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Experimental in vitro, ex vivo and in vivo models in prostate cancer research

Abstract

Androgen deprivation therapy has a central role in the treatment of advanced prostate cancer, often causing initial tumour remission before increasing independence from signal transduction mechanisms of the androgen receptor and then eventual disease progression. Novel treatment approaches are urgently needed, but only a fraction of promising drug candidates from the laboratory will eventually reach clinical approval, highlighting the demand for critical assessment of current preclinical models. Such models include standard, genetically modified and patient-derived cell lines, spheroid and organoid culture models, scaffold and hydrogel cultures, tissue slices, tumour xenograft models, patient-derived xenograft and circulating tumour cell eXplant models as well as transgenic and knockout mouse models. These models need to account for inter-patient and intra-patient heterogeneity, the acquisition of primary or secondary resistance, the interaction of tumour cells with their microenvironment, which make crucial contributions to tumour progression and resistance, as well as the effects of the 3D tissue network on drug penetration, bioavailability and efficacy.

Key points

  • Ideally, tumour models will reflect inter-patient and intra-patient heterogeneity, primary and/or secondary resistance, the interaction of tumour cells with their microenvironment, and the effects of the 3D tissue architecture on drug penetration, bioavailability and efficacy.

  • Various in vitro, ex vivo and in vivo models exist, each associated with defined advantages and disadvantages.

  • In vitro and ex vivo models include standard, genetically modified and patient-derived cell lines, spheroid and organoid culture models, scaffold and hydrogel cultures, and tissue slice models.

  • In vivo models — including tumour xenografts, patient-derived xenografts and circulating tumour cell eXplant models, as well as transgenic and knockout mouse models — are still indispensable for prostate cancer research.

  • Successful experimental prostate cancer research will require exploration of the full complexity of the disease, relying on the combined use of the broad spectrum of models.

  • Novel approaches will be required for holistic and sophisticated analyses, for example, characterizations at a single-cell level in vivo or the extensive integration of computational and/or artificial intelligence-based approaches.

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Fig. 1: Cellular properties and molecular hallmarks of prostate cancer.
Fig. 2: Overview of various models in prostate cancer research.
Fig. 3: Examples of prostate cancer research, based on the combined use of different models.

References

  1. Siegel, R. L., Miller, K. D. & Jemal, A. Cancer statistics, 2020. CA Cancer J. Clin. 70, 7–30 (2020).

    Article  PubMed  Google Scholar 

  2. Rebello, R. J. et al. Prostate cancer. Nat. Rev. Dis. Primers 7, 9 (2021).

    Article  PubMed  Google Scholar 

  3. Siegel, R. L., Miller, K. D. & Jemal, A. Cancer statistics, 2018. CA Cancer J. Clin. 68, 7–30 (2018).

    Article  PubMed  Google Scholar 

  4. Yamada, Y. & Beltran, H. The treatment landscape of metastatic prostate cancer. Cancer Lett. 519, 20–29 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Antonarakis, E. S., Gomella, L. G. & Petrylak, D. P. When and how to use PARP inhibitors in prostate cancer: a systematic review of the literature with an update on on-going trials. Eur. Urol. Oncol. 3, 594–611 (2020).

    Article  PubMed  Google Scholar 

  6. Sartor, O. et al. Lutetium-177-PSMA-617 for metastatic castration-resistant prostate cancer. N. Engl. J. Med. 385, 1091–1103 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Litwin, M. S. & Tan, H. J. The diagnosis and treatment of prostate cancer: a review. JAMA 317, 2532–2542 (2017).

    Article  PubMed  Google Scholar 

  8. Ali, A. et al. Prostate zones and cancer: lost in transition? Nat. Rev. Urol. 19, 101–115 (2022).

    Article  PubMed  Google Scholar 

  9. Kumar, A. et al. Substantial interindividual and limited intraindividual genomic diversity among tumors from men with metastatic prostate cancer. Nat. Med. 22, 369–378 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Cancer Genome Atlas Research Network. The molecular taxonomy of primary prostate cancer. Cell 163, 1011–1025 (2015).

    Article  Google Scholar 

  11. Tomlins, S. A. et al. Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer. Science 310, 644–648 (2005).

    Article  CAS  PubMed  Google Scholar 

  12. Clark, J. et al. Complex patterns of ETS gene alteration arise during cancer development in the human prostate. Oncogene 27, 1993–2003 (2008).

    Article  CAS  PubMed  Google Scholar 

  13. Clark, J. P. & Cooper, C. S. ETS gene fusions in prostate cancer. Nat. Rev. Urol. 6, 429–439 (2009).

    Article  CAS  PubMed  Google Scholar 

  14. Espiritu, S. M. G. et al. The evolutionary landscape of localized prostate cancers drives clinical aggression. Cell 173, 1003–1013.e1015 (2018).

    Article  CAS  PubMed  Google Scholar 

  15. Salami, S. S. et al. Transcriptomic heterogeneity in multifocal prostate cancer. JCI Insight 3, e123468 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  16. Falzarano, S. M. et al. ERG rearrangement is present in a subset of transition zone prostatic tumors. Mod. Pathol. 23, 1499–1506 (2010).

    Article  PubMed  Google Scholar 

  17. Varma, M., Shah, R. B., Williamson, S. R. & Berney, D. M. 2019 Gleason grading recommendations from ISUP and GUPS: broadly concordant but with significant differences. Virchows Arch. 478, 813–815 (2021).

    Article  PubMed  Google Scholar 

  18. Rubin, M. A., Girelli, G. & Demichelis, F. Genomic correlates to the newly proposed grading prognostic groups for prostate cancer. Eur. Urol. 69, 557–560 (2016).

    Article  PubMed  Google Scholar 

  19. Wilkinson, S. et al. Nascent prostate cancer heterogeneity drives evolution and resistance to intense hormonal therapy. Eur. Urol. 80, 746–757 (2021).

    Article  CAS  PubMed  Google Scholar 

  20. Aggarwal, R. et al. Clinical and genomic characterization of treatment-emergent small-cell neuroendocrine prostate cancer: a multi-institutional prospective study. J. Clin. Oncol. 36, 2492–2503 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Robinson, D. et al. Integrative clinical genomics of advanced prostate cancer. Cell 161, 1215–1228 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Binnewies, M. et al. Understanding the tumor immune microenvironment (TIME) for effective therapy. Nat. Med. 24, 541–550 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Hofbauer, L. C. et al. Novel approaches to target the microenvironment of bone metastasis. Nat. Rev. Clin. Oncol. 18, 488–505 (2021).

