Review Article | Published:

Translational models of prostate cancer bone metastasis

Nature Reviews Urology (2018) | Download Citation

Abstract

Metastatic disease is the principal cause of prostate-cancer-related mortality. Our ability to accurately recapitulate the spread of prostate cancer to bone — the most common site of metastasis — is critical to the development of novel metastasis-directed therapies. Several translational models of prostate cancer bone metastasis have been developed, including animal models, cell line injection models, 3D in vitro models, bone implant models, and patient-derived xenograft models. The use of these models has led to numerous advances in elucidating the molecular mechanisms of metastasis and innovations in targeted therapy. Despite this progress, current models are limited by a failure to holistically reproduce each individual element of the metastatic cascade in prostate cancer bone metastasis. In addition, factors such as accurate recapitulation of immunobiological events and improvements in tumour heterogeneity require further consideration. Knowledge gained from historical and currently used models will improve the development of next-generation models. An introspective appraisal of current preclinical models demonstrating bone metastases is warranted to narrow research focus, improve future translational modelling, and expedite the delivery of urgently needed metastasis-directed treatments.

Key points

  • The development of novel metastasis-directed prostate cancer therapies is highly reliant on our ability to accurately reproduce the underlying mechanisms in vivo.

  • Existing models frequently employ a modular approach towards recapitulating particular aspects of disease progression.

  • Each model possesses specific advantages and limitations that are important to experimental design and outcomes.

  • Several valuable molecular and therapeutic advances have been made, despite the potential limitations of current models.

  • The aims of next-generation models should be to improve tumour heterogeneity and enable the study of disease immunobiology.

  • Subscribe to Nature Reviews Urology for full access:

    $199

    Subscribe

Additional access options:

Already a subscriber?  Log in  now or  Register  for online access.

Additional information

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

References

  1. 1.

    Torre, L. A. et al. Global cancer statistics, 2012. CA Cancer J. Clin. 65, 87–108 (2015).

  2. 2.

    Howlander, N. et al. SEER cancer statistics review. National Cancer Institute https://seer.cancer.gov/csr/1975_2014/ (2017).

  3. 3.

    Hiraga, T. Targeted agents in preclinical and early clinical development for the treatment of cancer bone metastases. Expert Opin. Investig. Drugs 25, 319–334 (2016).

  4. 4.

    Clarke, N. W., Hart, C. A. & Brown, M. D. Molecular mechanisms of metastasis in prostate cancer. Asian J. Androl. 11, 57–67 (2009).

  5. 5.

    Smith, B. N. & Odero-Marah, V. A. The role of Snail in prostate cancer. Cell Adh. Migr. 6, 433–441 (2012).

  6. 6.

    Nagle, R. B. & Cress, A. E. Metastasis update: human prostate carcinoma invasion via tubulogenesis. Prostate Cancer 2011, 249290 (2011).

  7. 7.

    Taichman, R. S. et al. Use of the stromal cell-derived factor-1/CXCR4 pathway in prostate cancer metastasis to bone. Cancer Res. 62, 1832–1837 (2002).

  8. 8.

    Engl, T. et al. CXCR4 chemokine receptor mediates prostate tumor cell adhesion through alpha5 and beta3 integrins. Neoplasia 8, 290–301 (2006).

  9. 9.

    Greenbaum, A. et al. CXCL12 in early mesenchymal progenitors is required for haematopoietic stem-cell maintenance. Nature 495, 227–230 (2013).

  10. 10.

    McCabe, N. P., De, S., Vasanji, A., Brainard, J. & Byzova, T. V. Prostate cancer specific integrin alphavbeta3 modulates bone metastatic growth and tissue remodeling. Oncogene 26, 6238–6243 (2007).

  11. 11.

    Hall, C. L., Dai, J., van Golen, K. L., Keller, E. T. & Long, M. W. Type I collagen receptor (alpha 2 beta 1) signaling promotes the growth of human prostate cancer cells within the bone. Cancer Res. 66, 8648–8654 (2006).

  12. 12.

    Sottnik, J. L. et al. Integrin alpha2beta1 (α2β1) promotes prostate cancer skeletal metastasis. Clin. Exp. Metastasis 30, 569–578 (2013).

  13. 13.

    Lynch, C. C. et al. MMP-7 promotes prostate cancer-induced osteolysis via the solubilization of RANKL. Cancer Cell 7, 485–496 (2005).

  14. 14.

    Kruger, S. et al. Molecular characterization of exosome-like vesicles from breast cancer cells. BMC Cancer 14, 44 (2014).

  15. 15.

    Luzzi, K. J. et al. Multistep nature of metastatic inefficiency: dormancy of solitary cells after successful extravasation and limited survival of early micrometastases. Am. J. Pathol. 153, 865–873 (1998).

  16. 16.

    Williams, K. C. et al. Cancer dissemination from a physical sciences perspective. Converg. Sci. Phys. Oncol. 2, 23001 (2016).

  17. 17.

    Kan, C., Vargas, G., Le Pape, F. & Clézardin, P. Cancer cell colonisation in the bone microenvironment. Int. J. Mol. Sci. 17, 1674 (2016).

  18. 18.

    Shiozawa, Y. et al. Human prostate cancer metastases target the hematopoietic stem cell niche to establish footholds in mouse bone marrow. J. Clin. Invest. 121, 1298–1312 (2011).

  19. 19.

    Lawson, M. A. et al. Osteoclasts control reactivation of dormant myeloma cells by remodelling the endosteal niche. Nat. Commun. 6, 8983 (2015).

  20. 20.

    Ghajar, C. M. et al. The perivascular niche regulates breast tumour dormancy. Nat. Cell Biol. 15, 807–817 (2013).

  21. 21.

    Jung, Y. et al. Annexin 2–CXCL12 interactions regulate metastatic cell targeting and growth in the bone marrow. Mol. Cancer Res. 13, 197–207 (2015).

  22. 22.

    Taichman, R. S. et al. GAS6 receptor status is associated with dormancy and bone metastatic tumor formation. PLoS ONE 8, e61873 (2013).

  23. 23.

    Sosa, M. S. et al. NR2F1 controls tumour cell dormancy via SOX9- and RARβ-driven quiescence programmes. Nat. Commun. 6, 6170 (2015).

  24. 24.

    Ono, M. et al. Exosomes from bone marrow mesenchymal stem cells contain a microRNA that promotes dormancy in metastatic breast cancer cells. Sci. Signal. 7, ra63 (2014).

  25. 25.

    Giancotti, F. G. Mechanisms governing metastatic dormancy and reactivation. Cell 155, 750–764 (2013).

  26. 26.

    Pasero, C. et al. Inherent and tumor-driven immune tolerance in the prostate microenvironment impairs natural killer cell antitumor activity. Cancer Res. 76, 2153–2165 (2016).

  27. 27.

