Generation of Prostate Cancer Patient-Derived Xenografts to Investigate Mechanisms of Novel Treatments and Treatment Resistance

  • Hung-Ming Lam
  • Holly M. Nguyen
  • Eva CoreyEmail author
Part of the Methods in Molecular Biology book series (MIMB, volume 1786)


Treatment advances lead to survival benefits of patients with advanced prostate cancer. These treatments are highly efficacious in a subset of patients; however, similarly to other cancers, after initial responses the tumors develop resistance (acquired resistance) and the patients succumb to the disease. Furthermore, there is a subset of patients who do not respond to the treatment at all (de novo resistance). Preclinical testing using patient-derived xenografts (PDXs) has led to successful drug development, and PDXs will continue to provide valuable resources to generate clinically relevant data with translational potential. PDXs demonstrate tumor heterogeneity observed in patients, preserve tumor-microenvironment architecture, and provide clinically relevant treatment responses. In view of the evolving biology of the advanced prostate cancer associated with new treatments, PDXs representing these new tumor phenotypes are urgently needed for the study of treatment responses and resistance. In this chapter, we describe methodologies used to establish prostate cancer PDXs and use of these PDXs to study de novo and acquired resistance.

Key words

Prostate cancer Abiraterone Enzalutamide Resistance Testosterone 



We would like to thank the Richard M. Lucas Foundation and the Prostate Cancer Foundation for their long-term support for the generation and characterization of prostate cancer PDX models. The work is also supported by NIH PO1 CA085859 (to Robert L. Vessella) and the PNW Prostate Cancer SPORE NIH P50 CA097186 (to Peter S. Nelson). We very much appreciate Dr. Robert Vessella and Dr. Paul H. Lange for their continuous support of our work. We extend our gratitude to the patients who donated their tissues for research and the assistance of the many clinicians who facilitated this process.


  1. 1.
    De Bono JS, Logothetis CJ, Molina A et al (2011) Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med 364:1995–2005CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Scher HI, Fizazi K, Saad F et al (2012) Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med 367:1187–1197CrossRefPubMedGoogle Scholar
  3. 3.
    Lin D, Wyatt AW, Xue H et al (2014) High fidelity patient-derived xenografts for accelerating prostate cancer discovery and drug development. Cancer Res 74:1272–1283CrossRefPubMedGoogle Scholar
  4. 4.
    Li L, Chang W, Yang G et al (2014) Targeting poly (Adp-ribose) polymerase and the C-Myb-regulated dna damage response pathway in castration-resistant prostate cancer. Sci Signal 7:Ra47CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Fiebig HH, Maier A, Burger AM (2004) Clonogenic assay with established human tumour xenografts: correlation of in vitro to in vivo activity as a basis for anticancer drug discovery. Eur J Cancer 40:802–820CrossRefPubMedGoogle Scholar
  6. 6.
    Zhao H, Nolley R, Chen Z, Peehl DM (2010) Tissue slice grafts: an in vivo model of human prostate androgen signaling. Am J Pathol 177:229–239CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Priolo C, Agostini M, Vena N et al (2010) Establishment and genomic characterization of mouse xenografts of human primary prostate tumors. Am J Pathol 176:1901–1913CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Raheem O, Kulidjian AA, Wu C et al (2011) A novel patient-derived intra-femoral xenograft model of bone metastatic prostate cancer that recapitulates mixed osteolytic and osteoblastic lesions. J Transl Med 9:185CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Li ZG, Mathew P, Yang J et al (2008) Androgen receptor-negative human prostate cancer cells induce osteogenesis in mice through Fgf9-Mediated mechanisms. J Clin Invest 118:2697–2710CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Karlou M, Lu JF, Wu G et al (2012) Hedgehog signaling inhibition by the small molecule smoothened inhibitor Gdc-0449 in the bone forming prostate cancer xenograft Mda Pca 118b. Prostate 72:1638–1647CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Aparicio A, Tzelepi V, Araujo JC, Guo CC, Liang S, Troncoso P, Logothetis CJ, Navone NM, Maity SN (2011) Neuroendocrine prostate cancer xenografts with large-cell and small-cell features derived from a single patient’s tumor: morphological, immunohistochemical, and gene expression profiles. Prostate 71:846–856CrossRefPubMedGoogle Scholar
  12. 12.