    Article  PubMed  Google Scholar 

  24. Garon, E. B. et al. Pembrolizumab for the treatment of non-small-cell lung cancer. N. Engl. J. Med. 372, 2018–2028 (2015).

    Article  PubMed  Google Scholar 

  25. Robert, C. et al. Pembrolizumab versus ipilimumab in advanced melanoma. N. Engl. J. Med. 372, 2521–2532 (2015).

    Article  CAS  PubMed  Google Scholar 

  26. Abida, W. et al. Analysis of the prevalence of microsatellite instability in prostate cancer and response to immune checkpoint blockade. JAMA Oncol. 5, 471–478 (2019).

    Article  PubMed  Google Scholar 

  27. van Bokhoven, A. et al. Molecular characterization of human prostate carcinoma cell lines. Prostate 57, 205–225 (2003).

    Article  PubMed  Google Scholar 

  28. Russell, P. J. & Kingsley, E. A. Human prostate cancer cell lines. Methods Mol. Med. 81, 21–39 (2003).

    CAS  PubMed  Google Scholar 

  29. van Weerden, W. M., Bangma, C. & de Wit, R. Human xenograft models as useful tools to assess the potential of novel therapeutics in prostate cancer. Br. J. Cancer 100, 13–18 (2009).

    Article  PubMed  Google Scholar 

  30. Namekawa, T., Ikeda, K., Horie-Inoue, K. & Inoue, S. Application of prostate cancer models for preclinical study: advantages and limitations of cell lines, patient-derived xenografts, and three-dimensional culture of patient-derived cells. Cells 8, 74 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Young, S. R. et al. Establishment and serial passage of cell cultures derived from LuCaP xenografts. Prostate 73, 1251–1262 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  34. 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).

    CAS  PubMed  Google Scholar 

  35. 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).

    CAS  PubMed  Google Scholar 

  36. van Bokhoven, A., Varella-Garcia, M., Korch, C., Hessels, D. & Miller, G. J. Widely used prostate carcinoma cell lines share common origins. Prostate 47, 36–51 (2001).

    Article  PubMed  Google Scholar 

  37. van Bokhoven, A., Varella-Garcia, M., Korch, C. & Miller, G. J. TSU-Pr1 and JCA-1 cells are derivatives of T24 bladder carcinoma cells and are not of prostatic origin. Cancer Res. 61, 6340–6344 (2001).

    PubMed  Google Scholar 

  38. Rubin, M. A. et al. Rapid (“warm”) autopsy study for procurement of metastatic prostate cancer. Clin. Cancer Res. 6, 1038–1045 (2000).

    CAS  PubMed  Google Scholar 

  39. Lee, Y. G. et al. Establishment and characterization of a new human prostatic cancer cell line: DuCaP. Vivo 15, 157–162 (2001).

    CAS  Google Scholar 

  40. Korenchuk, S. et al. VCaP, a cell-based model system of human prostate cancer. Vivo 15, 163–168 (2001).

    CAS  Google Scholar 

  41. Sfanos, K. S. et al. Identification of replication competent murine gammaretroviruses in commonly used prostate cancer cell lines. PLoS ONE 6, e20874 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Griffiths, J. C. The laboratory diagnosis of prostatic adenocarcinoma. Crit. Rev. Clin. Lab. Sci. 19, 187–204 (1983).

    Article  CAS  PubMed  Google Scholar 

  43. Moch, H., Humphrey, P. A., Ulbright, T. M. & Reuter, V. WHO Classification of Tumours of the Urinary System and Male Genital Organs. (International Agency for Research on Cancer, 2016).

  44. Merkens, L. et al. Aggressive variants of prostate cancer: underlying mechanisms of neuroendocrine transdifferentiation. J. Exp. Clin. Cancer Res. 41, 46 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Grossman, H. B., Wedemeyer, G., Ren, L. & Carey, T. E. UM-SCP-1, a new human cell line derived from a prostatic squamous cell carcinoma. Cancer Res. 44, 4111–4117 (1984).

    CAS  PubMed  Google Scholar 

  46. Kim, C. J., Kushima, R., Okada, Y. & Seto, A. Establishment and characterization of a prostatic small-cell carcinoma cell line (PSK-1) derived from a patient with Klinefelter syndrome. Prostate 42, 287–294 (2000).

    Article  CAS  PubMed  Google Scholar 

  47. Okasho, K. et al. Establishment and characterization of a novel treatment-related neuroendocrine prostate cancer cell line KUCaP13. Cancer Sci. 112, 2781–2791 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Steinestel, J. et al. Detecting predictive androgen receptor modifications in circulating prostate cancer cells. Oncotarget 10, 4213–4223 (2019).

    Article  PubMed  Google Scholar 

  49. Jividen, K. et al. Genomic analysis of DNA repair genes and androgen signaling in prostate cancer. BMC Cancer 18, 960 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Cornford, P. et al. EAU-EANM-ESTRO-ESUR-SIOG Guidelines on Prostate Cancer. Part II-2020 Update: treatment of relapsing and metastatic prostate cancer. Eur. Urol. 79, 263–282 (2021).

    Article  CAS  PubMed  Google Scholar 

  51. Teroerde, M. et al. in Prostate Cancer [internet] (eds Bott, S. R. J. & Ng, K. L.) (Exon Publications, 2021).

  52. Perryman, L. A. et al. Over-expression of p53 mutants in LNCaP cells alters tumor growth and angiogenesis in vivo. Biochem. Biophys. Res. Commun. 345, 1207–1214 (2006).

    Article  CAS  PubMed  Google Scholar 

  53. Lee, J. K. et al. N-Myc drives neuroendocrine prostate cancer initiated from human prostate epithelial cells. Cancer Cell 29, 536–547 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Souza, A. G. et al. Comparative assay of 2D and 3D cell culture models: proliferation, gene expression and anticancer drug response. Curr. Pharm. Des. 24, 1689–1694 (2018).

    Article  CAS  PubMed  Google Scholar 

  55. Sutherland, R. M. Cell and environment interactions in tumor microregions: the multicell spheroid model. Science 240, 177–184 (1988).