    Weilbaecher, K. N., Guise, T. A. & McCauley, L. K. Cancer to bone: a fatal attraction. Nat. Rev. Cancer 11, 411–425 (2011).

  28. 28.

    Kozlow, W. & Guise, T. A. Breast cancer metastasis to bone: mechanisms of osteolysis and implications for therapy. J. Mammary Gland Biol. Neoplasia 10, 169–180 (2005).

  29. 29.

    Ell, B. & Kang, Y. SnapShot: bone metastasis. Cell 151, 690–690.e1 (2012).

  30. 30.

    Ren, G., Esposito, M. & Kang, Y. Bone metastasis and the metastatic niche. J. Mol. Med. 93, 1203–1212 (2015).

  31. 31.

    Roudier, M. P. et al. Histopathological assessment of prostate cancer bone osteoblastic metastases. J. Urol. 180, 1154–1160 (2008).

  32. 32.

    Hall, C. L., Daignault, S. D., Shah, R. B., Pienta, K. J. & Keller, E. T. Dickkopf-1 expression increases early in prostate cancer development and decreases during progression from primary tumor to metastasis. Prostate 68, 1396–1404 (2008).

  33. 33.

    Logothetis, C. J. & Lin, S.-H. Osteoblasts in prostate cancer metastasis to bone. Nat. Rev. Cancer 5, 21–28 (2005).

  34. 34.

    Dunning, W. F. Prostate cancer in the rat. Natl Cancer Inst. Monogr. 12, 351–369 (1963).

  35. 35.

    Isaacs, J. T., Heston, W. D., Weissman, R. M. & Coffey, D. S. Animal models of the hormone-sensitive and -insensitive prostatic adenocarcinomas, Dunning R-3327-H, R-3327-HI, and R-3327-AT. Cancer Res. 38, 4353–4359 (1978).

  36. 36.

    Isaacs, J. T., Isaacs, W. B., Feitz, W. F. J. & Scheres, J. Establishment and characterization of seven dunning rat prostatic cancer cell lines and their use in developing methods for predicting metastatic abilities of prostatic cancers. Prostate 9, 261–281 (1986).

  37. 37.

    Heinlein, C. A. & Chang, C. Androgen receptor in prostate cancer. Endocr. Rev. 25, 276–308 (2004).

  38. 38.

    Waters, D. J. et al. Workgroup 4: spontaneous prostate carcinoma in dogs and nonhuman primates. Prostate 36, 64–67 (1998).

  39. 39.

    Obradovich, J., Walshaw, R. & Goullaud, E. The influence of castration on the development of prostatic carcinoma in the dog 43 cases (1978–1985). J. Vet. Intern. Med. 1, 183–187 (1987).

  40. 40.

    Wang, M. & Stearns, M. E. Isolation and characterization of PC-3 human prostatic tumor sublines which preferentially metastasize to select organs in S.C.I.D. mice. Differentiation 48, 115–125 (1991). These researchers determine that invasive cell line sublines could be harvested from the metastases of a mouse inoculated with prostate cancer.

  41. 41.

    Haq, M., Goltzman, D., Tremblay, G., Cells, M. E. & Brodi, P. Rat prostate adenocarcinoma cells disseminate to bone and adhere preferentially to bone marrow-derived endothelial cells. Cancer Res. 52, 4613–4619 (1992). This paper describes the intracardiac injection method of cancer cell inoculation, first described by Haq et al., that is a cornerstone method to produce bone metastases.

  42. 42.

    Geldof, A. A. & Rao, B. R. Prostatic tumor (R3327) skeletal metastasis. Prostate 16, 279–290 (1990).

  43. 43.

    Arguello, F. et al. Pathogenesis of vertebral metastasis and epidural spinal cord compression. Cancer 65, 98–106 (1990).

  44. 44.

    Sobel, R. E. & Sadar, M. D. Cell lines used in prostate cancer research: a compendium of old and new lines-part 2. J. Urol. 173, 342–359 (2005).

  45. 45.

    Kaighn, M. E., Narayan, K. S., Ohnuki, Y., Lechner, J. F. & Jones, L. W. Establishment and characterization of a human prostatic carcinoma cell line (PC-3). Invest. Urol. 17, 16–23 (1979). In this article, Kaighn et al. describe the predominant cell line in prostate cancer research, PC3.

  46. 46.

    Keer, H. N. et al. Elevated transferrin receptor content in human prostate cancer cell lines assessed in vitro and in vivo. J. Urol. 143, 381–385 (1990).

  47. 47.

    Ching, K. Z. et al. Expression of mRNA for epidermal growth factor, transforming growth factor-alpha and their receptor in human prostate tissue and cell lines. Mol. Cell. Biochem. 126, 151–158 (1993).

  48. 48.

    Shi, X.-B., Nesslinger, N. J., Deitch, A. D., Gumerlock, P. H. & deVere White, R. W. Complex functions of mutantp53 alleles from human prostate cancer. Prostate 51, 59–72 (2002).

  49. 49.

    Vlietstra, R. J., van Alewijk, D. C., Hermans, K. G., van Steenbrugge, G. J. & Trapman, J. Frequent inactivation of PTEN in prostate cancer cell lines and xenografts. Cancer Res. 58, 2720–2723 (1998).

  50. 50.

    Tai, S. et al. PC3 is a cell line characteristic of prostatic small cell carcinoma. Prostate 71, 1668–1679 (2011).

  51. 51.

    Kozlowski, J. M. et al. Metastatic behavior of human tumor cell lines grown in the nude mouse. Cancer Res. 44, 3522–3529 (1984).

  52. 52.

    Pettaway, C. A. et al. Selection of highly metastatic variants of different human prostatic carcinomas using orthotopic implantation in nude mice. Clin. Cancer Res. 2, 1627–1636 (1996).

  53. 53.

    Dai, J., Hensel, J., Wang, N., Kruithof-de Julio, M. & Shiozawa, Y. Mouse models for studying prostate cancer bone metastasis. Bonekey Rep. 5, 777 (2016).

  54. 54.

    Ablin, R. J. & Mason, M. D. Metastasis of Prostate Cancer. (Springer, Netherlands, 2007).

  55. 55.

    Stone, K. R., Mickey, D. D., Wunderli, H., Mickey, G. H. & Paulson, D. F. Isolation of human prostate carcinoma cell line (DU 145). Int. J. Cancer 21, 274–281 (1978).

  56. 56.

    Bajgelman, M. C. & Strauss, B. E. The DU145 human prostate carcinoma cell line harbors a temperature-sensitive allele of p53. Prostate 66, 1455–1462 (2006).

  57. 57.

    Carruba, G. et al. Steroid-growth factor interaction in human prostate cancer. Short term effects of transforming growth factors on growth of human prostate cancer cells. Steroids 59, 412–420 (1994).

  58. 58.

