Advances in prostate cancer research models: From transgenic mice to tumor xenografting models

doi:10.1016/j.ajur.2016.02.004

Asian Journal of Urology, 2016, 3 (2): 64-74 doi: 10.1016/j.ajur.2016.02.004

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Advances in prostate cancer research models: From transgenic mice to tumor xenografting models

Yuejiao Huang^a, Chun Cheng^b, Chong Zhang^c, Yonghui Zhang^c, Miaomiao Chen^c, Douglas W. Strand^d, Ming Jiang^c,e

a Department of Oncology, Affiliated Cancer Hospital of Nantong University, Nantong, Jiangsu, China;
b Department of Immunology, Nantong University School of Medicine, Nantong, Jiangsu, China;
c Laboratory of Nuclear Receptors and Cancer Research, Center for Basic Medical Research, Nantong University School of Medicine, Nantong, Jiangsu, China;
d Department of Urology, UT Southernwestern Medical Center, Dallas, TX, USA;
e Institute of Medicine and Public Health, Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA

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Abstract The identification of the origin and molecular characteristics of prostate cancer (PCa) has crucial implications for personalized treatment. The development of effective treatments for PCa has been limited; however, the recent establishment of several transgenicmouse lines and/or xenografting models is better reflecting the disease in vivo. With appropriate models, valuable tools for elucidating the functions of specific genes have gone deep into prostate development and carcinogenesis. In the present review, we summarize a number of important PCa research models established in our laboratories (PSA-Cre-ER^T2/PTEN transgenic mouse models, AP-OX model, tissue recombination-xenografting models and PDX models), which represent advances of translational models from transgenic mouse lines to human tumor xenografting. Better understanding of the developments of these models will offer new insights into tumor progression and may help explain the functional significance of genetic variations in PCa. Additionally, this understanding could lead to new modes for curing PCa based on their particular biological phenotypes.

Key words： Prostate cancer Transgenic mouse lines Tumor xenografting models Translational medical systems

Received: 21 October 2015 Published: 13 May 2016

Fund:The study was supported by funding from the NIDDK (DK098277) to Douglas W. Strand, and from the National Nature Scientific Foundation of China (NSFC No. 81372772) to Dr. Ming Jiang, the Scientific Research Foundation for Jiangsu Specially-Appointed Professor (Sujiaoshi [2012] No. 34), to Dr. Ming Jiang, Department of Education in Jiangsu Province, China and the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD), China.

Corresponding Authors: Ming Jiang E-mail: ming.jiang@ntu.edu.cn,ming.jiang@vanderbilt.edu

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Yuejiao Huang,Chun Cheng,Chong Zhang, et al. Advances in prostate cancer research models: From transgenic mice to tumor xenografting models[J]. Asian Journal of Urology, 2016, 3(2): 64-74.

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http://www.ajurology.com/EN/10.1016/j.ajur.2016.02.004 OR http://www.ajurology.com/EN/Y2016/V3/I2/64

[1]	Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA Cancer J Clin 2013;63:11-30.
[2]	Kwak JT, Hong CW, Pinto PA, Williams M, Xu S, Kruecker J, et al. Is visual registration equivalent to semiautomated registration in prostate biopsy? Biomed Res Int 2015;2015:394742.
[3]	Feldman BJ, Feldman D. The development of androgen-independent prostate cancer. Nat Rev Cancer 2001;1:34-45.
[4]	Wu W, Liu X, Chaftari P, Cruz Carreras MT, Gonzalez C, Viets-Upchurch J, et al. Association of body composition with outcome of docetaxel chemotherapy in metastatic prostate cancer:a retrospective review. PLoS One 2015;10:e0122047.
[5]	Powers GL, Hammer KD, Domenech M, Frantskevich K, Malinowski RL, Bushman W, et al. Phosphodiesterase 4D inhibitors limit prostate cancer growth potential. Mol Cancer Res 2015;13:149-60.
[6]	Hayward SW, Cunha GR. The prostate:development and physiology. Radiol Clin North Am 2000;38:1-14.
[7]	Hayward SW, Baskin LS, Haughney PC, Cunha AR, Foster BA, Dahiya R, et al. Epithelial development in the rat ventral prostate, anterior prostate and seminal vesicle. Acta Anat (Basel) 1996;155:81-93.