    Article  CAS  PubMed  Google Scholar 

  56. Dietrichs, D. et al. Three-dimensional growth of prostate cancer cells exposed to simulated microgravity. Front. Cell Dev. Biol. 10, 841017 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  57. Grimm, D. et al. The fight against cancer by microgravity: the multicellular spheroid as a metastasis model. Int. J. Mol. Sci. 23, 3073 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Fontana, F. et al. Three-dimensional cell cultures as an in vitro tool for prostate cancer modeling and drug discovery. Int. J. Mol. Sci. 21, 6806 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Foty, R. A simple hanging drop cell culture protocol for generation of 3D spheroids. J. Vis. Exp. https://doi.org/10.3791/2720 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  60. Hagemann, J. et al. Spheroid-based 3D cell cultures enable personalized therapy testing and drug discovery in head and neck cancer. Anticancer. Res. 37, 2201–2210 (2017).

    Article  CAS  PubMed  Google Scholar 

  61. Halfter, K. et al. Prospective cohort study using the breast cancer spheroid model as a predictor for response to neoadjuvant therapy–the SpheroNEO study. BMC Cancer 15, 519 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  62. Bray, L. J., Hutmacher, D. W. & Bock, N. Addressing patient specificity in the engineering of tumor models. Front. Bioeng. Biotechnol. 7, 217 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  63. Gillet, J. P., Varma, S. & Gottesman, M. M. The clinical relevance of cancer cell lines. J. Natl Cancer Inst. 105, 452–458 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Ingram, M. et al. Tissue engineered tumor models. Biotech. Histochem. 85, 213–229 (2010).

    Article  CAS  PubMed  Google Scholar 

  65. Hsiao, A. Y. et al. Microfluidic system for formation of PC-3 prostate cancer co-culture spheroids. Biomaterials 30, 3020–3027 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Bansal, N. et al. BMI-1 Targeting interferes with patient-derived tumor-initiating cell survival and tumor growth in prostate cancer. Clin. Cancer Res. 22, 6176–6191 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Bansal, N. et al. Enrichment of human prostate cancer cells with tumor initiating properties in mouse and zebrafish xenografts by differential adhesion. Prostate 74, 187–200 (2014).

    Article  CAS  PubMed  Google Scholar 

  68. Linxweiler, J. et al. Patient-derived, three-dimensional spheroid cultures provide a versatile translational model for the study of organ-confined prostate cancer. J. Cancer Res. Clin. Oncol. 145, 551–559 (2019).

    Article  CAS  PubMed  Google Scholar 

  69. Jouberton, E., Voissiere, A., Penault-Llorca, F., Cachin, F. & Miot-Noirault, E. Multicellular tumor spheroids of LNCaP-Luc prostate cancer cells as in vitro screening models for cytotoxic drugs. Am. J. Cancer Res. 12, 1116–1128 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Gao, D. et al. Organoid cultures derived from patients with advanced prostate cancer. Cell 159, 176–187 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Cheaito, K. et al. Establishment and characterization of prostate organoids from treatment-naïve patients with prostate cancer. Oncol. Lett. 23, 6 (2022).

    Article  CAS  PubMed  Google Scholar 

  72. Drost, J. et al. Organoid culture systems for prostate epithelial and cancer tissue. Nat. Protoc. 11, 347–358 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Pauli, C. et al. Personalized in vitro and in vivo cancer models to guide precision medicine. Cancer Discov. 7, 462–477 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  74. Kamatar, A., Gunay, G. & Acar, H. Natural and synthetic biomaterials for engineering multicellular tumor spheroids. Polymers 12, 2506 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Van Hemelryk, A. et al. Modeling prostate cancer treatment responses in the organoid era: 3D environment impacts drug testing. Biomolecules 11, 1572 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Bray, L. J. et al. Multi-parametric hydrogels support 3D in vitro bioengineered microenvironment models of tumour angiogenesis. Biomaterials 53, 609–620 (2015).

    Article  CAS  PubMed  Google Scholar 

  78. Furesi, G., Rauner, M. & Hofbauer, L. C. Emerging players in prostate cancer-bone Niche communication. Trends Cancer 7, 112–121 (2021).

    Article  CAS  PubMed  Google Scholar 

  79. Shokoohmand, A. et al. Microenvironment engineering of osteoblastic bone metastases reveals osteomimicry of patient-derived prostate cancer xenografts. Biomaterials 220, 119402 (2019).

    Article  CAS  PubMed  Google Scholar 

  80. Bock, N. et al. Engineering osteoblastic metastases to delineate the adaptive response of androgen-deprived prostate cancer in the bone metastatic microenvironment. Bone Res. 7, 13 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  81. Bock, N. et al. In vitro engineering of a bone metastases model allows for study of the effects of antiandrogen therapies in advanced prostate cancer. Sci. Adv. 7, eabg2564 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Pereira, B. A. et al. Tissue engineered human prostate microtissues reveal key role of mast cell-derived tryptase in potentiating cancer-associated fibroblast (CAF)-induced morphometric transition in vitro. Biomaterials 197, 72–85 (2019).

    Article  CAS  PubMed  Google Scholar 

  83. Merz, L. et al. Tumor tissue slice cultures as a platform for analyzing tissue-penetration and biological activities of nanoparticles. Eur. J. Pharm. Biopharm. 112, 45–50 (2017).

    Article  CAS  PubMed  Google Scholar 

  84. Perez, L. M. & Nonn, L. Harnessing the utility of ex vivo patient prostate tissue slice cultures. Front. Oncol. 12, 864723 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  85. Zhao, H. et al. Patient-derived tissue slice grafts accurately depict response of high-risk primary prostate cancer to androgen deprivation therapy. J. Transl. Med. 11, 199 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  86. Figiel, S. et al. Functional organotypic cultures of prostate tissues: a relevant preclinical model that preserves hypoxia sensitivity and calcium signaling. Am. J. Pathol. 189, 1268–1275 (2019).

    Article  CAS  PubMed  Google Scholar 

  87. van de Merbel, A. F. et al. An ex vivo tissue culture model for the assessment of individualized drug responses in prostate and bladder cancer. Front. Oncol. 8, 400 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  88. Zhang, W. et al. Ex vivo treatment of prostate tumor tissue recapitulates in vivo therapy response. Prostate 79, 390–402 (2019).

    Article  CAS  PubMed  Google Scholar 

  89. Gerlach, M. M. et al. Slice cultures from head and neck squamous cell carcinoma: a novel test system for drug susceptibility and mechanisms of resistance. Br. J. Cancer 110, 479–488 (2014).