    Pietrzkowski, Z. et al. Inhibition of growth of prostatic cancer cell lines by peptide analogues of insulin-like growth factor. Cancer Res. 53, 1102–1106 (1993).

  59. 59.

    Connolly, J. M. & Rose, D. P. Production of epidermal growth factor and transforming growth factor-alpha by the androgen-responsive LNCaP human prostate cancer cell line. Prostate 16, 209–218 (1990).

  60. 60.

    Nakamoto, T., Chang, C., Li, A. & Chodak, G. W. Basic fibroblast growth factor in human prostate cancer cells. Cancer Res. 52, 571–577 (1992).

  61. 61.

    Carroll, A. G., Voeller, H. J., Sugars, L. & Gelmann, E. P. p53 oncogene mutations in three human prostate cancer cell lines. Prostate 23, 123–134 (1993).

  62. 62.

    Veldscholte, J. et al. A mutation in the ligand binding domain of the androgen receptor of human LNCaP cells affects steroid binding characteristics and response to anti-androgens. Biochem. Biophys. Res. Commun. 173, 534–540 (1990).

  63. 63.

    Thalmann, G. N. et al. Androgen-independent cancer progression and bone metastasis in the LNCaP model of human prostate cancer. Cancer Res. 54, 2577–2581 (1994).

  64. 64.

    Hong, M. K. H. et al. Tracking the origins and drivers of subclonal metastatic expansion in prostate cancer. Nat. Commun. 6, 6605 (2015).

  65. 65.

    Liepe, K. et al. New model for the induction of osteoblastic bone metastases in rat. Anticancer Res. 25, 1067–1073 (2005).

  66. 66.

    Wilson, M. J., Kapoor, S., Vogel, M. M. & Sinha, A. A. Characterization of gelatin-degrading metalloproteinase activities of the Dunning rat prostate tumor grown in nude mice. Prostate 19, 237–250 (1991).

  67. 67.

    Roodman, G. D. Mechanisms of bone metastasis. N. Engl. J. Med. 350, 1655–1664 (2004).

  68. 68.

    Blouin, S., Baslé, M. F. & Chappard, D. Rat models of bone metastases. Clin. Exp. Metastasis 22, 605–614 (2005).

  69. 69.

    Lamoureux, F. et al. Relevance of a new rat model of osteoblastic metastases from prostate carcinoma for preclinical studies using zoledronic acid. Int. J. Cancer 122, 751–760 (2008).

  70. 70.

    LeRoy, B. E. et al. New bone formation and osteolysis by a metastatic, highly invasive canine prostate carcinoma xenograft. Prostate 66, 1213–1222 (2006).

  71. 71.

    Simmons, J. K. et al. Animal models of bone metastasis. Vet. Pathol. 52, 827–841 (2015).

  72. 72.

    Thudi, N. K. et al. Dickkopf-1 (DKK-1) stimulated prostate cancer growth and metastasis and inhibited bone formation in osteoblastic bone metastases. Prostate 71, 615–625 (2011).

  73. 73.

    Thompson, T. C., Southgate, J., Kitchener, G. & Land, H. Multistage carcinogenesis induced by ras and myc oncognes in a reconstituted organ. Cell 56, 917–930 (1989).

  74. 74.

    Baley, P. A., Yoshida, K., Qian, W., Sehgal, I. & Thompson, T. C. Progression to androgen insensitivity in a novel in vitro mouse model for prostate cancer. J. Steroid Biochem. Mol. Biol. 52, 403–413 (1995).

  75. 75.

    Power, C. A. et al. A novel model of bone-metastatic prostate cancer in immunocompetent mice. Prostate 69, 1613–1623 (2009).

  76. 76.

    Lin, D. et al. Next generation patient-derived prostate cancer xenograft models. Asian J. Androl. 16, 407–412 (2014).

  77. 77.

    Lin, D. et al. High fidelity patient-derived xenografts for accelerating prostate cancer discovery and drug development. Cancer Res. 74, 1272–1283 (2014).

  78. 78.

    Ellis, J., Buhier, R., True, D., Vessella, L. & Bigler, A. Characterization of a novel antigen-producing prostatic carcinoma xenograft: LuCaP 23. Clin. Cancer Res. 2, 1039–1048 (1996).

  79. 79.

    Nguyen, H. M. et al. LuCaP prostate cancer patient-derived xenografts reflect the molecular heterogeneity of advanced disease and serve as models for evaluating cancer therapeutics. Prostate 77, 654–671 (2017). This article describes 21 developed and characterized PDX models, which encompass a wide variety of genomic and phenotypic features of prostate cancer.

  80. 80.

    Ben-David, U. et al. Patient-derived xenografts undergo mouse-specific tumor evolution. Nat. Genet. 49, 1567–1575 (2017). This is a critical look into the stability of the heterogeneity of PDX tumours that are serially propagated in mice.

  81. 81.

    Tentler, J. J. et al. Patient-derived tumour xenografts as models for oncology drug development. Nat. Rev. Clin. Oncol. 9, 338–350 (2012).

  82. 82.

    Wang, Y. et al. An orthotopic metastatic prostate cancer model in SCID mice via grafting of a transplantable human prostate tumor line. Lab. Invest. 85, 1392–1404 (2005). This study describes a PDX model that exhibits bone metastases after an orthotopic inoculation method, paving the way for PDX research that can follow the metastatic cascade from primary tumour growth to distant bone metastasis.

  83. 83.

    Godebu, E. et al. PCSD1, a new patient-derived model of bone metastatic prostate cancer, is castrate-resistant in the bone-niche. J. Transl Med. 12, 275–287 (2014).

  84. 84.

    Neudert, M., Fischer, C., Krempien, B., Bauss, F. & Seibel, M. J. Site-specific human breast cancer (MDA-MB-231) metastases in nude rats: model characterisation and in vivo effects of ibandronate on tumour growth. Int. J. Cancer 107, 468–477 (2003).

  85. 85.

    Valta, M. P. et al. Spheroid culture of LuCaP 136 patient-derived xenograft enables versatile preclinical models of prostate cancer. Clin. Exp. Metastasis 33, 325–337 (2016). This 3D culture method enables PDX models, which were formerly capable of being grown only in vivo, to be grown in vitro.

  86. 86.

    Fong, E. L. S. et al. Hydrogel-based 3D model of patient-derived prostate xenograft tumors suitable for drug screening. Mol. Pharm. 11, 2040–2050 (2014).

  87. 87.

    Rhee, H. W. et al. Permanent phenotypic and genotypic changes of prostate cancer cells cultured in a three-dimensional rotating-wall vessel. In Vitro Cell. Dev. Biol. Anim. 37, 127–140 (2001).

  88. 88.

    Sung, S.-Y. et al. Coevolution of prostate cancer and bone stroma in three-dimensional coculture: implications for cancer growth and metastasis. Cancer Res. 68, 9996–10003 (2008).

