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Preclinical models of prostate cancer — modelling androgen dependency and castration resistance in vitro, ex vivo and in vivo

Nature Reviews Urology volume 20, pages 480–493 (2023)Cite this article

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Abstract

Prostate cancer is well known to be dependent on the androgen receptor (AR) for growth and survival. Thus, AR is the main pharmacological target to treat this disease. However, after an initially positive response to AR-targeting therapies, prostate cancer will eventually evolve to castration-resistant prostate cancer, which is often lethal. Tumour growth was initially thought to become androgen-independent following treatments; however, results from molecular studies have shown that most resistance mechanisms involve the reactivation of AR. Consequently, tumour cells become resistant to castration — the blockade of testicular androgens — and not independent of AR per se. However, confusion still remains on how to properly define preclinical models of prostate cancer, including cell lines. Most cell lines were isolated from patients for cell culture after evolution of the tumour to castration-resistant prostate cancer, but not all of these cell lines are described as castration resistant. Moreover, castration refers to the blockade of testosterone production by the testes; thus, even the concept of “castration” in vitro is questionable. To ensure maximal transfer of knowledge from scientific research to the clinic, understanding the limitations and advantages of preclinical models, as well as how these models recapitulate cancer cell androgen dependency and can be used to study castration resistance mechanisms, is essential.

Key points

  • Androgens and androgen receptor (AR) are essential for prostate cancer progression from primary hormone-naive tumours to metastatic castration-resistant prostate cancer (CRPC).

  • Common prostate cancer cell lines used for scientific research, including AR-positive and AR-negative cells, all originate from patients with CRPC, but are often not described as CRPC. A standardized nomenclature is proposed to avoid any confusion.

  • Optimization of novel preclinical models such as patient-derived organoids and patient-derived xenografts will offer a complex multi-cell type environment to gain an improved understanding of prostate cancer landscape and evolution to CRPC.

  • Caution must be retained on how the hormonal environment of the prostate is reproduced using preclinical models; for example, castration in mice has different implications for steroid hormones compared with castration in humans.

  • Integration of prostate cancer endocrinology, including intracrinology, in preclinical models is essential to understand tumour biology and to facilitate transition from basic science to clinical applications.

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Fig. 1: Androgen synthesis regulation and androgen receptor signalling inhibitors mode of action.
Fig. 2: Genomic alterations of the androgen receptor promote castration resistance in prostate cancer.

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Acknowledgements

The authors thank Laure Devine for English edition. In a spirit of synthesis, the authors could not reference all the relevant work and apologize if some are missing. EAW holds a Tier 2 Canada Research Chair from the CIHR on targeting metabolic vulnerabilities in hormonal-dependent cancers. FP holds an FRQS Senior clinician scientist scholarship.

Author information

Author notes

  1. These authors contributed equally: Lucas Germain, Camille Lafront.

Authors and Affiliations

  1. Endocrinology - Nephrology Research Axis, CHU de Québec - Université Laval Research Center, Québec, QC, Canada

    Lucas Germain, Camille Lafront, Virginie Paquette & Étienne Audet-Walsh

  2. Department of molecular medicine, Faculty of Medicine, Université Laval, Québec, QC, Canada

    Lucas Germain, Camille Lafront, Virginie Paquette & Étienne Audet-Walsh

  3. Centre de recherche sur le cancer de l’Université Laval, Québec, QC, Canada

    Lucas Germain, Camille Lafront, Virginie Paquette, Bertrand Neveu, Frédéric Pouliot & Étienne Audet-Walsh

  4. Oncology Axis, Centre de recherche du CHU de Québec – Université Laval, Québec, QC, Canada

    Bertrand Neveu & Frédéric Pouliot

  5. Laboratoire de recherche et d’innovation en médecine de première ligne (ARIMED), Groupe de médecine de famille universitaire de Saint-Charles-Borromée, CISSS Lanaudière, Saint-Charles-Borromée, QC, Canada

    Jean-Sébastien Paquette

  6. VITAM Research Centre for Sustainable Health, Québec, QC, Canada

    Jean-Sébastien Paquette

  7. Department of Family Medicine and Emergency Medicine, Faculty of Medicine, Université Laval, Québec, QC, Canada

    Jean-Sébastien Paquette

  8. Department of surgery, Faculty of Medicine, Université Laval, Québec, QC, Canada

    Frédéric Pouliot

Authors
  1. Lucas Germain
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  2. Camille Lafront
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  3. Virginie Paquette
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  4. Bertrand Neveu
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  5. Jean-Sébastien Paquette
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  6. Frédéric Pouliot
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  7. Étienne Audet-Walsh
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Contributions

E.A.-W., L.G., C.L. and V.P. researched data for the article. All authors contributed substantially to discussion of the content. E.A.-W., L.G., C.L. and V.P. wrote the article. All authors reviewed and/or edited the manuscript before submission.

Corresponding author

Correspondence to Étienne Audet-Walsh.

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Nature Reviews Urology thanks D. Frigo; J. Luo, who co-reviewed with M. Kanayama; and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Related links

cBioPortal: https://www.cbioportal.org/

Count Me In: https://joincountmein.org

The Metastatic Prostate Cancer Project: https://mpcproject.org/

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Germain, L., Lafront, C., Paquette, V. et al. Preclinical models of prostate cancer — modelling androgen dependency and castration resistance in vitro, ex vivo and in vivo. Nat Rev Urol 20, 480–493 (2023). https://doi.org/10.1038/s41585-023-00726-1

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