    Article  CAS  PubMed  Google Scholar 

  90. Koerfer, J. et al. Organotypic slice cultures of human gastric and esophagogastric junction cancer. Cancer Med. 5, 1444–1453 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Sonnichsen, R. et al. Individual susceptibility analysis using patient-derived slice cultures of colorectal carcinoma. Clin. Colorectal Cancer 17, e189–e199 (2018).

    Article  PubMed  Google Scholar 

  92. Merz, F. et al. Organotypic slice cultures of human glioblastoma reveal different susceptibilities to treatments. Neuro Oncol. 15, 670–681 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Chakrabarty, S. et al. A microfluidic cancer-on-chip platform predicts drug response using organotypic tumor slice culture. Cancer Res. 82, 510–520 (2021).

    Article  PubMed  Google Scholar 

  94. Astolfi, M. et al. Micro-dissected tumor tissues on chip: an ex vivo method for drug testing and personalized therapy. Lab Chip 16, 312–325 (2016).

    Article  CAS  PubMed  Google Scholar 

  95. Dorrigiv, D. et al. Microdissected tissue vs tissue slices-a comparative study of tumor explant models cultured on-chip and off-chip. Cancers 13, 4208 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Kashaninejad, N. et al. Organ-tumor-on-a-chip for chemosensitivity assay: a critical review. Micromachines 7, 130 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  97. Pandya, H. J. et al. A microfluidic platform for drug screening in a 3D cancer microenvironment. Biosens. Bioelectron. 94, 632–642 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Kunzi-Rapp, K. et al. Chorioallantoic membrane assay: vascularized 3-dimensional cell culture system for human prostate cancer cells as an animal substitute model. J. Urol. 166, 1502–1507 (2001).

    Article  CAS  PubMed  Google Scholar 

  99. Wu, X., Gong, S., Roy-Burman, P., Lee, P. & Culig, Z. Current mouse and cell models in prostate cancer research. Endocr. Relat. Cancer 20, R155–R170 (2013).

    Article  CAS  PubMed  Google Scholar 

  100. Chung, L. W. et al. Co-inoculation of tumorigenic rat prostate mesenchymal cells with non-tumorigenic epithelial cells results in the development of carcinosarcoma in syngeneic and athymic animals. Int. J. Cancer 43, 1179–1187 (1989).

    Article  CAS  PubMed  Google Scholar 

  101. Li, Y. et al. Decrease in stromal androgen receptor associates with androgen-independent disease and promotes prostate cancer cell proliferation and invasion. J. Cell Mol. Med. 12, 2790–2798 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Craig, M., Ying, C. & Loberg, R. D. Co-inoculation of prostate cancer cells with U937 enhances tumor growth and angiogenesis in vivo. J. Cell Biochem. 103, 1–8 (2008).

    Article  CAS  PubMed  Google Scholar 

  103. Aigner, A. et al. Ribozyme-targeting of a secreted FGF-binding protein (FGF-BP) inhibits proliferation of prostate cancer cells in vitro and in vivo. Oncogene 21, 5733–5742 (2002).

    Article  CAS  PubMed  Google Scholar 

  104. Klink, J. C. et al. Resveratrol worsens survival in SCID mice with prostate cancer xenografts in a cell-line specific manner, through paradoxical effects on oncogenic pathways. Prostate 73, 754–762 (2013).

    Article  CAS  PubMed  Google Scholar 

  105. Chen, Q. H. Curcumin-based anti-prostate cancer agents. Anticancer. Agents Med. Chem. 15, 138–156 (2015).

    Article  CAS  PubMed  Google Scholar 

  106. Jin, X. et al. DUB3 promotes BET inhibitor resistance and cancer progression by deubiquitinating BRD4. Mol. Cell 71, 592–605.e594 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Metzger, E. et al. KMT9 monomethylates histone H4 lysine 12 and controls proliferation of prostate cancer cells. Nat. Struct. Mol. Biol. 26, 361–371 (2019).

    Article  CAS  PubMed  Google Scholar 

  108. Voskoglou-Nomikos, T., Pater, J. L. & Seymour, L. Clinical predictive value of the in vitro cell line, human xenograft, and mouse allograft preclinical cancer models. Clin. Cancer Res. 9, 4227–4239 (2003).

    PubMed  Google Scholar 

  109. Yin, Z. et al. Current research developments of patient-derived tumour xenograft models (Review). Exp. Ther. Med. 22, 1206 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Xin, L., Ide, H., Kim, Y., Dubey, P. & Witte, O. N. In vivo regeneration of murine prostate from dissociated cell populations of postnatal epithelia and urogenital sinus mesenchyme. Proc. Natl Acad. Sci. USA 100, 11896–11903 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. 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).

    Article  PubMed  Google Scholar 

  112. Liao, C. P., Adisetiyo, H., Liang, M. & Roy-Burman, P. Cancer-associated fibroblasts enhance the gland-forming capability of prostate cancer stem cells. Cancer Res. 70, 7294–7303 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Wang, X. et al. A luminal epithelial stem cell that is a cell of origin for prostate cancer. Nature 461, 495–500 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Stephenson, R. A. et al. Metastatic model for human prostate cancer using orthotopic implantation in nude mice. J. Natl Cancer Inst. 84, 951–957 (1992).

    Article  CAS  PubMed  Google Scholar 

  115. Jäger, W. et al. Orthotopic mouse models of urothelial cancer. Methods Mol. Biol. 1655, 177–197 (2018).

    Article  PubMed  Google Scholar 

  116. Singh, A. S. & Figg, W. D. In vivo models of prostate cancer metastasis to bone. J. Urol. 174, 820–826 (2005).

    Article  PubMed  Google Scholar 

  117. Parajuli, K. R., Zhang, Q., Liu, S. & You, Z. Aminomethylphosphonic acid inhibits growth and metastasis of human prostate cancer in an orthotopic xenograft mouse model. Oncotarget 7, 10616–10626 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  118. Hoffman, R. M. Orthotopic metastatic (MetaMouse) models for discovery and development of novel chemotherapy. Methods Mol. Med. 111, 297–322 (2005).

    CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. 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).

    CAS  PubMed  Google Scholar 

  121. 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).

    CAS  PubMed  Google Scholar 

  122. Patel, B. J. et al. CL1-GFP: an androgen independent metastatic tumor model for prostate cancer. J. Urol. 164, 1420–1425 (2000).

    Article  CAS  PubMed  Google Scholar 

  123. Duan, Z. et al. Th17 cells promote tumor growth in an immunocompetent orthotopic mouse model of prostate cancer. Am. J. Clin. Exp. Urol. 7, 249–261 (2019).