  89. 89.

    Kim, W. et al. RUNX1 is essential for mesenchymal stem cell proliferation and myofibroblast differentiation. Proc. Natl Acad. Sci. USA 111, 16389–16394 (2014).

  90. 90.

    Parikh, M. R., Minser, K. E., Rank, L. M., Glackin, C. A. & Kirshner, J. A reconstructed metastasis model to recapitulate the metastatic spread in vitro. Biotechnol. J. 9, 1129–1139 (2014).

  91. 91.

    Bostwick, D. G. et al. Human prostate cancer risk factors. Cancer 101, 2371–2490 (2004).

  92. 92.

    Greenberg, N. M. et al. Prostate cancer in a transgenic mouse. Proc. Natl Acad. Sci. USA 92, 3439–3443 (1995).

  93. 93.

    Gingrich, J. R. et al. Metastatic prostate cancer in a transgenic mouse. Cancer Res. 56, 4096–4102 (1996). This article describes a transgenic model of prostate cancer that could show metastasis to bone, albeit infrequently.

  94. 94.

    Jeet, V., Russell, P. J. & Khatri, A. Modeling prostate cancer: a perspective on transgenic mouse models. Cancer Metastasis Rev. 29, 123–142 (2010).

  95. 95.

    Kasper, S. et al. Development, progression, and androgen-dependence of prostate tumors in probasin-large T antigen transgenic mice: a model for prostate cancer. Lab. Invest. 78, i–xv (1998).

  96. 96.

    Klezovitch, O. et al. Hepsin promotes prostate cancer progression and metastasis. Cancer Cell 6, 185–195 (2004).

  97. 97.

    Hu, Y., Ippolito, J. E., Garabedian, E. M., Humphrey, P. A. & Gordon, J. I. Molecular characterization of a metastatic neuroendocrine cell cancer arising in the prostates of transgenic mice. J. Biol. Chem. 277, 44462–44474 (2002).

  98. 98.

    Perez-Stable, C. et al. Prostate, adrenocortical, and brown adipose tumors in fetal globin/T antigen transgenic mice. Lab. Invest. 74, 363–373 (1996).

  99. 99.

    Lawson, D. A. et al. Basal epithelial stem cells are efficient targets for prostate cancer initiation. Proc. Natl Acad. Sci. USA 107, 2610–2615 (2010).

  100. 100.

    Ding, Z. et al. Genome unstable murine prostate cancers acquire genomic aberrations and bone metastatic features of the human disease. Cell 148, 896–907 (2012).

  101. 101.

    Ku, S. Y. et al. Rb1 and Trp53 cooperate to suppress prostate cancer lineage plasticity, metastasis, and antiandrogen resistance. Science 355, 78–83 (2017).

  102. 102.

    Chang, M. T. et al. Identifying recurrent mutations in cancer reveals widespread lineage diversity and mutational specificity. Nat. Biotechnol. 34, 155–163 (2016).

  103. 103.

    Kasper, S. Survey of genetically engineered mouse models for prostate cancer: analyzing the molecular basis of prostate cancer development, progression, and metastasis. J. Cell. Biochem. 94, 279–297 (2005).

  104. 104.

    Alanee, S. et al. Contemporary incidence and mortality rates of neuroendocrine prostate cancer. Anticancer Res. 35, 4145–4150 (2015).

  105. 105.

    Nemeth, J. A. et al. Severe combined immunodeficient-hu model of human prostate cancer metastasis to human bone. Cancer Res. 59, 1987–1993 (1999).

  106. 106.

    Schuster, J., Zhang, J. & Longo, M. A novel human osteoblast-derived severe combined immunodeficiency mouse model of bone metastasis. J. Neurosurg. Spine 4, 388–391 (2006).

  107. 107.

    Lee, Y. P. et al. Use of zoledronate to treat osteoblastic versus osteolytic lesions in a severe-combined-immunodeficient mouse model. Cancer Res. 62, 5564–5570 (2002).

  108. 108.

    Pettway, G. J. & McCauley, L. K. Ossicle and vossicle implant model systems. Methods Mol. Biol. 455, 101–110 (2008).

  109. 109.

    Koh, A. J. et al. Cells of the osteoclast lineage as mediators of the anabolic actions of parathyroid hormone in bone. Endocrinology 146, 4584–4596 (2005). In this article, Koh et al. describe the method to transplant mouse vossicles into host mice, paving the way for a novel bone implant model of prostate cancer.

  110. 110.

    Shiozawa, Y. et al. GAS6/AXL axis regulates prostate cancer invasion, proliferation, and survival in the bone marrow niche. Neoplasia 12, 116–127 (2010).

  111. 111.

    Park, H.-J. & Bolton, E. C. Glial cell line-derived neurotrophic factor induces cell proliferation in the mouse urogenital sinus. Mol. Endocrinol. 29, 289–306 (2015).

  112. 112.

    Thompson, T. C. et al. Loss of p53 function leads to metastasis in ras+myc-initiated mouse prostate cancer. Oncogene 10, 869–879 (1995).

  113. 113.

    Li, Z. G. et al. Androgen receptor-negative human prostate cancer cells induce osteogenesis in mice through FGF9-mediated mechanisms. J. Clin. Invest. 118, 2697–2710 (2008).

  114. 114.

    Huang, Y. et al. Overexpression of FGF9 in prostate epithelial cells augments reactive stroma formation and promotes prostate cancer progression. Int. J. Biol. Sci. 11, 948–960 (2015).

  115. 115.

    Lee, Y.-C. et al. Secretome analysis of an osteogenic prostate tumor identifies complex signaling networks mediating cross-talk of cancer and stromal cells within the tumor microenvironment. Mol. Cell. Proteom. 14, 471–483 (2015).

  116. 116.

    Deng, M. et al. miR-26a suppresses tumor growth and metastasis by targeting FGF9 in gastric cancer. PLoS ONE 8, e72662 (2013).

  117. 117.

    Hurley, P. J. et al. Secreted protein, acidic and rich in cysteine-like 1 (SPARCL1) is down regulated in aggressive prostate cancers and is prognostic for poor clinical outcome. Proc. Natl Acad. Sci. USA 109, 14977–14982 (2012).

  118. 118.

    Xiang, Y. et al. SPARCL1 suppresses metastasis in prostate cancer. Mol. Oncol. 7, 1019–1030 (2013).

  119. 119.

    Guo, W. et al. HEF1 promotes epithelial mesenchymal transition and bone invasion in prostate cancer under the regulation of microRNA-145. J. Cell. Biochem. 114, 1606–1615 (2013).

  120. 120.

    Mundi, P. S., Sachdev, J., McCourt, C. & Kalinsky, K. AKT in cancer: new molecular insights and advances in drug development. Br. J. Clin. Pharmacol. 82, 943–956 (2016).

  121. 121.