[8]	Hayward SW, Baskin LS, Haughney PC, Foster BA, Cunha AR, Dahiya R, et al. Stromal development in the ventral prostate, anterior prostate and seminal vesicle of the rat. Acta Anat (Basel) 1996;155:94-103.
[9]	Wang Y, Hayward S, Cao M, Thayer K, Cunha G. Cell differentiation lineage in the prostate. Differentiation 2001;68:270-9.
[10]	Suzuki A, Yamaguchi MT, Ohteki T, Sasaki T, Kaisho T, Kimura Y, et al. T cell-specific loss of Pten leads to defects in central and peripheral tolerance. Immunity 2001;14:523-34.
[11]	Peraldo-Neia C, Migliardi G, Mello-Grand M, Montemurro F, Segir R, Pignochino Y, et al. Epidermal Growth Factor Receptor (EGFR) mutation analysis, gene expression profiling and EGFR protein expression in primary prostate cancer. BMC Cancer 2011;11:31.
[12]	Carvalho JR, Filipe L, Costa VL, Ribeiro FR, Martins AT, Teixeira MR, et al. Detailed analysis of expression and promoter methylation status of apoptosis-related genes in prostate cancer. Apoptosis 2010;15:956-65.
[13]	de Muga S, Hernandez S, Agell L, Salido M, Juanpere N, Lorenzo M, et al. Molecular alterations of EGFR and PTEN in prostate cancer:association with high-grade and advancedstage carcinomas. Mod Pathol 2010;23:703-12.
[14]	Lamb LE, Knudsen BS, Miranti CK. E-cadherin-mediated survival of androgen-receptor-expressing secretory prostate epithelial cells derived from a stratified in vitro differentiation model. J Cell Sci 2010;123:266-76.
[15]	Abate-Shen C, Shen MM. Molecular genetics of prostate cancer. Genes Dev 2000;14:2410-34.
[16]	Shappell SB, Thomas GV, Roberts RL, Herbert R, Ittmann MM, Rubin MA, et al. Prostate pathology of genetically engineered mice:definitions and classification. The consensus report from the Bar Harbor meeting of the mouse models of human Cancer Consortium prostate pathology committee. Cancer Res 2004;64:2270-305.
[17]	Freeman D, Lesche R, Kertesz N, Wang S, Li G, Gao J, et al. Genetic background controls tumor development in PTENdeficient mice. Cancer Res 2006;66:6492-6.
[18]	Wu X, Wu J, Huang J, Powell WC, Zhang J, Matusik RJ, et al. Generation of a prostate epithelial cell-specific Cre transgenic mouse model for tissue-specific gene ablation. Mech Dev 2001;101:61-9.
[19]	Stambolic V, Tsao MS, Macpherson D, Suzuki A, Chapman WB, Mak TW. High incidence of breast and endometrial neoplasia resembling human Cowden syndrome in pten+/- mice. Cancer Res 2000;60:3605-11.
[20]	Jin C, McKeehan K, Wang F. Transgenic mouse with high Cre recombinase activity in all prostate lobes, seminal vesicle, and ductus deferens. Prostate 2003;57:160-4.
[21]	Wang X, Kruithof-de Julio M, Economides KD, Walker D, Yu H, Halili MV, et al. A luminal epithelial stem cell that is a cell of origin for prostate cancer. Nature 2009;461:495-500.
[22]	Kurita T, Medina RT, Mills AA, Cunha GR. Role of p63 and basal cells in the prostate. Development 2004;131:4955-64.
[23]	Tsujimura A, Koikawa Y, Salm S, Takao T, Coetzee S, Moscatelli D, et al. Proximal location of mouse prostate epithelial stem cells:a model of prostatic homeostasis. J Cell Biol 2002;157:1257-65.
[24]	Wang ZA, Mitrofanova A, Bergren SK, Abate-Shen C, Cardiff RD, Califano A, et al. Lineage analysis of basal epithelial cells reveals their unexpected plasticity and supports a cell-of-origin model for prostate cancer heterogeneity. Nat Cell Biol 2013;15:274-83.
[25]	Choi N, Zhang B, Zhang L, Ittmann M, Xin L. Adult murine prostate basal and luminal cells are self-sustained lineages that can both serve as targets for prostate cancer initiation. Cancer Cell 2012;21:253-65.
[26]	Taylor BS, Schultz N, Hieronymus H, Gopalan A, Xiao Y, Carver BS, et al. Integrative genomic profiling of human prostate cancer. Cancer Cell 2010;18:11-22.