    PubMed  PubMed Central  Google Scholar 

  124. Lardizabal, J., Ding, J., Delwar, Z., Rennie, P. S. & Jia, W. A TRAMP-derived orthotopic prostate syngeneic (TOPS) cancer model for investigating anti-tumor treatments. Prostate 78, 457–468 (2018).

    Article  CAS  PubMed  Google Scholar 

  125. Anker, J. F., Mok, H., Naseem, A. F., Thumbikat, P. & Abdulkadir, S. A. A bioluminescent and fluorescent orthotopic syngeneic murine model of androgen-dependent and castration-resistant prostate cancer. J. Vis. Exp. https://doi.org/10.3791/57301 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  126. Lange, T. et al. Development and characterization of a spontaneously metastatic patient-derived xenograft model of human prostate cancer. Sci. Rep. 8, 17535 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  127. Shi, M., Wang, Y., Lin, D. & Wang, Y. Patient-derived xenograft models of neuroendocrine prostate cancer. Cancer Lett. 525, 160–169 (2022).

    Article  CAS  PubMed  Google Scholar 

  128. Rea, D. et al. Mouse models in prostate cancer translational research: from xenograft to PDX. Biomed. Res. Int. 2016, 9750795 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  129. van Weerden, W. M. et al. Development of seven new human prostate tumor xenograft models and their histopathological characterization. Am. J. Pathol. 149, 1055–1062 (1996).

    PubMed  PubMed Central  Google Scholar 

  130. Palanisamy, N. et al. The MD Anderson prostate cancer patient-derived xenograft series (MDA PCa PDX) captures the molecular landscape of prostate cancer and facilitates marker-driven therapy development. Clin. Cancer Res. 26, 4933–4946 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Risbridger, G. P. et al. The MURAL collection of prostate cancer patient-derived xenografts enables discovery through preclinical models of uro-oncology. Nat. Commun. 12, 5049 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Evrard, Y. A. et al. Systematic establishment of robustness and standards in patient-derived xenograft experiments and analysis. Cancer Res. 80, 2286–2297 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  134. Marques, R. B. et al. High efficacy of combination therapy using PI3K/AKT inhibitors with androgen deprivation in prostate cancer preclinical models. Eur. Urol. 67, 1177–1185 (2015).

    Article  CAS  PubMed  Google Scholar 

  135. Varkaris, A. et al. Integrating murine and clinical trials with cabozantinib to understand roles of MET and VEGFR2 as targets for growth inhibition of prostate cancer. Clin. Cancer Res. 22, 107–121 (2016).

    Article  CAS  PubMed  Google Scholar 

  136. Hammer, S. et al. Preclinical efficacy of a PSMA-targeted thorium-227 conjugate (PSMA-TTC), a targeted alpha therapy for prostate cancer. Clin. Cancer Res. 26, 1985–1996 (2020).

    Article  CAS  PubMed  Google Scholar 

  137. Ben-David, U. et al. Patient-derived xenografts undergo mouse-specific tumor evolution. Nat. Genet. 49, 1567–1575 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Woo, X. Y. et al. Conservation of copy number profiles during engraftment and passaging of patient-derived cancer xenografts. Nat. Genet. 53, 86–99 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Verma, B., Ritchie, M. & Mancini, M. Development and applications of patient-derived xenograft models in humanized mice for oncology and immune-oncology drug discovery. Curr. Protoc. Pharmacol. 78, 14.41.11–14.41.12 (2017).

    Article  Google Scholar 

  140. Shultz, L. D., Brehm, M. A., Garcia-Martinez, J. V. & Greiner, D. L. Humanized mice for immune system investigation: progress, promise and challenges. Nat. Rev. Immunol. 12, 786–798 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. 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).

    Article  PubMed  PubMed Central  Google Scholar 

  142. Valta, M. et al. Critical evaluation of the subcutaneous engraftments of hormone naïve primary prostate cancer. Transl. Androl. Urol. 9, 1120–1134 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  143. Liu, G. et al. Perturbation of NK cell peripheral homeostasis accelerates prostate carcinoma metastasis. J. Clin. Invest. 123, 4410–4422 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Alix-Panabières, C. & Pantel, K. Liquid biopsy: from discovery to clinical application. Cancer Discov. 11, 858–873 (2021).

    Article  PubMed  Google Scholar 

  145. Faugeroux, V. et al. Genetic characterization of a unique neuroendocrine transdifferentiation prostate circulating tumor cell-derived eXplant model. Nat. Commun. 11, 1884 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Keller, L. & Pantel, K. Unravelling tumour heterogeneity by single-cell profiling of circulating tumour cells. Nat. Rev. Cancer 19, 553–567 (2019).

    Article  CAS  PubMed  Google Scholar 

  147. Mout, L. et al. Generating human prostate cancer organoids from leukapheresis enriched circulating tumour cells. Eur. J. Cancer 150, 179–189 (2021).

    Article  CAS  PubMed  Google Scholar 

  148. Gunti, S., Hoke, A. T. K., Vu, K. P. & London, N. R. Jr Organoid and spheroid tumor models: techniques and applications. Cancers 13, 874 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Köcher, S. et al. A functional ex vivo assay to detect PARP1-EJ repair and radiosensitization by PARP-inhibitor in prostate cancer. Int. J. Cancer 144, 1685–1696 (2019).

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Ellwood-Yen, K. et al. Myc-driven murine prostate cancer shares molecular features with human prostate tumors. Cancer Cell 4, 223–238 (2003).

    Article  CAS  PubMed  Google Scholar 

  152. Freeman, K. W. et al. Inducible prostate intraepithelial neoplasia with reversible hyperplasia in conditional FGFR1-expressing mice. Cancer Res. 63, 8256–8263 (2003).

    CAS  PubMed  Google Scholar 

  153. Hurwitz, A. A., Foster, B. A., Allison, J. P., Greenberg, N. M. & Kwon, E. D. The TRAMP mouse as a model for prostate cancer. Curr. Protoc. Immunol. https://doi.org/10.1002/0471142735.im2005s45 (2001).

    Article  PubMed  Google Scholar 

  154. Alajati, A. et al. CDCP1 overexpression drives prostate cancer progression and can be targeted in vivo. J. Clin. Invest. 130, 2435–2450 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Jin, R. J. et al. The nuclear factor-κB pathway controls the progression of prostate cancer to androgen-independent growth. Cancer Res. 68, 6762–6769 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Wu, X. et al. Generation of a prostate epithelial cell-specific Cre transgenic mouse model for tissue-specific gene ablation. Mech. Dev. 101, 61–69 (2001).