    Salmena, L., Carracedo, A. & Pandolfi, P. P. Tenets of PTEN tumor suppression. Cell 133, 403–414 (2008).

  122. 122.

    Berquin, I. M., Min, Y., Wu, R., Wu, H. & Chen, Y. Q. Expression signature of the mouse prostate. J. Biol. Chem. 280, 36442–36451 (2005).

  123. 123.

    Conley-LaComb, M. K. et al. PTEN loss mediated Akt activation promotes prostate tumor growth and metastasis via CXCL12/CXCR4 signaling. Mol. Cancer 12, 85 (2013).

  124. 124.

    Gravina, G. L. et al. CXCR4 pharmacogical inhibition reduces bone and soft tissue metastatic burden by affecting tumor growth and tumorigenic potential in prostate cancer preclinical models. Prostate 75, 1227–1246 (2015).

  125. 125.

    Winkler, I. G. et al. Vascular niche E-selectin regulates hematopoietic stem cell dormancy, self renewal and chemoresistance. Nat. Med. 18, 1651–1657 (2012).

  126. 126.

    Dimitroff, C. J., Lechpammer, M., Long-Woodward, D. & Kutok, J. L. Rolling of human bone-metastatic prostate tumor cells on human bone marrow endothelium under shear flow is mediated by E-selectin. Cancer Res. 64, 5261–5269 (2004).

  127. 127.

    Li, J. et al. Human fucosyltransferase 6 enables prostate cancer metastasis to bone. Br. J. Cancer 109, 3014–3022 (2013).

  128. 128.

    Verras, M. & Sun, Z. Roles and regulation of Wnt signaling and beta-catenin in prostate cancer. Cancer Lett. 237, 22–32 (2006).

  129. 129.

    Lu, W. et al. Suppression of Wnt/beta-catenin signaling inhibits prostate cancer cell proliferation. Eur. J. Pharmacol. 602, 8–14 (2009).

  130. 130.

    Lennartsson, J. & Rönnstrand, L. The stem cell factor receptor/c-Kit as a drug target in cancer. Curr. Cancer Drug Targets 6, 65–75 (2006).

  131. 131.

    Regan, J. L. et al. c-Kit is required for growth and survival of the cells of origin of Brca1-mutation-associated breast cancer. Oncogene 31, 869–883 (2012).

  132. 132.

    Mainetti, L. E. et al. Bone-induced c-kit expression in prostate cancer: A driver of intraosseous tumor growth. Int. J. Cancer 136, 11–20 (2015).

  133. 133.

    Moro, L. et al. Loss of BRCA2 promotes prostate cancer cell invasion through up-regulation of matrix metalloproteinase-9. Cancer Sci. 99, 553–563 (2008).

  134. 134.

    Karayi, M. K. & Markham, A. F. Molecular biology of prostate cancer. Prostate Cancer Prostat. Dis. 7, 6–20 (2004).

  135. 135.

    Bubendorf, L. et al. Metastatic patterns of prostate cancer: an autopsy study of 1,589 patients. Hum. Pathol. 31, 578–583 (2000).

  136. 136.

    Drake, M. T., Clarke, B. L. & Khosla, S. Bisphosphonates: mechanism of action and role in clinical practice. Mayo Clin. Proc. 83, 1032–1045 (2008).

  137. 137.

    Rogers, M. J., Crockett, J. C., Coxon, F. P. & Mönkkönen, J. Biochemical and molecular mechanisms of action of bisphosphonates. Bone 49, 34–41 (2011).

  138. 138.

    Stresing, V., Daubiné, F., Benzaid, I., Mönkkönen, H. & Clézardin, P. Bisphosphonates in cancer therapy. Cancer Lett. 257, 16–35 (2007).

  139. 139.

    Yang, M. et al. The bisphosphonate olpadronate inhibits skeletal prostate cancer progression in a green fluorescent protein nude mouse model. Clin. Cancer Res. 12, 2602–2606 (2006).

  140. 140.

    Tuomela, J. M., Valta, M. P., Väänänen, K. & Härkönen, P. L. Alendronate decreases orthotopic PC-3 prostate tumor growth and metastasis to prostate-draining lymph nodes in nude mice. BMC Cancer 8, 81 (2008).

  141. 141.

    Stearns, M. E. & Wang, M. Alendronate blocks metalloproteinase secretion and bone collagen I release by PC-3 ML cells in SCID mice. Clin. Exp. Metastasis 16, 693–702 (1998).

  142. 142.

    Miwa, S. et al. The bisphosphonate YM529 inhibits osteolytic and osteoblastic changes and CXCR-4-induced invasion in prostate cancer. Cancer Res. 65, 8818–8825 (2005).

  143. 143.

    Berry, S., Waldron, T., Winquist, E. & Lukka, H. The use of bisphosphonates in men with hormone-refractory prostate cancer: a systematic review of randomized trials. Can. J. Urol. 13, 3180–3188 (2006).

  144. 144.

    Dearnaley, D. P., Mason, M. D., Parmar, M. K., Sanders, K. & Sydes, M. R. Adjuvant therapy with oral sodium clodronate in locally advanced and metastatic prostate cancer: long-term overall survival results from the MRC PR04 and PR05 randomised controlled trials. Lancet Oncol. 10, 872–876 (2009).

  145. 145.

    Brown, J. M. et al. Osteoprotegerin and rank ligand expression in prostate cancer. Urology 57, 611–616 (2001).

  146. 146.

    Anderson, D. M. et al. A homologue of the TNF receptor and its ligand enhance T cell growth and dendritic-cell function. Nature 390, 175–179 (1997).

  147. 147.

    Zhau, H. E. et al. Epithelial to mesenchymal transition (EMT) in human prostate cancer: lessons learned from ARCaP model. Clin. Exp. Metastasis 25, 601–610 (2008).

  148. 148.

    Lacey, D. L. et al. Bench to bedside: elucidation of the OPG-RANK-RANKL pathway and the development of denosumab. Nat. Rev. Drug Discov. 11, 401–419 (2012).

  149. 149.

    Foltz, I. N., Gunasekaran, K. & King, C. T. Discovery and bio-optimization of human antibody therapeutics using the XenoMouse® transgenic mouse platform. Immunol. Rev. 270, 51–64 (2016).

  150. 150.

    Jakobovits, A., Amado, R. G., Yang, X., Roskos, L. & Schwab, G. From XenoMouse technology to panitumumab, the first fully human antibody product from transgenic mice. Nat. Biotechnol. 25, 1134–1143 (2007).

  151. 151.

    Kostenuik, P. J. et al. Denosumab, a fully human monoclonal antibody to RANKL, inhibits bone resorption and increases BMD in knock-in mice that express chimeric (murine/human) RANKL. J. Bone Miner. Res. 24, 182–195 (2009).

  152. 152.