[27]	Schubbert S, Shannon K, Bollag G. Hyperactive Ras in developmental disorders and cancer. Nat Rev Cancer 2007;7:295-308.
[28]	Joerger AC, Fersht AR. Structure-function-rescue:the diverse nature of common p53 cancer mutants. Oncogene 2007;26:2226-42.
[29]	Vogelstein B, Papadopoulos N, Velculescu VE, Zhou S, Diaz Jr LA, Kinzler KW. Cancer genome landscapes. Science 2013;339:1546-58.
[30]	Wang S, Gao J, Lei Q, Rozengurt N, Pritchard C, Jiao J, et al. Prostate-specific deletion of the murine Pten tumor suppressor gene leads to metastatic prostate cancer. Cancer Cell 2003;4:209-21.
[31]	Ma X, Ziel-van der Made AC, Autar B, van der Korput HA, Vermeij M, van Duijn P, et al. Targeted biallelic inactivation of Pten in the mouse prostate leads to prostate cancer accompanied by increased epithelial cell proliferation but not by reduced apoptosis. Cancer Res 2005;65:5730-9.
[32]	Royuela M, Arenas MI, Bethencourt FR, Sanchez-Chapado M, Fraile B, Paniagua R. Regulation of proliferation/apoptosis equilibrium by mitogen-activated protein kinases in normal, hyperplastic, and carcinomatous human prostate. Hum Pathol 2002;33:299-306.
[33]	Leong KG, Gao WQ. The Notch pathway in prostate development and cancer. Differentiation 2008;76:699-716.
[34]	South AP, Cho RJ, Aster JC. The double-edged sword of Notch signaling in cancer. Semin Cell Dev Biol 2012;23:458-64.
[35]	Ranganathan P, Weaver KL, Capobianco AJ. Notch signalling in solid tumours:a little bit of everything but not all the time. Nat Rev Cancer 2011;11:338-51.
[36]	Heer R, Collins AT, Robson CN, Shenton BK, Leung HY. KGF suppresses alpha2beta1 integrin function and promotes differentiation of the transient amplifying population in human prostatic epithelium. J Cell Sci 2006;119:1416-24.
[37]	van Leenders GJ, Schalken JA. Epithelial cell differentiation in the human prostate epithelium:implications for the pathogenesis and therapy of prostate cancer. Crit Rev Oncol Hematol 2003;46(Suppl:S3-10).
[38]	Ousset M, Van Keymeulen A, Bouvencourt G, Sharma N, Achouri Y, Simons BD, et al. Multipotent and unipotent progenitors contribute to prostate postnatal development. Nat Cell Biol 2012;14:1131-8.
[39]	Li H, Jiang M, Honorio S, Patrawala L, Jeter CR, Calhoun-Davis T, et al. Methodologies in assaying prostate cancer stem cells. Methods Mol Biol 2009;568:85-138.
[40]	Metzger D, Indra AK, Li M, Chapellier B, Calleja C, Ghyselinck NB, et al. Targeted conditional somatic mutagenesis in the mouse:temporally-controlled knock out of retinoid receptors in epidermal keratinocytes. Methods Enzymol 2003;364:379-408.
[41]	Bhatia B, Jiang M, Suraneni M, Patrawala L, Badeaux M, Schneider-Broussard R, et al. Critical and distinct roles of p16 and telomerase in regulating the proliferative life span of normal human prostate epithelial progenitor cells. J Biol Chem 2008;283:27957-72.
[42]	Verhagen PC, van Duijn PW, Hermans KG, Looijenga LH, van Gurp RJ, Stoop H, et al. The PTEN gene in locally progressive prostate cancer is preferentially inactivated by bi-allelic gene deletion. J Pathol 2006;208:699-707.
[43]	Lotan TL, Gurel B, Sutcliffe S, Esopi D, Liu W, Xu J, et al. PTEN protein loss by immunostaining:analytic validation and prognostic indicator for a high risk surgical cohort of prostate cancer patients. Clin Cancer Res 2011;17:6563-73.
[44]	Yoshimoto M, Cutz JC, Nuin PA, Joshua AM, Bayani J, Evans AJ, et al. Interphase FISH analysis of PTEN in histologic sections shows genomic deletions in 68% of primary prostate cancer and 23% of high-grade prostatic intra-epithelial neoplasias. Cancer Genet Cytogenet 2006;169:128-37.
[45]	Song MS, Salmena L, Pandolfi PP. The functions and regulation of the PTEN tumour suppressor. Nat Rev Mol Cell Biol 2012;13:283-96.