    Article  CAS  PubMed  Google Scholar 

  157. Kim, M. J. et al. Cooperativity of Nkx3.1 and Pten loss of function in a mouse model of prostate carcinogenesis. Proc. Natl Acad. Sci. USA 99, 2884–2889 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Wang, S. et al. Prostate-specific deletion of the murine Pten tumor suppressor gene leads to metastatic prostate cancer. Cancer Cell 4, 209–221 (2003).

    Article  CAS  PubMed  Google Scholar 

  159. Mulholland, D. J. et al. Cell autonomous role of PTEN in regulating castration-resistant prostate cancer growth. Cancer Cell 19, 792–804 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Blattner, M. et al. SPOP mutation drives prostate tumorigenesis in vivo through coordinate regulation of PI3K/mTOR and AR signaling. Cancer Cell 31, 436–451 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Ding, Z. et al. Telomerase reactivation following telomere dysfunction yields murine prostate tumors with bone metastases. Cell 148, 896–907 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Mulholland, D. J. et al. Pten loss and RAS/MAPK activation cooperate to promote EMT and metastasis initiated from prostate cancer stem/progenitor cells. Cancer Res. 72, 1878–1889 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Dardenne, E. et al. N-Myc induces an EZH2-mediated transcriptional program driving neuroendocrine prostate cancer. Cancer Cell 30, 563–577 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Ding, Z. et al. SMAD4-dependent barrier constrains prostate cancer growth and metastatic progression. Nature 470, 269–273 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Zhao, D. et al. Chromatin regulator CHD1 remodels the immunosuppressive tumor microenvironment in PTEN-deficient prostate cancer. Cancer Discov. 10, 1374–1387 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Lu, X. et al. Effective combinatorial immunotherapy for castration-resistant prostate cancer. Nature 543, 728–732 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Taavitsainen, S. et al. Single-cell ATAC and RNA sequencing reveal pre-existing and persistent cells associated with prostate cancer relapse. Nat. Commun. 12, 5307 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Brady, L. et al. Inter- and intra-tumor heterogeneity of metastatic prostate cancer determined by digital spatial gene expression profiling. Nat. Commun. 12, 1426 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Zhao, T. et al. Spatial genomics enables multi-modal study of clonal heterogeneity in tissues. Nature 601, 85–91 (2022).

    Article  CAS  PubMed  Google Scholar 

  170. Chelebian, E. et al. Morphological features extracted by AI associated with spatial transcriptomics in prostate cancer. Cancers 13, 4837 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  171. Haffner, M. C. et al. Genomic and phenotypic heterogeneity in prostate cancer. Nat. Rev. Urol. 18, 79–92 (2021).

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  173. Gundem, G. et al. The evolutionary history of lethal metastatic prostate cancer. Nature 520, 353–357 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. van de Wetering, M. et al. Prospective derivation of a living organoid biobank of colorectal cancer patients. Cell 161, 933–945 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  175. Cao, J., Chan, W. C. & Chow, M. S. S. Use of conditional reprogramming cell, patient derived xenograft and organoid for drug screening for individualized prostate cancer therapy: current and future perspectives (Review). Int. J. Oncol. 60, 52 (2022).

    Article  CAS  PubMed  Google Scholar 

  176. Heidegger, I. et al. Comprehensive characterization of the prostate tumor microenvironment identifies CXCR4/CXCL12 crosstalk as a novel antiangiogenic therapeutic target in prostate cancer. Mol. Cancer 21, 132 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Zhang, Z. et al. Tumor microenvironment-derived NRG1 promotes antiandrogen resistance in prostate cancer. Cancer Cell 38, 279–296.e279 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Javier-DesLoges, J. et al. The microbiome and prostate cancer. Prostate Cancer Prostatic Dis. 25, 159–174 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  179. Poore, G. D. et al. Microbiome analyses of blood and tissues suggest cancer diagnostic approach. Nature 579, 567–574 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. Daisley, B. A. et al. Abiraterone acetate preferentially enriches for the gut commensal Akkermansia muciniphila in castrate-resistant prostate cancer patients. Nat. Commun. 11, 4822 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  181. Pernigoni, N. et al. Commensal bacteria promote endocrine resistance in prostate cancer through androgen biosynthesis. Science 374, 216–224 (2021).

    Article  CAS  PubMed  Google Scholar 

  182. Terrisse, S. et al. Immune system and intestinal microbiota determine efficacy of androgen deprivation therapy against prostate cancer. J. Immunother. Cancer 10, e004191 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  183. Meijer, T. G., Naipal, K. A., Jager, A. & van Gent, D. C. Ex vivo tumor culture systems for functional drug testing and therapy response prediction. Future Sci. OA 3, FSO190 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. Contreras-Trujillo, H. et al. Deciphering intratumoral heterogeneity using integrated clonal tracking and single-cell transcriptome analyses. Nat. Commun. 12, 6522 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  185. von Amsberg, G. et al. Immunotherapy in advanced prostate cancer-light at the end of the tunnel? Int. J. Mol. Sci. 23, 2569 (2022).

    Article  Google Scholar 

  186. Goldenberg, S. L., Nir, G. & Salcudean, S. E. A new era: artificial intelligence and machine learning in prostate cancer. Nat. Rev. Urol. 16, 391–403 (2019).

    Article  PubMed  Google Scholar 

  187. Kann, B. H., Hosny, A. & Aerts, H. Artificial intelligence for clinical oncology. Cancer Cell 39, 916–927 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  188. Gupta, R. et al. Artificial intelligence to deep learning: machine intelligence approach for drug discovery. Mol. Divers. 25, 1315–1360 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  189. Mickey, D. D., Stone, K. R., Stone, M. P. & Paulson, D. F. Morphologic and immunologic studies of human prostatic carcinoma. Cancer Treat. Rep. 61, 133–138 (1977).

    CAS  PubMed  Google Scholar 

  190. Williams, R. D. et al. Biochemical markers of cultured human prostatic epithelium. J. Urol. 119, 768–771 (1978).

    Article  CAS  PubMed  Google Scholar 

  191. Williams, R. D. Human urologic cancer cell lines. Invest. Urol. 17, 359–363 (1980).

    CAS  PubMed  Google Scholar 

  192. Horoszewicz, J. S. et al. LNCaP model of human prostatic carcinoma. Cancer Res. 43, 1809–1818 (1983).

    CAS  PubMed  Google Scholar 

  193. Claas, F. H. & van Steenbrugge, G. J. Expression of HLA-like structures on a permanent human tumor line PC-93. Tissue Antigens 21, 227–232 (1983).