    Tzelepi V, Zhang J, Lu JF et al (2012) Modeling a lethal prostate cancer variant with small-cell carcinoma features. Clin Cancer Res 18:666–677CrossRefPubMedGoogle Scholar
  13. 13.
    Sircar K, Huang H, Hu L et al (2012) Integrative molecular profiling reveals asparagine synthetase is a target in castration-resistant prostate cancer. Am J Pathol 180:895–903CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Wang Y, Xue H, Cutz JC et al (2005) An orthotopic metastatic prostate cancer model in scid mice via grafting of a transplantable human prostate tumor line. Lab Investig 85:1392–1404CrossRefPubMedGoogle Scholar
  15. 15.
    Lin D, Bayani J, Wang Y, Sadar MD, Yoshimoto M, Gout PW, Squire JA, Wang Y (2010) Development of metastatic and non-metastatic tumor lines from a patient’s prostate cancer specimen-identification of a small subpopulation with metastatic potential in the primary tumor. Prostate 70:1636–1644CrossRefPubMedGoogle Scholar
  16. 16.
    Russell PJ, Russell P, Rudduck C, Tse BW, Williams ED, Raghavan D (2015) Establishing prostate cancer patient derived xenografts: lessons learned from older studies. Prostate 75:628–636CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Mcculloch DR, Opeskin K, Thompson EW, Williams ED (2005) Bm18: a novel androgen-dependent human prostate cancer xenograft model derived from a bone metastasis. Prostate 65:35–43CrossRefPubMedGoogle Scholar
  18. 18.
    Wang Y, Revelo MP, Sudilovsky D et al (2005) Development and characterization of efficient xenograft models for benign and malignant human prostate tissue. Prostate 64:149–159CrossRefPubMedGoogle Scholar
  19. 19.
    Lawrence MG, Taylor RA, Toivanen R et al (2013) A preclinical xenograft model of prostate cancer using human tumors. Nat Protoc 8:836–848CrossRefPubMedGoogle Scholar
  20. 20.
    Van Weerden WM, De Ridder CM, Verdaasdonk CL, Romijn JC, Van Der Kwast TH, Schroder FH, Van Steenbrugge GJ (1996) Development of seven new human prostate tumor xenograft models and their histopathological characterization. Am J Pathol 149:1055–1062PubMedPubMedCentralGoogle Scholar
  21. 21.
    Bostwick DG, Ramnani D, Qian J (2000) Prostatic intraepithelial neoplasia: animal models 2000. Prostate 43:286–294CrossRefPubMedGoogle Scholar
  22. 22.
    Marques RB, Van Weerden WM, Erkens-Schulze S, De Ridder CM, Bangma CH, Trapman J, Jenster G (2006) The human Pc346 xenograft and cell line panel: a model system for prostate cancer progression. Eur Urol 49:245–257CrossRefPubMedGoogle Scholar
  23. 23.
    Beltran H, Tomlins S, Aparicio A et al (2014) Aggressive variants of castration-resistant prostate cancer. Clin Cancer Res 20:2846–2850CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Jongsma J, Oomen MH, Noordzij MA, Van Weerden WM, Martens GJ, Van Der Kwast TH, Schroder FH, Van Steenbrugge GJ (1999) Kinetics of neuroendocrine differentiation in an androgen-dependent human prostate xenograft model. Am J Pathol 154:543–551CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Jongsma J, Oomen MH, Noordzij MA, Van Weerden WM, Martens GJ, Van Der Kwast TH, Schroder FH, Van Steenbrugge GJ (2000) Androgen deprivation of the Pc-310 [correction of prohormone convertase-310] human prostate cancer model system induces neuroendocrine differentiation. Cancer Res 60:741–748PubMedGoogle Scholar
  26. 26.
    True LD, Buhler K, Quinn J et al (2002) A neuroendocrine/small cell prostate carcinoma xenograft-Lucap 49. Am J Pathol 161:705–715CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Festing MFW (1968) International index of laboratory animals. University Of Leicester, LeicesterGoogle Scholar
  28. 28.
    Otto U, Wagner B, Becker H, Schroder S, Klosterhalfen H (1992) Transplantation of human benign hyperplastic prostate tissue into nude mice: first results of systemic therapy. Urol Int 48:167–170CrossRefPubMedGoogle Scholar
  29. 29.