    Smith, M. R. et al. Denosumab in men receiving androgen-deprivation therapy for prostate cancer. N. Engl. J. Med. 361, 745–755 (2009).

  153. 153.

    Smith, M. R. et al. Denosumab and bone-metastasis-free survival in men with castration-resistant prostate cancer: results of a phase 3, randomised, placebo-controlled trial. Lancet 379, 39–46 (2012).

  154. 154.

    Ignatoski, K. M. W. et al. RANKL inhibition is an effective adjuvant for docetaxel in a prostate cancer bone metastases model. Prostate 68, 820–829 (2008).

  155. 155.

    Virk, M. S. et al. Influence of simultaneous targeting of the bone morphogenetic protein pathway and RANK/RANKL axis in osteolytic prostate cancer lesion in bone. Bone 44, 160–167 (2009).

  156. 156.

    Miller, R. E. et al. RANK ligand inhibition plus docetaxel improves survival and reduces tumor burden in a murine model of prostate cancer bone metastasis. Mol. Cancer Ther. 7, 2160–2169 (2008).

  157. 157.

    Fizazi, K. The role of Src in prostate cancer. Ann. Oncol. 18, 1765–1773 (2007).

  158. 158.

    Yeatman, T. J. A renaissance for SRC. Nat. Rev. Cancer 4, 470–480 (2004).

  159. 159.

    Slack, J. K. et al. Alterations in the focal adhesion kinase/Src signal transduction pathway correlate with increased migratory capacity of prostate carcinoma cells. Oncogene 20, 1152–1163 (2001).

  160. 160.

    Koreckij, T. et al. Dasatinib inhibits the growth of prostate cancer in bone and provides additional protection from osteolysis. Br. J. Cancer 101, 263–268 (2009).

  161. 161.

    Yu, E. Y. et al. Phase II study of dasatinib in patients with metastatic castration-resistant prostate cancer. Clin. Cancer Res. 15, 7421–7428 (2009).

  162. 162.

    Araujo, J. C. et al. Docetaxel and dasatinib or placebo in men with metastatic castration-resistant prostate cancer (READY): a randomised, double-blind phase 3 trial. Lancet Oncol. 14, 1307–1316 (2013).

  163. 163.

    Yang, J. C. et al. Effect of the specific Src family kinase inhibitor saracatinib on osteolytic lesions using the PC-3 bone model. Mol. Cancer Ther. 9, 1629–1637 (2010).

  164. 164.

    US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/ct2/show/NCT01267266 (2015).

  165. 165.

    Posadas, E. M. et al. Saracatinib as a metastasis inhibitor in metastatic castration-resistant prostate cancer: a University of Chicago Phase 2 Consortium and DOD/PCF. Prostate Cancer Clinical Trials Consortium Study. Prostate 76, 286–293 (2016).

  166. 166.

    Naidoo, A., Naidoo, K., Yende-zuma, N. & Gengiah, T. N. Peptidomimetic src/pretubulin inhibitor KX-01 alone and in combination with paclitaxel suppresses growth, metastasis in human ER/PR/HER2-negative tumor xenografts. Mol. Cancer Ther. 19, 161–169 (2012).

  167. 167.

    US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/ct2/show/NCT01074138 (2016).

  168. 168.

    Antonarakis, E. S. et al. A phase 2 study of KX2-391, an oral inhibitor of Src kinase and tubulin polymerization, in men with bone-metastatic castration-resistant prostate cancer. Cancer Chemother. Pharmacol. 71, 883–892 (2013).

  169. 169.

    Rabbani, S. A., Valentino, M. L., Arakelian, A., Ali, S. & Boschelli, F. SKI-606 (Bosutinib) blocks prostate cancer invasion, growth, and metastasis in vitro and in vivo through regulation of genes involved in cancer growth and skeletal metastasis. Mol. Cancer Ther. 9, 1147–1157 (2010).

  170. 170.

    Tucker, G. C. Integrins: molecular targets in cancer therapy. Curr. Oncol. Rep. 8, 96–103 (2006).

  171. 171.

    Horton, M. A. The alpha v beta 3 integrin ‘vitronectin receptor’. Int. J. Biochem. Cell Biol. 29, 721–725 (1997).

  172. 172.

    Mulgrew, K. et al. Direct targeting of AvB3 integrin on tumor cells with a monoclonal antibody. Abegrin. Mol. Cancer Ther. 5, 3122–3129 (2006).

  173. 173.

    US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/ct2/show/study/NCT00072930 (2008).

  174. 174.

    Mestas, J. & Hughes, C. C. W. Of mice and not men: differences between mouse and human immunology. J. Immunol. 172, 2731–2738 (2004).

  175. 175.

    Hackam, D. G. & Redelmeier, D. A. Translation of research evidence from animals to humans. JAMA 296, 1727 (2006).

  176. 176.

    Fu, J. et al. Autologous reconstitution of human cancer and immune system in vivo. Oncotarget 8, 2053–2068 (2017).

  177. 177.

    Schaue, D., Koya, R. C., Liao, Y.-P., Ribas, A. & McBride, W. H. Immune rejection in a humanized model of murine prostate cancer. Anticancer Res. 30, 409–414 (2010).

  178. 178.

    Roth, M. D. & Harui, A. Human tumor infiltrating lymphocytes cooperatively regulate prostate tumor growth in a humanized mouse model. J. Immunother. Cancer 3, 12 (2015).

  179. 179.

    Wu, T. T. et al. Establishing human prostate cancer cell xenografts in bone: Induction of osteoblastic reaction by prostate-specific antigen-producing tumors in athymic and SCID/bg mice using LNCaP and lineage-derived metastatic sublines. Int. J. Cancer 77, 887–894 (1998).

  180. 180.

    Chu, L. W., Pettaway, C. A. & Liang, J. C. Genetic abnormalities specifically associated with varying metastatic potential of prostate cancer cell lines as detected by comparative genomic hybridization. Cancer Genet. Cytogenet. 127, 161–167 (2001).

  181. 181.

    Dudley, a C., Shih, S.-C., Cliffe, a R., Hida, K. & Klagsbrun, M. Attenuated p53 activation in tumour-associated stromal cells accompanies decreased sensitivity to etoposide and vincristine. Br. J. Cancer 99, 118–125 (2008).

  182. 182.

    Horoszewicz, J. S. et al. The LNCaP cell line — a new model for studies on human prostatic carcinoma. Prog. Clin. Biol. Res. 37, 115–132 (1980).

  183. 183.

    Jia, L. & Coetzee, G. A. Androgen receptor-dependent PSA expression in androgen-independent prostate cancer cells does not involve androgen receptor occupancy of the PSA locus. Cancer Res. 65, 8003–8008 (2005).

  184. 184.

    Gravina, G. L. et al. KPT-330, a potent and selective exportin-1 (XPO-1) inhibitor, shows antitumor effects modulating the expression of cyclin D1 and surviving in prostate cancer models. BMC Cancer 15, 941 (2015).