    Article  CAS  PubMed  Google Scholar 

  194. Romijn, J. C., Verkoelen, C. F. & Schroeder, F. H. Application of the MTT assay to human prostate cancer cell lines in vitro: establishment of test conditions and assessment of hormone-stimulated growth and drug-induced cytostatic and cytotoxic effects. Prostate 12, 99–110 (1988).

    Article  CAS  PubMed  Google Scholar 

  195. Carney, D. N. et al. Establishment and identification of small cell lung cancer cell lines having classic and variant features. Cancer Res. 45, 2913–2923 (1985).

    CAS  PubMed  Google Scholar 

  196. Johnson, B. E. et al. Retention of chromosome 3 in extrapulmonary small cell cancer shown by molecular and cytogenetic studies. J. Natl Cancer Inst. 81, 1223–1228 (1989).

    Article  CAS  PubMed  Google Scholar 

  197. Gingrich, J. R. et al. Establishment and characterization of a new human prostatic carcinoma cell line (DuPro-1). J. Urol. 146, 915–919 (1991).

    Article  CAS  PubMed  Google Scholar 

  198. Plymate, S. R. et al. Effects of sex hormone binding globulin (SHBG) on human prostatic carcinoma. J. Steroid Biochem. Mol. Biol. 40, 833–839 (1991).

    Article  CAS  PubMed  Google Scholar 

  199. Mehta, P. P. et al. Gap-junctional communication in normal and neoplastic prostate epithelial cells and its regulation by cAMP. Mol. Carcinog. 15, 18–32 (1996).

    Article  CAS  PubMed  Google Scholar 

  200. Marques, R. B. et al. Androgen receptor modifications in prostate cancer cells upon long-term androgen ablation and antiandrogen treatment. Int. J. Cancer 117, 221–229 (2005).

    Article  CAS  PubMed  Google Scholar 

  201. Zhau, H. Y. et al. Androgen-repressed phenotype in human prostate cancer. Proc. Natl Acad. Sci. USA 93, 15152–15157 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  202. Klein, K. A. et al. Progression of metastatic human prostate cancer to androgen independence in immunodeficient SCID mice. Nat. Med. 3, 402–408 (1997).

    Article  CAS  PubMed  Google Scholar 

  203. Navone, N. M. et al. Establishment of two human prostate cancer cell lines derived from a single bone metastasis. Clin. Cancer Res. 3, 2493–2500 (1997).

    CAS  PubMed  Google Scholar 

  204. Navone, N. M. et al. TabBO: a model reflecting common molecular features of androgen-independent prostate cancer. Clin. Cancer Res. 6, 1190–1197 (2000).

    CAS  PubMed  Google Scholar 

  205. Pretlow, T. G. et al. Xenografts of primary human prostatic carcinoma. J. Natl Cancer Inst. 85, 394–398 (1993).

    Article  CAS  PubMed  Google Scholar 

  206. Wainstein, M. A. et al. CWR22: androgen-dependent xenograft model derived from a primary human prostatic carcinoma. Cancer Res. 54, 6049–6052 (1994).

    CAS  PubMed  Google Scholar 

  207. Sramkoski, R. M. et al. A new human prostate carcinoma cell line, 22Rv1. Vitr. Cell Dev. Biol. Anim. 35, 403–409 (1999).

    Article  CAS  Google Scholar 

  208. Gregory, C. W., Johnson, R. T. Jr, Mohler, J. L., French, F. S. & Wilson, E. M. Androgen receptor stabilization in recurrent prostate cancer is associated with hypersensitivity to low androgen. Cancer Res. 61, 2892–2898 (2001).

    CAS  PubMed  Google Scholar 

  209. Wu, H. C. et al. Derivation of androgen-independent human LNCaP prostatic cancer cell sublines: role of bone stromal cells. Int. J. Cancer 57, 406–412 (1994).

    Article  CAS  PubMed  Google Scholar 

  210. Loop, S. M., Rozanski, T. A. & Ostenson, R. C. Human primary prostate tumor cell line, ALVA-31: a new model for studying the hormonal regulation of prostate tumor cell growth. Prostate 22, 93–108 (1993).

    Article  CAS  PubMed  Google Scholar 

  211. Nakhla, A. M. & Rosner, W. Characterization of ALVA-41 cells, a new human prostatic cancer cell line. Steroids 59, 586–589 (1994).

    Article  CAS  PubMed  Google Scholar 

  212. Brothman, A. R., Lesho, L. J., Somers, K. D., Wright, G. L. Jr & Merchant, D. J. Phenotypic and cytogenetic characterization of a cell line derived from primary prostatic carcinoma. Int. J. Cancer 44, 898–903 (1989).

    Article  CAS  PubMed  Google Scholar 

  213. Bae, V. L., Jackson-Cook, C. K., Brothman, A. R., Maygarden, S. J. & Ware, J. L. Tumorigenicity of SV40 T antigen immortalized human prostate epithelial cells: association with decreased epidermal growth factor receptor (EGFR) expression. Int. J. Cancer 58, 721–729 (1994).

    Article  CAS  PubMed  Google Scholar 

  214. Bello, D., Webber, M. M., Kleinman, H. K., Wartinger, D. D. & Rhim, J. S. Androgen responsive adult human prostatic epithelial cell lines immortalized by human papillomavirus 18. Carcinogenesis 18, 1215–1223 (1997).

    Article  CAS  PubMed  Google Scholar 

  215. Rhim, J. S. et al. Stepwise immortalization and transformation of adult human prostate epithelial cells by a combination of HPV-18 and v-Ki-ras. Proc. Natl Acad. Sci. USA 91, 11874–11878 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  216. Webber, M. M. et al. Prostate specific antigen and androgen receptor induction and characterization of an immortalized adult human prostatic epithelial cell line. Carcinogenesis 17, 1641–1646 (1996).

    Article  CAS  PubMed  Google Scholar 

  217. Webber, M. M. et al. A human prostatic stromal myofibroblast cell line WPMY-1: a model for stromal-epithelial interactions in prostatic neoplasia. Carcinogenesis 20, 1185–1192 (1999).

    Article  CAS  PubMed  Google Scholar 

  218. Koochekpour, S. et al. Establishment and characterization of a primary androgen-responsive African-American prostate cancer cell line, E006AA. Prostate 60, 141–152 (2004).