[46]	Hafsi S, Pezzino FM, Candido S, Ligresti G, Spandidos DA, Soua Z, et al. Gene alterations in the PI3K/PTEN/AKT pathway as a mechanism of drug-resistance (review). Int J Oncol 2012;40:639-44.
[47]	Chetram MA, Hinton CV. PTEN regulation of ERK1/2 signaling in cancer. J Recept Signal Transduct Res 2012;32:190-5.
[48]	Ai J, Pascal LE, O'Malley KJ, Dar JA, Isharwal S, Qiao Z, et al. Concomitant loss of EAF2/U19 and Pten synergistically promotes prostate carcinogenesis in the mouse model. Oncogene 2014;33:2286-94.
[49]	Cuzick J, Yang ZH, Fisher G, Tikishvili E, Stone S, Lanchbury JS, et al. Prognostic value of PTEN loss in men with conservatively managed localised prostate cancer. Br J Cancer 2013;108:2582-9.
[50]	Chetram MA, Odero-Marah V, Hinton CV. Loss of PTEN permits CXCR4-mediated tumorigenesis through ERK1/2 in prostate cancer cells. Mol Cancer Res 2011;9:90-102.
[51]	Qin J, Liu X, Laffin B, Chen X, Choy G, Jeter CR, et al. The PSA(-/lo) prostate cancer cell population harbors selfrenewing long-term tumor-propagating cells that resist castration. Cell Stem Cell 2012;10:556-69.
[52]	Valkenburg KC, Williams BO. Mouse models of prostate cancer. Prostate Cancer 2011;2011:895238.
[53]	Pienta KJ, Abate-Shen C, Agus DB, Attar RM, Chung LW, Greenberg NM, et al. The current state of preclinical prostate cancer animal models. Prostate 2008;68:629-39.
[54]	Lu TL, Huang YF, You LR, Chao NC, Su FY, Chang JL, et al. Conditionally ablated Pten in prostate basal cells promotes basal-to-luminal differentiation and causes invasive prostate cancer in mice. Am J Pathol 2013;182:975-91.
[55]	Metzger D, Chambon P. Site- and time-specific gene targeting in the mouse. Methods 2001;24:71-80.
[56]	Ryding AD, Sharp MG, Mullins JJ. Conditional transgenic technologies. J Endocrinol 2001;171:1-14.
[57]	Weber P, Metzger D, Chambon P. Temporally controlled targeted somatic mutagenesis in the mouse brain. Eur J Neurosci 2001;14:1777-83.
[58]	Imai T, Chambon P, Metzger D. Inducible site-specific somatic mutagenesis in mouse hepatocytes. Genesis 2000;26:147-8.
[59]	Kwan KM. Conditional alleles in mice:practical considerations for tissue-specific knockouts. Genesis 2002;32:49-62.
[60]	Gao D, Vela I, Sboner A, Iaquinta PJ, Karthaus WR, Gopalan A, et al. Organoid cultures derived from patients with advanced prostate cancer. Cell 2014;159:176-87.
[61]	Cleutjens KB, van der Korput HA, Ehren-van Eekelen CC, Sikes RA, Fasciana C, Chung LW, et al. A 6-kb promoter fragment mimics in transgenic mice the prostate-specific and androgen-regulated expression of the endogenous prostatespecific antigen gene in humans. Mol Endocrinol 1997;11:1256-65.
[62]	Indra AK, Warot X, Brocard J, Bornert JM, Xiao JH, Chambon P, et al. Temporally-controlled site-specific mutagenesis in the basal layer of the epidermis:comparison of the recombinase activity of the tamoxifen-inducible Cre-ER(T) and Cre-ER(T2) recombinases. Nucleic Acids Res 1999;27:4324-7.
[63]	Podsypanina K, Ellenson LH, Nemes A, Gu J, Tamura M, Yamada KM, et al. Mutation of Pten/Mmac1 in mice causes neoplasia in multiple organ systems. Proc Natl Acad Sci U S A 1999;96:1563-8.
[64]	Metzger D, Li M, Chambon P. Targeted somatic mutagenesis in the mouse epidermis. Methods Mol Biol 2005;289:329-40.
[65]	Feil R, Wagner J, Metzger D, Chambon P. Regulation of Cre recombinase activity by mutated estrogen receptor ligandbinding domains. Biochem Biophys Res Commun 1997;237:752-7.