    Bosma GC, Custer RP, Bosma MJ (1983) A severe combined immunodeficiency mutation in the mouse. Nature 301:527–530CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Dorshkind K, Pollack SB, Bosma MJ, Phillips RA (1985) Natural killer (Nk) cells are present in mice with severe combined immunodeficiency (Scid). J Immunol 134:3798–3801PubMedGoogle Scholar
  31. 31.
    Czitrom AA, Edwards S, Phillips RA, Bosma MJ, Marrack P, Kappler JW (1985) The function of antigen-presenting cells in mice with severe combined immunodeficiency. J Immunol 134:2276–2280PubMedPubMedCentralGoogle Scholar
  32. 32.
    Dorshkind K, Keller GM, Phillips RA, Miller RG, Bosma GC, O’toole M, Bosma MJ (1984) Functional status of cells from lymphoid and myeloid tissues in mice with severe combined immunodeficiency disease. J Immunol 132:1804–1808PubMedGoogle Scholar
  33. 33.
    Bosma GC, Fried M, Custer RP, Carroll A, Gibson DM, Bosma MJ (1988) Evidence of functional lymphocytes in some (Leaky) Scid mice. J Exp Med 167:1016–1033CrossRefPubMedGoogle Scholar
  34. 34.
    Carroll AM, Hardy RR, Bosma MJ (1989) Occurrence of mature B (Igm+, B220+) And T (Cd3+) lymphocytes in Scid mice. J Immunol 143:1087–1093PubMedGoogle Scholar
  35. 35.
    Shinkai Y, Rathbun G, Lam KP et al (1992) Rag-2-deficient mice lack mature lymphocytes owing to inability to initiate V(D)J rearrangement. Cell 68:855–867CrossRefPubMedGoogle Scholar
  36. 36.
    Kwant-Mitchell A, Pek EA, Rosenthal KL, Ashkar AA (2009) Development of functional human Nk cells in an immunodeficient mouse model with the ability to provide protection against tumor challenge. PLoS One 4:E8379CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Mosier DE, Stell KL, Gulizia RJ, Torbett BE, Gilmore GL (1993) Homozygous Scid/Scid;Beige/Beige mice have low levels of spontaneous or neonatal T cell-induced B cell generation. J Exp Med 177:191–194CrossRefPubMedGoogle Scholar
  38. 38.
    Shultz LD, Schweitzer PA, Christianson SW et al (1995) Multiple defects in innate and adaptive immunologic function in Nod/Ltsz-Scid mice. J Immunol 154:180–191PubMedPubMedCentralGoogle Scholar
  39. 39.
    Nguyen HM, Corey E (2011) Methodology to investigate androgen-sensitive and castration-resistant human prostate cancer xenografts in preclinical setting. Methods Mol Biol 776:295–312CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Lin D, Xue H, Wang Y et al (2014) Next generation patient-derived prostate cancer xenograft models. Asian J Androl 16:407–412CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Dipippo VA, Olson WC, Nguyen HM, Brown LG, Vessella RL, Corey E (2015) Efficacy studies of an antibody-drug conjugate Psma-Adc in patient-derived prostate cancer xenografts. Prostate 75:303–313CrossRefPubMedGoogle Scholar
  42. 42.
    Nguyen HM, Ruppender N, Zhang X et al (2013) Cabozantinib inhibits growth of androgen-sensitive and castration-resistant prostate cancer and affects bone remodeling. PLoS One 8:E78881CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Morrissey C, Dowell A, Koreckij TD, Nguyen H, Lakely B, Fanslow WC, True LD, Corey E, Vessella RL (2010) Inhibition of angiopoietin-2 in Lucap 23.1 prostate cancer tumors decreases tumor growth and viability. Prostate 70:1799–1808PubMedPubMedCentralGoogle Scholar
  44. 44.
    Montgomery B, Nelson PS, Vessella R, Kalhorn T, Hess D, Corey E (2010) Estradiol suppresses tissue androgens and prostate cancer growth in castration resistant prostate cancer. BMC Cancer 10:244CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Coleman IM, Kiefer JA, Brown LG, Pitts TE, Nelson PS, Brubaker KD, Vessella RL, Corey E (2006) Inhibition of androgen-independent prostate cancer by estrogenic compounds is associated with increased expression of immune-related genes. Neoplasia 8:862–878CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Stangelberger A, Schally AV, Letsch M, Szepeshazi K, Nagy A, Halmos G, Kanashiro CA, Corey E, Vessella R (2006) Targeted chemotherapy with cytotoxic bombesin analogue An-215 inhibits growth of experimental human prostate cancers. Int J Cancer 118:222–229CrossRefPubMedGoogle Scholar
  47. 47.