    Article  PubMed  Google Scholar 

  219. Ke, X. S. et al. Epithelial to mesenchymal transition of a primary prostate cell line with switches of cell adhesion modules but without malignant transformation. PLoS ONE 3, e3368 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  220. Theodore, S. et al. Establishment and characterization of a pair of non-malignant and malignant tumor derived cell lines from an African American prostate cancer patient. Int. J. Oncol. 37, 1477–1482 (2010).

    CAS  PubMed  Google Scholar 

  221. Szczyrba, J. et al. The microRNA profile of prostate carcinoma obtained by deep sequencing. Mol. Cancer Res. 8, 529–538 (2010).

    Article  CAS  PubMed  Google Scholar 

  222. Acevedo, V. D. et al. Inducible FGFR-1 activation leads to irreversible prostate adenocarcinoma and an epithelial-to-mesenchymal transition. Cancer Cell 12, 559–571 (2007).

    Article  CAS  PubMed  Google Scholar 

  223. Bhatia-Gaur, R. et al. Roles for Nkx3.1 in prostate development and cancer. Genes Dev. 13, 966–977 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  224. Wan, X. et al. Prostate cancer cell-stromal cell crosstalk via FGFR1 mediates antitumor activity of dovitinib in bone metastases. Sci. Transl. Med. 6, 252ra122 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  225. Pecqueux, C. et al. FGF-2 is a driving force for chromosomal instability and a stromal factor associated with adverse clinico-pathological features in prostate cancer. Urol. Oncol. 36, 365.e315–365.e326 (2018).

    Article  Google Scholar 

  226. Wach, S. et al. MicroRNA profiles of prostate carcinoma detected by multiplatform microRNA screening. Int. J. Cancer 130, 611–621 (2012).

    Article  CAS  PubMed  Google Scholar 

  227. Wach, S. et al. Exploring the MIR143-UPAR axis for the inhibition of human prostate cancer cells in vitro and in vivo. Mol. Ther. Nucleic Acids 16, 272–283 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  228. McClurg, U. L. et al. Human ex vivo prostate tissue model system identifies ING3 as an oncoprotein. Br. J. Cancer 118, 713–726 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  229. Ewe, A. et al. Optimized polyethylenimine (PEI)-based nanoparticles for siRNA delivery, analyzed in vitro and in an ex vivo tumor tissue slice culture model. Drug Deliv. Transl. Res. 7, 206–216 (2017).

    Article  CAS  PubMed  Google Scholar 

  230. Karimov, M., Appelhans, D., Ewe, A. & Aigner, A. The combined disulfide cross-linking and tyrosine-modification of very low molecular weight linear PEI synergistically enhances transfection efficacies and improves biocompatibility. Eur. J. Pharm. Biopharm. 161, 56–65 (2021).

    Article  CAS  PubMed  Google Scholar 

  231. Hu, R. et al. Ligand-independent androgen receptor variants derived from splicing of cryptic exons signify hormone-refractory prostate cancer. Cancer Res. 69, 16–22 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  232. Antonarakis, E. S. et al. AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer. N. Engl. J. Med. 371, 1028–1038 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  233. Scher, H. I. et al. Association of AR-V7 on circulating tumor cells as a treatment-specific biomarker with outcomes and survival in castration-resistant prostate cancer. JAMA Oncol. 2, 1441–1449 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  234. Armstrong, A. J. et al. Prospective multicenter validation of androgen receptor splice variant 7 and hormone therapy resistance in high-risk castration-resistant prostate cancer: the PROPHECY study. J. Clin. Oncol. 37, 1120–1129 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  235. Bernemann, C. et al. Expression of AR-V7 in circulating tumour cells does not preclude response to next generation androgen deprivation therapy in patients with castration resistant prostate cancer. Eur. Urol. 71, 1–3 (2017).

    Article  CAS  PubMed  Google Scholar 

  236. Bernemann, C., Krabbe, L. M. & Schrader, A. J. Considerations for AR-V7 testing in clinical routine practice. Ann. Transl. Med. 7, S378 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  237. Del Re, M. et al. The detection of androgen receptor splice variant 7 in plasma-derived exosomal RNA strongly predicts resistance to hormonal therapy in metastatic prostate cancer patients. Eur. Urol. 71, 680–687 (2017).

    Article  PubMed  Google Scholar 

  238. Del Re, M. et al. Androgen receptor gain in circulating free DNA and splicing variant 7 in exosomes predict clinical outcome in CRPC patients treated with abiraterone and enzalutamide. Prostate Cancer Prostatic Dis. 24, 524–531 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  239. Lieb, V. et al. Cell-free DNA variant sequencing using plasma and AR-V7 testing of circulating tumor cells in prostate cancer patients. Cells 10, 3223 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  240. Li, Q. et al. Clinicopathological characteristics of androgen receptor splicing variant 7 (AR-V7) expression in patients with castration resistant prostate cancer: a systematic review and meta-analysis. Transl. Oncol. 14, 101145 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  241. Brown, L. C., Lu, C., Antonarakis, E. S., Luo, J. & Armstrong, A. J. Androgen receptor variant-driven prostate cancer II: advances in clinical investigation. Prostate Cancer Prostatic Dis. 23, 367–380 (2020).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The authors‘ own research related to the topics of this article was supported by the Deutsche Forschungsgemeinschaft (DFG; AI 24/26-1 (A.A.), TA 145/17-1 (H.T.), WE 5844/5-1 (St.W.), SPP2048 ‘microbone’ SA 3254/1-1 (V.S.), SPP2048 ‘microbone’ (Project-ID 401179983; S.P.), Ki 672/6-1 (J.K.), SPP ‘microbone’ and ERC Advanced Investigator Grant INJURMET (No. 834974; K.P.) as well as SFB 992 (Project-ID 403222702), SFB 1381 (Project-ID 89986987), SFB 850 and Schu688/15-1 to R.S.). The work was further supported by a grant of the Rudolf Becker-Foundation (T0321/36080/2020/kg) to S.P. and J.K., by the Federal Ministry for Economic Affairs and Climate Action (S.D.), by a fellowship of the University of Lübeck and by a Gerok fellowship within the SPP 2084 to S.P.

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Sailer, V., von Amsberg, G., Duensing, S. et al. Experimental in vitro, ex vivo and in vivo models in prostate cancer research. Nat Rev Urol (2022). https://doi.org/10.1038/s41585-022-00677-z

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