[66]	Ratnacaram CK, Teletin M, Jiang M, Meng X, Chambon P, Metzger D. Temporally controlled ablation of PTEN in adult mouse prostate epithelium generates a model of invasive prostatic adenocarcinoma. Proc Natl Acad Sci U S A 2008;105:2521-6.
[67]	Liu J, Pascal LE, Isharwal S, Metzger D, Ramos Garcia R, Pilch J, et al. Regenerated luminal epithelial cells are derived from preexisting luminal epithelial cells in adult mouse prostate. Mol Endocrinol 2011;25:1849-57.
[68]	Coleman RE. Clinical features of metastatic bone disease and risk of skeletal morbidity. Clin Cancer Res 2006;12:6243se9s.
[69]	Corn PG. The tumor microenvironment in prostate cancer:elucidating molecular pathways for therapy development. Cancer Manag Res 2012;4:183-93.
[70]	Alphonso A, Alahari SK. Stromal cells and integrins:conforming to the needs of the tumor microenvironment. Neoplasia 2009;11:1264-71.
[71]	Ganguly SS, Li X, Miranti CK. The host microenvironment influences prostate cancer invasion, systemic spread, bone colonization, and osteoblastic metastasis. Front Oncol 2014; 4:364.
[72]	Kim SJ, Johnson M, Koterba K, Herynk MH, Uehara H, Gallick GE. Reduced c-Met expression by an adenovirus expressing a c-Met ribozyme inhibits tumorigenic growth and lymph node metastases of PC3-LN4 prostate tumor cells in an orthotopic nude mouse model. Clin Cancer Res 2003;9:5161e70.
[73]	Josson S, Nomura T, Lin JT, Huang WC, Wu D, Zhau HE, et al. beta2-microglobulin induces epithelial to mesenchymal transition and confers cancer lethality and bone metastasis in human cancer cells. Cancer Res 2011;71:2600e10.
[74]	Park SI, Kim SJ, McCauley LK, Gallick GE. Pre-clinical mouse models of human prostate cancer and their utility in drug discovery. Curr Protoc Pharmacol 2010[Chapter 14]:Unit 1415.
[75]	Hafeez BB, Zhong W, Fischer JW, Mustafa A, Shi X, Meske L, et al. Plumbagin, a medicinal plant (Plumbago zeylanica)-derived 1,4-naphthoquinone, inhibits growth and metastasis of human prostate cancer PC-3M-luciferase cells in an orthotopic xenograft mouse model. Mol Oncol 2013;7:428e39.
[76]	Hansen AG, Arnold SA, Jiang M, Palmer TD, Ketova T, Merkel A, et al. ALCAM/CD166 is a TGF-beta-responsive marker and functional regulator of prostate cancer metastasis to bone. Cancer Res 2014;74:1404e15.
[77]	Xiang Y, Qiu Q, Jiang M, Jin R, Lehmann BD, Strand DW, et al. SPARCL1 suppresses metastasis in prostate cancer. Mol Oncol 2013;7:1019e30.
[78]	Trevino JG, Summy JM, Lesslie DP, Parikh NU, Hong DS, Lee FY, et al. Inhibition of SRC expression and activity inhibits tumor progression and metastasis of human pancreatic adenocarcinoma cells in an orthotopic nude mouse model. Am J Pathol 2006;168:962e72.
[79]	Zhang J, Park SI, Artime MC, Summy JM, Shah AN, Bomser JA, et al. AFAP-110 is overexpressed in prostate cancer and contributes to tumorigenic growth by regulating focal contacts. J Clin Invest 2007;117:2962e73.
[80]	Park SI, Zhang J, Phillips KA, Araujo JC, Najjar AM, Volgin AY, et al. Targeting SRC family kinases inhibits growth and lymph node metastases of prostate cancer in an orthotopic nude mouse model. Cancer Res 2008;68:3323e33.
[81]	Pettaway CA, Pathak S, Greene G, Ramirez E, Wilson MR, Killion JJ, et al. Selection of highly metastatic variants of different human prostatic carcinomas using orthotopic implantation in nude mice. Clin Cancer Res 1996;2:1627e36.
[82]	Paget S. The distribution of secondary growths in cancer of the breast. Cancer Metastasis Rev 1889;1989(8):98e101.
[83]	Wang Y, Xue H, Cutz JC, Bayani J, Mawji NR, Chen WG, et al. An orthotopic metastatic prostate cancer model in SCID mice via grafting of a transplantable human prostate tumor line. Lab Invest 2005;85:1392e404.