    Corey E, Quinn JE, Buhler KR, Nelson PS, Macoska JA, True LD, Vessella RL (2003) Lucap 35: a new model of prostate cancer progression to androgen independence. Prostate 55:239–246CrossRefPubMedGoogle Scholar
  48. 48.
    Corey E, Quinn JE, Emond MJ, Buhler KR, Brown LG, Vessella RL (2002) Inhibition of androgen-independent growth of prostate cancer xenografts by 17beta-estradiol. Clin Cancer Res 8:1003–1007PubMedGoogle Scholar
  49. 49.
    Rubin MA, Putzi M, Mucci N, Smith DC, Wojno K, Korenchuk S, Pienta KJ (2000) Rapid (“Warm”) autopsy study for procurement of metastatic prostate cancer. Clin Cancer Res 6:1038–1045PubMedGoogle Scholar
  50. 50.
    Bubendorf L, Schopfer A, Wagner U, Sauter G, Moch H, Willi N, Gasser TC, Mihatsch MJ (2000) Metastatic patterns of prostate cancer: an autopsy study of 1,589 patients. Hum Pathol 31:578–583CrossRefPubMedGoogle Scholar
  51. 51.
    Harada M, Iida M, Yamaguchi M, Shida K (1992) Analysis of bone metastasis of prostatic adenocarcinoma in 137 autopsy cases. Adv Exp Med Biol 324:173–182CrossRefPubMedGoogle Scholar
  52. 52.
    Saitoh H, Hida M, Shimbo T, Nakamura K, Yamagata J, Satoh T (1984) Metastatic patterns of prostatic cancer. Correlation between sites and number of organs involved. Cancer 54:3078–3084CrossRefPubMedGoogle Scholar
  53. 53.
    Roudier MP, True LD, Higano CS, Vesselle H, Ellis W, Lange P, Vessella RL (2003) Phenotypic heterogeneity of end-stage prostate carcinoma metastatic to bone. Hum Pathol 34:646–653CrossRefPubMedGoogle Scholar
  54. 54.
    Roudier MP, Corey E, True LD, Hiagno CS, Ott SM, Vessell RL (2004) Histological, immunophenotypic and histomorphometric characterization of prostate cancer bone metastases. Cancer Treat Res 118:311–339CrossRefPubMedGoogle Scholar
  55. 55.
    Corey E, Quinn JE, Bladou F, Brown LG, Roudier MP, Brown JM, Buhler KR, Rl V (2002) Establishment and characterization of osseous prostate cancer models: intra-tibial injection of human prostate cancer cells. Prostate 52:20–33CrossRefPubMedGoogle Scholar
  56. 56.
    Corey E, Brown LG, Quinn JE, Poot M, Roudier MP, Higano CS, Vessella RL (2003) Zoledronic acid exhibits inhibitory effects on osteoblastic and osteolytic metastases of prostate cancer. Clin Cancer Res 9:295–306PubMedGoogle Scholar
  57. 57.
    Brubaker KD, Brown LG, Vessella RL, Corey E (2006) Administration of zoledronic acid enhances the effects of docetaxel on growth of prostate cancer in the bone environment. BMC Cancer 6:15CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Koreckij T, Nguyen H, Brown LG, Yu EY, Vessella RL, Corey E (2009) Dasatinib inhibits the growth of prostate cancer in bone and provides additional protection from osteolysis. Br J Cancer 101:263–268CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Morgan TM, Pitts TE, Gross TS, Poliachik SL, Vessella RL, Corey E (2008) Rad001 (Everolimus) inhibits growth of prostate cancer in the bone and the inhibitory effects are increased by combination with docetaxel and zoledronic acid. Prostate 68:861–871CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Kundra V, Ng CS, Ma J, Bankson JA, Price RE, Cody DD, Do KA, Han L, Navone NM (2007) In vivo imaging of prostate cancer involving bone in a mouse model. Prostate 67:50–60CrossRefPubMedGoogle Scholar
  61. 61.