  185. 185.

    Voigt, W. & Dunning, W. F. In vivo metabolism of testosterone-3 H in R-3327, an androgen-sensitive rat prostatic adenocarcinoma. Cancer Res. 34, 1447–1450 (1974).

  186. 186.

    Newhall, K. R., Isaacs, J. T. & Wright, G. L. Dunning rat prostate tumors and cultured cell lines fail to express human prostate carcinoma-associated antigens. Prostate 17, 317–325 (1990).

  187. 187.

    Cooke, D. B., Quarmby, V. E., Mickey, D. D., Isaacs, J. T. & French, F. S. Oncogene expression in prostate cancer: Dunning R3327 rat dorsal prostatic adenocarcinoma system. Prostate 13, 263–272 (1988).

  188. 188.

    Isaacs, J. T. & Hukku, B. Nonrandom involvement of chromosome 4 in the progression of rat prostatic cancer. Prostate 13, 165–188 (1988).

  189. 189.

    Chekmareva, M. A. et al. Localization of prostate cancer metastasis-suppressor activity on human chromosome 17. Prostate 33, 271–280 (1997).

  190. 190.

    Pollard, M. Mestastatic adenocarcinoma of the prostate. Anim. Model. Hum. Dis. 86, 277–280 (1977).

  191. 191.

    Pollard, M., Luckert, P. H. & Scheu, J. Effects of diphosphonate and x-rays on bone lesions induced in rats by prostate cancer cells. Cancer 61, 2027–2032 (1988).

  192. 192.

    Boulanger, J., Reyes-Moreno, C. & Koutsilieris, M. Mediation of glucocorticoid receptor function by the activation of latent transforming growth factor beta 1 in MG-63 human osteosarcoma cells. Int. J. Cancer 61, 692–697 (1995).

  193. 193.

    Suckow, M. A., Wheeler, J. & Yan, M. PAIII prostate tumors express prostate specific antigen (PSA) in Lobund-Wistar rats. Can. J. Vet. Res. 73, 39–41 (2009).

  194. 194.

    Fisher, J. et al. An in vivo model of prostate carcinoma growth and invasion in bone. Cell Tissue Res. 307, 337–345 (2002).

  195. 195.

    Bonfil, R. D. et al. Prostate cancer-associated membrane type 1-matrix metalloproteinase: a pivotal role in bone response and intraosseous tumor growth. Am. J. Pathol. 170, 2100–2111 (2007).

  196. 196.

    Zou, M. et al. Multiple metastases in a novel LNCaP model of human prostate cancer. Oncol. Rep. 30, 615–622 (2013).

  197. 197.

    Corey, E. et al. Establishment and characterization of osseous prostate cancer models: Intra-tibial injection of human prostate cancer cells. Prostate 52, 20–33 (2002).

  198. 198.

    Jantscheff, P. et al. Anti-metastatic effects of liposomal gemcitabine in a human orthotopic LNCaP prostate cancer xenograft model. Clin. Exp. Metastasis 26, 981–992 (2009).

  199. 199.

    Bi, X. et al. Prostate cancer metastases alter bone mineral and matrix composition independent of effects on bone architecture in mice — a quantitative study using microCT and Raman spectroscopy. Bone 56, 454–460 (2013).

  200. 200.

    Kitagawa, Y. et al. Vascular endothelial growth factor contributes to prostate cancer-mediated osteoblastic activity. Cancer Res. 65, 10921–10929 (2005).

  201. 201.

    Havens, A. M. et al. An in vivo mouse model for human prostate cancer metastasis. Neoplasia 10, 371–380 (2008).

  202. 202.

    Wang, N. et al. The frequency of osteolytic bone metastasis is determined by conditions of the soil, not the number of seeds; evidence from in vivo models of breast and prostate cancer. J. Exp. Clin. Cancer Res. 34, 124 (2015).

  203. 203.

    Chu, K. et al. Cadherin-11 promotes the metastasis of prostate cancer cells to bone. Mol. Cancer Res. 6, 1259–1267 (2008).

  204. 204.

    Schneider, A. et al. Bone turnover mediates preferential localization of prostate cancer in the skeleton. Endocrinology 146, 1727–1736 (2005).

  205. 205.

    Xu, S. et al. An EP4 antagonist ONO-AE3-208 suppresses cell invasion, migration, and metastasis of prostate cancer. Cell Biochem. Biophys. 70, 521–527 (2014).

  206. 206.

    Li, X. et al. Inhibitory effects of megakaryocytic cells in prostate cancer skeletal metastasis. J. Bone Miner. Res. 26, 125–134 (2011).

  207. 207.

    Winkelmann, C. T., Figueroa, S. D., Sieckman, G. L., Rold, T. L. & Hoffman, T. J. Non-invasive MicroCT imaging characterization and in vivo targeting of BB2 receptor expression of a PC-3 bone metastasis model. Mol. Imag. Biol. 14, 667–675 (2012).

  208. 208.

    Angelucci, A. et al. Suppression of EGF-R signaling reduces the incidence of prostate cancer metastasis in nude mice. Endocr. Relat. Cancer 13, 197–210 (2006).

  209. 209.

    Margheri, F. et al. Effects of blocking urokinase receptor signaling by antisense oligonucleotides in a mouse model of experimental prostate cancer bone metastases. Gene Ther. 12, 702–714 (2005).

  210. 210.

    Jung, Y. et al. Prevalence of prostate cancer metastases after intravenous inoculation provides clues into the molecular basis of dormancy in the bone marrow microenvironment. Neoplasia 14, 429–439 (2012).

  211. 211.

    Valta, M. P. et al. FGF-8 is involved in bone metastasis of prostate cancer. Int. J. Cancer 123, 22–31 (2008).

  212. 212.

    Zhang, Y. et al. Real-time GFP intravital imaging of the differences in cellular and angiogenic behavior of subcutaneous and orthotopic nude-mouse models of human PC-3 prostate cancer. J. Cell. Biochem. 117, 2546–2551 (2016).

  213. 213.

    Gamradt, S. C. et al. The effect of cyclooxygenase-2 (COX-2) inhibition on human prostate cancer induced osteoblastic and osteolytic lesions in bone. Anticancer Res. 25, 107–115 (2005).

  214. 214.

    Whang, P. G., Schwarz, E. M., Gamradt, S. C., Dougall, W. C. & Lieberman, J. R. The effects of RANK blockade and osteoclast depletion in a model of pure osteoblastic prostate cancer metastasis in bone. J. Orthop. Res. 23, 1475–1483 (2005).

  215. 215.

    Yang, J. et al. Prostate cancer cells induce osteoblast differentiation through a Cbfa1-dependent pathway. Cancer Res. 61, 5652–5659 (2001).

  216. 216.

