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  • Review Article
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Prostate luminal progenitor cells: from mouse to human, from health to disease

Nature Reviews Urology volume 19, pages 201–218 (2022)Cite this article

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Abstract

Stem and progenitor cells of the adult prostate epithelium have historically been believed to reside mainly or exclusively within the basal cell compartment and to possess basal-like phenotypic characteristics. Within the past decade, evidence of the existence of luminal epithelial cells exhibiting stem/progenitor properties has been obtained by lineage tracing and by functional characterization of sorted luminal-like cells. In 2020, the boom of single-cell transcriptomics led to increasingly exhaustive profiling of putative mouse luminal progenitor cells and, importantly, to the identification of cognate cells in the human prostate. The enrichment of luminal progenitor cells in genetically modified mouse models of prostate inflammation, benign prostate hypertrophy and prostate cancer, and the intrinsic castration tolerance of these cells, suggest their potential role in prostate pathogenesis and in resistance to androgen deprivation therapy. This Review bridges different approaches that have been used in the field to characterize luminal progenitor cells, including the unification of multiple identifiers employed to define these cells (names and markers). It also provides an overview of the intrinsic functional properties of luminal progenitor cells, and addresses their relevance in mouse and human prostate pathophysiology.

Key points

  • LSCmed defines a prototypic population of epithelial cells discovered in 2014 in the mouse prostate that exhibit luminal and stem-like features and were therefore called luminal progenitor cells. Their signature includes Krt4 and Psca.

  • Phenotypically similar cells have been identified in the human prostate. In both species, these cells reside mainly, but not only, in proximal regions of the gland (peri-urethral area and/or central transition zones).

  • In the adult mouse prostate in situ, luminal progenitor cells are unipotent stem-like cells that contribute to post-castration prostatic tissue regeneration in cooperation with alternative cell-driven mechanisms.

  • Luminal progenitor cells are amplified in various pathological states (such as inflammation, benign prostatic hyperplasia and cancer). The underlying molecular and cellular mechanisms are virtually unknown but might involve complex circuitry with inflammatory and stromal cells.

  • Luminal progenitor cells are more castration-tolerant than differentiated luminal cells. Thus, they could contribute to resistance to androgen-targeting therapeutic strategies (5α-reductase inhibitors and androgen deprivation therapy) and promote disease progression.

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Fig. 1: Enrichment of mouse prostate luminal progenitor cells by cell sorting.
Fig. 2: Transcriptomic similarity between FACS-enriched LSCmed cells and putative luminal progenitor cell clusters identified by scRNA-seq analyses of wild-type mouse and healthy human prostates.
Fig. 3: Overview of luminal progenitor cell properties in prostate pathophysiology.
Fig. 4: Regulation of disease-associated luminal progenitor cell amplification.

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References

  1. Devlin, C. M., Simms, M. S. & Maitland, N. J. Benign prostatic hyperplasia — what do we know? BJU Int. 127, 389–399 (2021).

    CAS  PubMed  Google Scholar 

  2. Strand, D. W., Costa, D. N., Francis, F., Ricke, W. A. & Roehrborn, C. G. Targeting phenotypic heterogeneity in benign prostatic hyperplasia. Differentiation 96, 49–61 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Lee, S. W. H., Chan, E. M. C. & Lai, Y. K. The global burden of lower urinary tract symptoms suggestive of benign prostatic hyperplasia: a systematic review and meta-analysis. Sci. Rep. 7, 7984 (2017).

    PubMed  PubMed Central  Google Scholar 

  4. Bell, K. J., Del Mar, C., Wright, G., Dickinson, J. & Glasziou, P. Prevalence of incidental prostate cancer: a systematic review of autopsy studies. Int. J. Cancer 137, 1749–1757 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Gandaglia, G. et al. Epidemiology and prevention of prostate cancer. Eur. Urol. Oncol. 4, 877–892 (2021).

    PubMed  Google Scholar 

  6. Neal, D. E. et al. Ten-year mortality, disease progression, and treatment-related side effects in men with localised prostate cancer from the ProtecT randomised controlled trial according to treatment received. Eur. Urol. 77, 320–330 (2020).

    PubMed  Google Scholar 

  7. Cunha, G. R., Hayward, S. W. & Wang, Y. Z. Role of stroma in carcinogenesis of the prostate. Differentiation 70, 473–485 (2002).

    PubMed  Google Scholar 

  8. Hayward, S. W., Rosen, M. A. & Cunha, G. R. Stromal-epithelial interactions in the normal and neoplastic prostate. Br. J. Urol. 79 (Suppl. 2), 18–26 (1997).

    PubMed  Google Scholar 

  9. Cunha, G. R., Donjacour, A. A. & Sugimura, Y. Stromal-epithelial interactions and heterogeneity of proliferative activity within the prostate. Biochem. Cell Biol. 64, 608–614 (1986).

