-007-9094-7.PubMedCrossRefGoogle Scholar
  106. 106.
    Pantel, K., & Alix-Panabieres, C. (2010). Circulating tumour cells in cancer patients: challenges and perspectives. Trends in Molecular Medicine, 16, 398–406. doi: 10.1016/j.molmed.2010.07.001.PubMedCrossRefGoogle Scholar
  107. 107.
    Nicolson, G. L. (1988). Cancer metastasis: tumor cell and host organ properties important in metastasis to specific secondary sites. Biochimica et Biophysica Acta, 948, 175–224.PubMedGoogle Scholar
  108. 108.
    van der Pluijm, G. (2011). Epithelial plasticity, cancer stem cells and bone metastasis formation. Bone, 48, 37–43. doi: 10.1016/j.bone.2010.07.023.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Boris Michael Holzapfel
    • 1
    • 2
    Email author
  • Laure Thibaudeau
    • 1
  • Parisa Hesami
    • 1
  • Anna Taubenberger
    • 3
  • Nina Pauline Holzapfel
    • 1
  • Susanne Mayer-Wagner
    • 4
  • Carl Power
    • 5
  • Judith Clements
    • 6
    • 7
  • Pamela Russell
    • 6
    • 7
  • Dietmar Werner Hutmacher
    • 1
    • 8
    • 9
  1. 1.Regenerative Medicine, Institute of Health and Biomedical InnovationQueensland University of TechnologyBrisbaneAustralia
  2. 2.Orthopedic Center for Musculoskeletal ResearchUniversity of WuerzburgWuerzburgGermany
  3. 3.Group of Cellular Machines, Biotechnology CenterUniversity of Technology DresdenDresdenGermany
  4. 4.Department of Orthopedic Surgery, Campus GrosshadernLudwigs-Maximilians University MunichMunichGermany
  5. 5.Biological Resources Imaging Laboratory, Lowy Cancer Research Centre (C25), Lower Ground and BasementKensington University of New South WalesSydneyAustralia
  6. 6.Australian Prostate Cancer Research CentreTranslational Research InstituteBrisbaneAustralia
  7. 7.Cells and Tissue Domain, Institute of Health and Biomedical InnovationQueensland University of TechnologyBrisbaneAustralia
  8. 8.George W Woodruff School of Mechanical EngineeringGeorgia Institute of TechnologyAtlantaUSA
  9. 9.Institute for Advanced StudyTechnical University MunichGarchingGermany

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