    Mohamedali, K. A. et al. Inhibition of prostate tumor growth and bone remodeling by the vascular targeting agent VEGF121/rGel. Cancer Res. 66, 10919–10928 (2006).

  217. 217.

    Hsu, Y.-H. et al. Anti-IL-20 monoclonal antibody suppresses prostate cancer growth and bone osteolysis in murine models. PLoS ONE 10, e0139871 (2015).

  218. 218.

    Shevrin, D. H., Kukreja, S. C., Ghosh, L. & Lad, T. E. Development of skeletal metastasis by human prostate cancer in athymic nude mice. Clin. Exp. Metastasis 6, 401–409 (1988).

  219. 219.

    Yang, M. et al. A fluorescent orthotopic bone metastasis model of human prostate cancer. Cancer Res. 59, 781–786 (1999).

  220. 220.

    Raheem, O. et al. A novel patient-derived intra-femoral xenograft model of bone metastatic prostate cancer that recapitulates mixed osteolytic and osteoblastic lesions. J. Transl Med. 9, 185–168 (2011).

  221. 221.

    Wise-Milestone, L. et al. Evaluating the effects of mixed osteolytic/osteoblastic metastasis on vertebral bone quality in a new rat model. J. Orthop. Res. 30, 817–823 (2012).

  222. 222.

    Thudi, N. K. et al. Zoledronic acid decreased osteolysis but not bone metastasis in a nude mouse model of canine prostate cancer with mixed bone lesions. Prostate 68, 1116–1125 (2008).

  223. 223.

    McCabe, N. P., Madajka, M., Vasanji, A. & Byzova, T. V. Intraosseous injection of RM1 murine prostate cancer cells promotes rapid osteolysis and periosteal bone deposition. Clin. Exp. Metastasis 25, 581–590 (2008).

  224. 224.

    Llorián-Salvador, M. et al. Hypernociceptive responses following the intratibial inoculation of RM1 prostate cancer cells in mice. Prostate 75, 70–83 (2015).

  225. 225.

    Hung, T.-T., Chan, J., Russell, P. J. & Power, C. A. Zoledronic acid preserves bone structure and increases survival but does not limit tumour incidence in a prostate cancer bone metastasis model. PLoS ONE 6, e19389 (2011).

  226. 226.

    Yonou, H. et al. The bisphosphonate YM529 inhibits osteoblastic bone tumor proliferation of prostate cancer. Prostate 67, 999–1009 (2007).

  227. 227.

    Yonou, H. et al. 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 (2004).

  228. 228.

    Nie, D. et al. Increased metastatic potential in human prostate carcinoma cells by over-expression of arachidonate 12-lipoxygenase. Clin. Exp. Metasis 20, 657–663 (2003).

  229. 229.

    Hesami, P. 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).

  230. 230.

    Thompson, T. C., Timme, T. L., Park, S. H., Yang, G. & Ren, C. Mouse prostate reconstitution model system: a series of in vivo and in vitro models for benign and malignant prostatic disease. Prostate 43, 248–254 (2000).

  231. 231.

    Proctor, J. W., Auclair, B. G. & Rudenstam, C. M. The distribution and fate of blood-borne 125IUdR-labelled tumour cells in immune syngeneic rats. Int. J. Cancer 18, 255–262 (1976).

Download references

Acknowledgements

The authors’ research work was supported by the Prostate Cancer Canada's Rising Star Research Grant to H.S.L.

Author information

Author notes

  1. These authors contributed equally: Richard B. Berish, Aymon N. Ali.

Affiliations

  1. Department of Surgery, Division of Urology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada

    • Richard B. Berish
    • , Aymon N. Ali
    • , Patrick G. Telmer
    •  & Hon S. Leong
  2. Department of Microbiology and Immunology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada

    • Richard B. Berish
    • , John A. Ronald
    •  & Hon S. Leong
  3. Department of Medical Biophysics, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada

    • John A. Ronald
  4. Department of Urology, Physiology and Biomedical Engineering, Mayo Clinic College of Medicine, Rochester, MN, USA

    • Hon S. Leong

Authors

  1. Search for Richard B. Berish in:

  2. Search for Aymon N. Ali in:

  3. Search for Patrick G. Telmer in:

  4. Search for John A. Ronald in:

  5. Search for Hon S. Leong in:

Contributions

All authors researched data for the article, wrote the manuscript, made substantial contributions to discussions of content, and edited the manuscript before submission.

Competing interests

The authors declare no competing interests.

Corresponding author

Correspondence to Hon S. Leong.

Glossary

Intravasation

The migration of a cancer cell into a blood or lymphatic vessel from its primary site or the surrounding tissue.

Extravasation

The migration of a cancer cell out of the vasculature into a secondary site, typically bone for prostate cancer.

Metastatic cascade

The series of events describing the progression of cancer from a primary site to distant metastasis.

Cell lines

Populations of cells originally derived from living tissue but adapted to be grown in vitro indefinitely.

Patient-derived xenograft

(PDX). Tumour line derived from patient tissue that is usually maintained in vivo and retains natural tumour heterogeneity.

Epithelial-to-mesenchymal transition

(EMT). The evolution of a cancer cell into an invasive phenotype before metastasizing; often characterized based on the changes to cytoskeletal and adhesion proteins.

Dormancy

The ability of a cancer cell to remain in a latent, inactive state before the production of overt metastases.

Perivascular niche

A microenvironmental target adjacent to blood vessels that supports the long-term survival of specific cell types, including stem or progenitor cells.

Osteolytic lesions

Lesions characterized by the demineralization and destruction of bone.

Lateral tail vein

A commonly used vein on the lateral aspect of rodent tails used for the systematic inoculation of cancer cells; often produces lung metastases.

Intracardiac injections

Systematic inoculations of cancer cells by injection into the left ventricle of the heart; often used to initiate bone metastasis.

Osteoblastic lesions

Lesions characterized by the formation of mechanically weak woven bone.

Mouse prostate reconstitution

A model of prostate cancer involving the generation of a cancerous reconstituted prostate from fetal urogenital sinus tissue.

Subrenal capsule

A region surrounding the kidney where cells can be engrafted for the study of primary tumours; offers high take rate owing to high regional vascularity.

Orthotopic

A region where cells can be engrafted primarily for the study of primary tumours or local invasion; defined as being the region where the cell normally belongs, such as the prostate.

Tumour heterogeneity

A characteristic of tumours that are derived from more than one clonally expanded cell, giving them mixed populations of phenotypically different cells.

Transgenic mouse models

Spontaneous disease models generated by modifying expression of specific genes.

Bone implant models

Models that are often humanized disease models in which foreign mouse, human, or engineered bone tissue is engrafted subcutaneously into recipient mice.

About this article

Publication history

Published

DOI

https://doi.org/10.1038/s41585-018-0020-2

Rights and permissions

To obtain permission to re-use content from this article visit RightsLink.