[84]	Foster JR. Cell death and cell proliferation in the control of normal and neoplastic tissue growth. Toxicol Pathol 2000;28:441e6.
[85]	Hayward SW, Haughney PC, Rosen MA, Greulich KM, Weier HU, Dahiya R, et al. Interactions between adult human prostatic epithelium and rat urogenital sinus mesenchyme in a tissue recombination model. Differentiation 1998;63:131e40.
[86]	Hayward SW, Dahiya R, Cunha GR, Bartek J, Deshpande N, Narayan P. Establishment and characterization of an immortalized but non-transformed human prostate epithelial cell line:BPH-1. In Vitro Cell Dev Biol Anim 1995;31:14e24.
[87]	Hayward SW, Wang Y, Cao M, Hom YK, Zhang B, Grossfeld GD, et al. Malignant transformation in a nontumorigenic human prostatic epithelial cell line. Cancer Res 2001;61:8135e42.
[88]	Jiang M, Strand DW, Fernandez S, He Y, Yi Y, Birbach A, et al. Functional remodeling of benign human prostatic tissues in vivo by spontaneously immortalized progenitor and intermediate cells. Stem Cells 2010;28:344e56.
[89]	Foster BA, Gangavarapu KJ, Mathew G, Azabdaftari G, Morrison CD, Miller A, et al. Human prostate side population cells demonstrate stem cell properties in recombination with urogenital sinus mesenchyme. PLoS One 2013;8:e55062.
[90]	Xin L. Cells of origin for cancer:an updated view from prostate cancer. Oncogene 2013;32:3655e63.
[91]	Bethel CR, Faith D, Li X, Guan B, Hicks JL, Lan F, et al. Decreased NKX3.1 protein expression in focal prostatic atrophy, prostatic intraepithelial neoplasia, and adenocarcinoma:association with gleason score and chromosome 8p deletion. Cancer Res 2006;66:10683e90.
[92]	Signoretti S, Waltregny D, Dilks J, Isaac B, Lin D, Garraway L, et al. p63 is a prostate basal cell marker and is required for prostate development. Am J Pathol 2000;157:1769e75.
[93]	Korenchuk S, Lehr JE, MClean L, Lee YG, Whitney S, Vessella R, et al. VCaP, a cell-based model system of human prostate cancer. In Vivo 2001;15:163e8.
[94]	Sramkoski RM, Pretlow 2nd TG, Giaconia JM, Pretlow TP, Schwartz S, Sy MS, et al. A new human prostate carcinoma cell line, 22Rv1. In Vitro Cell Dev Biol Anim 1999;35:403e9.
[95]	Vela I, Chen Y. Prostate cancer organoids:a potential new tool for testing drug sensitivity. Expert Rev Anticancer Ther 2015;15:261e3.
[96]	Lancaster MA, Knoblich JA. Organogenesis in a dish:modeling development and disease using organoid technologies. Science 2014;345:1247125.
[97]	Sachs N, Clevers H. Organoid cultures for the analysis of cancer phenotypes. Curr Opin Genet Dev 2014;24:68e73.
[98]	Karthaus WR, Iaquinta PJ, Drost J, Gracanin A, van Boxtel R, Wongvipat J, et al. Identification of multipotent luminal progenitor cells in human prostate organoid cultures. Cell 2014;159:163e75.
[99]	Chua CW, Shibata M, Lei M, Toivanen R, Barlow LJ, Bergren SK, et al. Single luminal epithelial progenitors can generate prostate organoids in culture. Nat Cell Biol 2014;16:951e61. 951-4.
[100]	Marker PC, Donjacour AA, Dahiya R, Cunha GR. Hormonal, cellular, and molecular control of prostatic development. Dev Biol 2003;253:165e74.
[101]	Cunha GR. Mesenchymal-epithelial interactions:past, present, and future. Differentiation 2008;76:578e86.
[102]	Schwank G, Koo BK, Sasselli V, Dekkers JF, Heo I, Demircan T, et al. Functional repair of CFTR by CRISPR/Cas9 in intestinal stem cell organoids of cystic fibrosis patients. Cell Stem Cell 2013;13:653e8.
[103]	Ellwood-Yen K, Graeber TG, Wongvipat J, Iruela-Arispe ML, Zhang J, Matusik R, et al. Myc-driven murine prostate cancer shares molecular features with human prostate tumors. Cancer Cell 2003;4:223e38.