    Lu Y, Cai Z, Xiao G, Keller ET, Mizokami A, Yao Z, Roodman GD, Zhang J (2007) Monocyte chemotactic protein-1 mediates prostate cancer-induced bone resorption. Cancer Res 67:3646–3653CrossRefPubMedGoogle Scholar
  62. 62.
    Zhang J, Dai J, Qi Y et al (2001) Osteoprotegerin inhibits prostate cancer-induced osteoclastogenesis and prevents prostate tumor growth in the bone. J Clin Invest 107:1235–1244CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Turner PV, Brabb T, Pekow C, Vasbinder MA (2011) Administration of substances to laboratory animals: routes of administration and factors to consider. J Am Assoc Lab Anim Sci 50:600–613PubMedPubMedCentralGoogle Scholar
  64. 64.
    Gotloib L, Wajsbrot V, Shostak A (2005) A short review of experimental peritoneal sclerosis: from mice to men. Int J Artif Organs 28:97–104CrossRefPubMedGoogle Scholar
  65. 65.
    Lukas G, Brindle SD, Greengard P (1971) The route of absorption of intraperitoneally administered compounds. J Pharmacol Exp Ther 178:562–564PubMedGoogle Scholar
  66. 66.
    Morrissey C, True LD, Roudier MP et al (2008) Differential expression of angiogenesis associated genes in prostate cancer bone, liver and lymph node metastases. Clin Exp Metastasis 25:377–388CrossRefPubMedGoogle Scholar
  67. 67.
    Morrissey C, Roudier MP, Dowell AT et al (2013) Effects of androgen deprivation therapy and bisphosphonate treatment on bone in patients with metastatic castration-resistant prostate cancer: results from the University Of Washington Rapid Autopsy Series. J Bone Miner Res 28:333–340CrossRefPubMedPubMedCentralGoogle Scholar
  68. 68.
    Ristevski B, Jenkinson RJ, Stephen DJ, Finkelstein J, Schemitsch EH, Mckee MD, Kreder HJ (2009) Mortality and complications following stabilization of femoral metastatic lesions: a population-based study of regional variation and outcome. Can J Surg 52:302–308PubMedPubMedCentralGoogle Scholar
  69. 69.
    Michiel Sedelaar JP, Dalrymple SS, Isaacs JT (2013) Of mice and men—warning: intact versus castrated adult male mice as xenograft hosts are equivalent to hypogonadal versus abiraterone treated aging human males, respectively. Prostate 73:1316–1325CrossRefPubMedGoogle Scholar
  70. 70.
    Janne M, Deol HK, Power SG, Yee SP, Hammond GL (1998) Human sex hormone-binding globulin gene expression in transgenic mice. Mol Endocrinol 12:123–136CrossRefPubMedGoogle Scholar
  71. 71.
    Van Weerden WM, Bierings HG, Van Steenbrugge GJ, De Jong FH, Schroder FH (1992) Adrenal glands of mouse and rat do not synthesize androgens. Life Sci 50:857–861CrossRefPubMedGoogle Scholar
  72. 72.
    Mostaghel EA, Marck BT, Plymate SR, Vessella RL, Balk S, Matsumoto AM, Nelson PS, Montgomery RB (2011) Resistance To Cyp17a1 inhibition with abiraterone in castration-resistant prostate cancer: induction of steroidogenesis and androgen receptor splice variants. Clin Cancer Res 17:5913–5925CrossRefPubMedPubMedCentralGoogle Scholar
  73. 73.
    Chuu CP, Kokontis JM, Hiipakka RA, Fukuchi J, Lin HP, Lin CY, Huo C, Su LC (2011) Androgens as therapy for androgen receptor-positive castration-resistant prostate cancer. J Biomed Sci 18:63CrossRefPubMedPubMedCentralGoogle Scholar
  74. 74.
    Wege AK, Ernst W, Eckl J, Frankenberger B, Vollmann-Zwerenz A, Mannel DN, Ortmann O, Kroemer A, Brockhoff G (2011) Humanized tumor mice—a new model to study and manipulate the immune response in advanced cancer therapy. Int J Cancer 129:2194–2206CrossRefPubMedGoogle Scholar
  75. 75.
    Pienta KJ, Abate-Shen C, Agus DB et al (2008) The current state of preclinical prostate cancer animal models. Prostate 68:629–639CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of UrologyUniversity of WashingtonSeattleUSA

Personalised recommendations