    CAS  PubMed  Google Scholar 

  10. Abate-Shen, C. & Shen, M. M. Molecular genetics of prostate cancer. Genes Dev. 14, 2410–2434 (2000).

    CAS  PubMed  Google Scholar 

  11. Zhang, D., Zhao, S., Li, X., Kirk, J. S. & Tang, D. G. Prostate luminal progenitor cells in development and cancer. Trends Cancer 4, 769–783 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Li, J. J. & Shen, M. M. Prostate stem cells and cancer stem cells. Cold Spring Harb. Perspect. Med. 9, a030395 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Rycaj, K. & Tang, D. G. Cell-of-origin of cancer versus cancer stem cells: assays and interpretations. Cancer Res. 75, 4003–4011 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Ittmann, M. Anatomy and histology of the human and murine prostate. Cold Spring Harb. Perspect. Med. 8, a030346 (2018).

    PubMed  PubMed Central  Google Scholar 

  15. Roy-Burman, P., Wu, H., Powell, W. C., Hagenkord, J. & Cohen, M. B. Genetically defined mouse models that mimic natural aspects of human prostate cancer development. Endocr. Relat. Cancer 11, 225–254 (2004).

    CAS  PubMed  Google Scholar 

  16. Shappell, S. B. 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. 64, 2270–2305 (2004).

    CAS  PubMed  Google Scholar 

  17. Bruchovsky, N., Lesser, B., Van Doorn, E. & Craven, S. Hormonal effects on cell proliferation in rat prostate. Vitam. Horm. 33, 61–102 (1975).

    CAS  PubMed  Google Scholar 

  18. English, H. F., Santen, R. J. & Isaacs, J. T. Response of glandular versus basal rat ventral prostatic epithelial cells to androgen withdrawal and replacement. Prostate 11, 229–242 (1987).

    CAS  PubMed  Google Scholar 

  19. Wang, Y., Hayward, S., Cao, M., Thayer, K. & Cunha, G. Cell differentiation lineage in the prostate. Differentiation 68, 270–279 (2001).

    CAS  PubMed  Google Scholar 

  20. Taylor, R. A., Toivanen, R. & Risbridger, G. P. Stem cells in prostate cancer: treating the root of the problem. Endocr. Relat. Cancer 17, R273–R285 (2010).

    CAS  PubMed  Google Scholar 

  21. Goldstein, A. S., Stoyanova, T. & Witte, O. N. Primitive origins of prostate cancer: in vivo evidence for prostate-regenerating cells and prostate cancer-initiating cells. Mol. Oncol. 4, 385–396 (2010).

    PubMed  PubMed Central  Google Scholar 

  22. Lawson, D. A., Xin, L., Lukacs, R. U., Cheng, D. & Witte, O. N. Isolation and functional characterization of murine prostate stem cells. Proc. Natl Acad. Sci. USA 104, 181–186 (2007).

    CAS  PubMed  Google Scholar 

  23. Evans, G. S. & Chandler, J. A. Cell proliferation studies in rat prostate. I. The proliferative role of basal and secretory epithelial cells during normal growth. Prostate 10, 163–178 (1987).

    CAS  PubMed  Google Scholar 

  24. Evans, G. S. & Chandler, J. A. Cell proliferation studies in the rat prostate: II. The effects of castration and androgen-induced regeneration upon basal and secretory cell proliferation. Prostate 11, 339–351 (1987).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  26. 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 21, 253–265 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Liu, J. et al. Regenerated luminal epithelial cells are derived from preexisting luminal epithelial cells in adult mouse prostate. Mol. Endocrinol. 25, 1849–1857 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Sackmann-Sala, L. et al. Prolactin-induced prostate tumorigenesis links sustained stat5 signaling with the amplification of basal/stem cells and emergence of putative luminal progenitors. Am. J. Pathol. 184, 3105–3119 (2014).

    CAS  PubMed  Google Scholar 

  30. Kwon, O. J., Zhang, L. & Xin, L. Stem cell antigen-1 identifies a distinct androgen-independent murine prostatic luminal cell lineage with bipotent potential. Stem Cell 34, 191–202 (2016).

    CAS  Google Scholar 

  31. Sackmann Sala, L. et al. A rare castration-resistant progenitor cell population is highly enriched in Pten-null prostate tumors. J. Pathol. 243, 54–64 (2017).

    Google Scholar 

  32. Guo, W. et al. Single-cell transcriptomics identifies a distinct luminal progenitor cell type in distal prostate invagination tips. Nat. Genet. 52, 908–918 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Karthaus, W. R. et al. Regenerative potential of prostate luminal cells revealed by single-cell analysis. Science 368, 497–505 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Crowley, L. et al. A single-cell atlas of the mouse and human prostate reveals heterogeneity and conservation of epithelial progenitors. eLife https://doi.org/10.7554/eLife.59465 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  35. Mevel, R. et al. RUNX1 marks a luminal castration-resistant lineage established at the onset of prostate development. eLife 9, e59465. (2020).