[104]	Aytes A, Mitrofanova A, Lefebvre C, Alvarez MJ, Castillo-Martin M, Zheng T, et al. Cross-species regulatory network analysis identifies a synergistic interaction between FOXM1 and CENPF that drives prostate cancer malignancy. Cancer Cell 2014;25:638e51.
[105]	Ranga A, Gjorevski N, Lutolf MP. Drug discovery through stem cell-based organoid models. Adv Drug Deliv Rev 2014;69e70:19e28.
[106]	Phillips R. Innovation:organoids-a better model for prostate cancer. Nat Rev Urol 2014;11:604.
[107]	Lin D, Wyatt AW, Xue H, Wang Y, Dong X, Haegert A, et al. High fidelity patient-derived xenografts for accelerating prostate cancer discovery and drug development. Cancer Res 2014;74:1272e83.
[108]	Johnson JI, Decker S, Zaharevitz D, Rubinstein LV, Venditti JM, Schepartz S, et al. Relationships between drug activity in NCI preclinical in vitro and in vivo models and early clinical trials. Br J Cancer 2001;84:1424e31.
[109]	Choi SY, Lin D, Gout PW, Collins CC, Xu Y, Wang Y. Lessons from patient-derived xenografts for better in vitro modeling of human cancer. Adv Drug Deliv Rev 2014;79e80:222e37.
[110]	Raheem O, Kulidjian AA, Wu C, Jeong YB, Yamaguchi T, Smith KM, 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 2011;9:185.
[111]	Tentler JJ, Tan AC, Weekes CD, Jimeno A, Leong S, Pitts TM, et al. Patient-derived tumour xenografts as models for oncology drug development. Nat Rev Clin Oncol 2012;9:338e50.
[112]	Gray DR, Huss WJ, Yau JM, Durham LE, Werdin ES, Funkhouser Jr WK, et al. Short-term human prostate primary xenografts:an in vivo model of human prostate cancer vasculature and angiogenesis. Cancer Res 2004;64:1712e21.
[113]	Toivanen R, Frydenberg M, Murphy D, Pedersen J, Ryan A, Pook D, et al. A preclinical xenograft model identifies castration-tolerant cancer-repopulating cells in localized prostate tumors. Sci Transl Med 2013;5. 187ra171.
[114]	Yoshida T, Kinoshita H, Segawa T, Nakamura E, Inoue T, Shimizu Y, et al. Antiandrogen bicalutamide promotes tumor growth in a novel androgen-dependent prostate cancer xenograft model derived from a bicalutamide-treated patient. Cancer Res 2005;65:9611e6.
[115]	Garber K. From human to mouse and back:‘tumorgraft’ models surge in popularity. J Natl Cancer Inst 2009;101:6e8.
[116]	Daniel VC, Marchionni L, Hierman JS, Rhodes JT, Devereux WL, Rudin CM, et al. A primary xenograft model of small-cell lung cancer reveals irreversible changes in gene expression imposed by culture. In Vitro Cancer Res 2009;69:3364e73.
[117]	Zhang X, Claerhout S, Prat A, Dobrolecki LE, Petrovic I, Lai Q, et al. A renewable tissue resource of phenotypically stable, biologically and ethnically diverse, patient-derived human breast cancer xenograft models. Cancer Res 2013;73:4885e97.
[118]	Bertotti A, Migliardi G, Galimi F, Sassi F, Torti D, Isella C, et al. A molecularly annotated platform of patient-derived xenografts ("xenopatients") identifies HER2 as an effective therapeutic target in cetuximab-resistant colorectal cancer. Cancer Discov 2011;1:508e23.
[119]	Fichtner I, Rolff J, Soong R, Hoffmann J, Hammer S, Sommer A, et al. Establishment of patient-derived non-small cell lung cancer xenografts as models for the identification of predictive biomarkers. Clin Cancer Res 2008;14:6456e68.
[120]	DeRose YS, Wang G, Lin YC, Bernard PS, Buys SS, Ebbert MT, et al. Tumor grafts derived from women with breast cancer authentically reflect tumor pathology, growth, metastasis and disease outcomes. Nat Med 2011;17:1514e20.
[121]	Reyal F, Guyader C, Decraene C, Lucchesi C, Auger N, Assayag F, et al. Molecular profiling of patient-derived breast cancer xenografts. Breast Cancer Res 2012;14:R11.