    Google Scholar 

  36. Joseph, D. B. et al. Urethral luminal epithelia are castration-insensitive cells of the proximal prostate. Prostate 80, 872–884 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Joseph, D. B., Turco, A. E., Vezina, C. M. & Strand, D. W. Progenitors in prostate development and disease. Dev. Biol. 473, 50–58 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Freeland, J., Crowell, P. D., Giafaglione, J. M., Boutros, P. C. & Goldstein, A. S. Aging of the progenitor cells that initiate prostate cancer. Cancer Lett. 515, 28–35 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Lukacs, R. U., Goldstein, A. S., Lawson, D. A., Cheng, D. & Witte, O. N. Isolation, cultivation and characterization of adult murine prostate stem cells. Nat. Protoc. 5, 702–713 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Mulholland, D. J. et al. Lin−Sca-1+CD49fhigh stem/progenitors are tumor-initiating cells in the Pten-null prostate cancer model. Cancer Res. 69, 8555–8562 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Wang, Z. 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. 15, 274–283 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Goffin, V., Hoang, D. T., Bogorad, R. L. & Nevalainen, M. T. Prolactin regulation of the prostate gland: a female player in a male game. Nat. Rev. Urol. 8, 597–607 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Crowell, P. D. et al. Expansion of luminal progenitor cells in the aging mouse and human prostate. Cell Rep. 28, 1499–1510.e6 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Kwon, O. J. et al. The Sca-1+ and Sca-1− mouse prostatic luminal cell lineages are independently sustained. Stem Cell 38, 1479–1491 (2020).

    CAS  Google Scholar 

  45. Tsujimura, A. et al. Proximal location of mouse prostate epithelial stem cells: a model of prostatic homeostasis. J. Cell Biol. 157, 1257–1265 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Lawson, D. A. & Witte, O. N. Stem cells in prostate cancer initiation and progression. J. Clin. Invest. 117, 2044–2050 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Burger, P. E. et al. Sca-1 expression identifies stem cells in the proximal region of prostatic ducts with high capacity to reconstitute prostatic tissue. Proc. Natl Acad. Sci. USA 102, 7180–7185 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Goldstein, A. S. et al. Trop2 identifies a subpopulation of murine and human prostate basal cells with stem cell characteristics. Proc. Natl Acad. Sci. USA 105, 20882–20887 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Shen, M. M. & Abate-Shen, C. Molecular genetics of prostate cancer: new prospects for old challenges. Genes Dev. 24, 1967–2000 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Puig Lombardi, E., Baures, M., Dariane, C., Guidotti, J.-E. & Goffin, V. In silico computed clusters of prostate luminal progenitors match FACS-Enriched LSCmed cells. Preprint at bioRxiv https://doi.org/10.1101/2021.06.16.448624 (2021).

    Article  Google Scholar 

  51. Henry, G. H. et al. A cellular anatomy of the normal adult human prostate and prostatic urethra. Cell Rep. 25, 3530–3542.e5 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Hu, W. Y. et al. Isolation and functional interrogation of adult human prostate epithelial stem cells at single cell resolution. Stem Cell Res. 23, 1–12 (2017).

    PubMed  PubMed Central  Google Scholar 

  53. Liu, X. et al. Low CD38 identifies progenitor-like inflammation-associated luminal cells that can initiate human prostate cancer and predict poor outcome. Cell Rep. 17, 2596–2606 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Zhang, D. et al. Histone 2B-GFP label-retaining prostate luminal cells possess progenitor cell properties and are intrinsically resistant to castration. Stem Cell Rep. 10, 228–242 (2018).

    CAS  Google Scholar 

  55. Kwon, O. J., Zhang, L., Jia, D. & Xin, L. Sox2 is necessary for androgen ablation-induced neuroendocrine differentiation from Pten null Sca-1+ prostate luminal cells. Oncogene 40, 203–214 (2021).

    CAS  PubMed  Google Scholar 

  56. Sugimura, Y., Cunha, G. R., Donjacour, A. A., Bigsby, R. M. & Brody, J. R. Whole-mount autoradiography study of DNA synthetic activity during postnatal development and androgen-induced regeneration in the mouse prostate. Biol. Reprod. 34, 985–995 (1986).

    CAS  PubMed  Google Scholar 

  57. Yoo, Y. A. et al. Bmi1 marks distinct castration-resistant luminal progenitor cells competent for prostate regeneration and tumour initiation. Nat. Commun. 7, 12943 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Yoo, Y. A. et al. The role of castration-resistant Bmi1+Sox2+ cells in driving recurrence in prostate cancer. J. Natl Cancer Inst. 111, 311–321 (2019).