[122]	McEvoy J, Ulyanov A, Brennan R, Wu G, Pounds S, Zhang J, et al. Analysis of MDM2 and MDM4 single nucleotide polymorphisms, mRNA splicing and protein expression in retinoblastoma. PLoS One 2012;7:e42739.
[123]	Krumbach R, Schuler J, Hofmann M, Giesemann T, Fiebig HH, Beckers T. Primary resistance to cetuximabina panel of patientderived tumour xenograft models:activation of MET as one mechanismfor drug resistance. Eur J Cancer 2011;47:1231e43.
[124]	Hidalgo M, Bruckheimer E, Rajeshkumar NV, Garrido-Laguna I, De Oliveira E, Rubio-Viqueira B, et al. A pilot clinical study of treatment guided by personalized tumorgrafts in patients with advanced cancer. Mol Cancer Ther 2011;10:1311e6.
[125]	Bernards R. A missing link in genotype-directed cancer therapy. Cell 2012;151:465e8.
[126]	Sato T, Stange DE, Ferrante M, Vries RG, Van Es JH, Van den Brink S, et al. Long-term expansion of epithelial organoids from human colon, adenoma, adenocarcinoma, and Barrett's epithelium. Gastroenterology 2011;141:1762e72.
[127]	Russell PJ, Russell P, Rudduck C, Tse BW, Williams ED, Raghavan D. Establishing prostate cancer patient derived xenografts:lessons learned from older studies. Prostate 2015;75:628e36.
[128]	Zhao H, Nolley R, Chen Z, Peehl DM. Tissue slice grafts:an in vivo model of human prostate androgen signaling. Am J Pathol 2010;177:229e39.
[129]	Conway T, Wazny J, Bromage A, Tymms M, Sooraj D, Williams ED, et al. Xenomeea tool for classifying reads from xenograft samples. Bioinformatics 2012;28:i172e8.
[130]	Li ZG, Mathew P, Yang J, Starbuck MW, Zurita AJ, Liu J, et al. Androgen receptor-negative human prostate cancer cells induce osteogenesis in mice through FGF9-mediated mechanisms. J Clin Invest 2008;118:2697e710.
[131]	Fong EL, Martinez M, Yang J, Mikos AG, Navone NM, Harrington DA, et al. Hydrogel-based 3D model of patientderived prostate xenograft tumors suitable for drug screening. Mol Pharm 2014;11:2040e50.
[132]	Li X, Liu Z, Xu X, Blair CA, Sun Z, Xie J, et al. Kava components down-regulate expression of AR and AR splice variants and reduce growth in patient-derived prostate cancer xenografts in mice. PLoS One 2012;7:e31213.
[133]	Wang Y, Revelo MP, Sudilovsky D, Cao M, Chen WG, Goetz L, et al. Development and characterization of efficient xenograft models for benign and malignant human prostate tissue. Prostate 2005;64:149e59.
[134]	Caponigro G, Sellers WR. Advances in the preclinical testing of cancer therapeutic hypotheses. Nat Rev Drug Discov 2011; 10:179e87.
[135]	Shultz LD, Lyons BL, Burzenski LM, Gott B, Chen X, Chaleff S, et al. Human lymphoid and myeloid cell development in NOD/LtSz-scid IL2R gamma null mice engrafted with mobilized human hemopoietic stem cells. J Immunol 2005;174:6477e89.
[136]	Rongvaux A, Willinger T, Martinek J, Strowig T, Gearty SV, Teichmann LL, et al. Development and function of human innate immune cells in a humanized mouse model. Nat Biotechnol 2014;32:364e72.
[137]	Siolas D, Hannon GJ. Patient-derived tumor xenografts:transforming clinical samples into mouse models. Cancer Res 2013;73:5315e9.
[138]	Hidalgo M, Amant F, Biankin AV, Budinska E, Byrne AT, Caldas C, et al. Patient-derived xenograft models:an emerging platform for translational cancer research. Cancer Discov 2014;4:998e1013.
[139]	Klein KA, Reiter RE, Redula J, Moradi H, Zhu XL, Brothman AR, et al. Progression of metastatic human prostate cancer to androgen independence in immunodeficient SCID mice. Nat Med 1997;3:402e8.
[140]	Ittmann M, Huang J, Radaelli E, Martin P, Signoretti S, Sullivan R, et al. Animal models of human prostate cancer:the consensus report of the New York meeting of the mouse models of human Cancers Consortium prostate pathology Committee. Cancer Res 2013;73:2718e36.