    PubMed  Google Scholar 

  59. Henry, G. H. & Strand, D. W. Strand Lab analysis of single-cell RNA sequencing. Zenodo https://doi.org/10.5281/zenodo.3687064 (2020).

    Article  Google Scholar 

  60. Leong, K. G., Wang, B. E., Johnson, L. & Gao, W. Q. Generation of a prostate from a single adult stem cell. Nature 456, 804–808 (2008).

    CAS  PubMed  Google Scholar 

  61. Richardson, G. D. et al. CD133, a novel marker for human prostatic epithelial stem cells. J. Cell Sci. 117, 3539–3545 (2004).

    CAS  PubMed  Google Scholar 

  62. Agarwal, S. et al. Identification of different classes of luminal progenitor cells within prostate tumors. Cell Rep. 13, 2147–2158 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Wang, L. et al. Expansion of prostate epithelial progenitor cells after inflammation of the mouse prostate. Am. J. Physiol. Renal Physiol. 308, F1421–F1430 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Wang, B. E. et al. Castration-resistant Lgr5+ cells are long-lived stem cells required for prostatic regeneration. Stem Cell Rep. 4, 768–779 (2015).

    CAS  Google Scholar 

  65. Barros-Silva, J. D. et al. Single-cell analysis identifies LY6D as a marker linking castration-resistant prostate luminal cells to prostate progenitors and cancer. Cell Rep. 25, 3504–3518.e6 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. McAuley, E. et al. Sox2 expression marks castration-resistant progenitor cells in the adult murine prostate. Stem Cell 37, 690–700 (2019).

    CAS  Google Scholar 

  67. Korsten, H., Ziel-van der Made, A., Ma, X., van der Kwast, T. & Trapman, J. Accumulating progenitor cells in the luminal epithelial cell layer are candidate tumor initiating cells in a Pten knockout mouse prostate cancer model. PLoS ONE 4, e5662 (2009).

    PubMed  PubMed Central  Google Scholar 

  68. Xin, L., Lawson, D. A. & Witte, O. N. The Sca-1 cell surface marker enriches for a prostate-regenerating cell subpopulation that can initiate prostate tumorigenesis. Proc. Natl Acad. Sci. USA 102, 6942–6947 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Wei, X. et al. Spatially restricted stromal Wnt signaling restrains prostate epithelial progenitor growth through direct and indirect mechanisms. Cell Stem Cell 24, 753–768.e6 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Ousset, M. et al. Multipotent and unipotent progenitors contribute to prostate postnatal development. Nat. Cell Biol. 14, 1131–1138 (2012).

    CAS  PubMed  Google Scholar 

  71. Wang, J. et al. Symmetrical and asymmetrical division analysis provides evidence for a hierarchy of prostate epithelial cell lineages. Nat. Commun. 5, 4758 (2014).

    CAS  PubMed  Google Scholar 

  72. Wuidart, A. et al. Quantitative lineage tracing strategies to resolve multipotency in tissue-specific stem cells. Genes Dev. 30, 1261–1277 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Tika, E., Ousset, M., Dannau, A. & Blanpain, C. Spatiotemporal regulation of multipotency during prostate development. Development 146, dev180224 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Shibata, M., Epsi, N. J., Xuan, S., Mitrofanova, A. & Shen, M. M. Bipotent progenitors do not require androgen receptor for luminal specification during prostate organogenesis. Stem Cell Rep. 15, 1026–1036 (2020).

    CAS  Google Scholar 

  75. Ceder, J. A., Aalders, T. W. & Schalken, J. A. Label retention and stem cell marker expression in the developing and adult prostate identifies basal and luminal epithelial stem cell subpopulations. Stem Cell Res. Ther. 8, 95 (2017).

    PubMed  PubMed Central  Google Scholar 

  76. Moad, M. et al. Multipotent basal stem cells, maintained in localized proximal niches, support directed long-ranging epithelial flows in human prostates. Cell Rep. 20, 1609–1622 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Treutlein, B. et al. Reconstructing lineage hierarchies of the distal lung epithelium using single-cell RNA-seq. Nature 509, 371–375 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Rawlins, E. L. et al. The role of Scgb1a1+ Clara cells in the long-term maintenance and repair of lung airway, but not alveolar, epithelium. Cell Stem Cell 4, 525–534 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Karthaus, W. R. et al. Identification of multipotent luminal progenitor cells in human prostate organoid cultures. Cell 159, 163–175 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Chua, C. W. et al. Single luminal epithelial progenitors can generate prostate organoids in culture. Nat. Cell Biol. 16, 951–954 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Pignon, J. C. et al. Cell kinetic studies fail to identify sequentially proliferating progenitors as the major source of epithelial renewal in the adult murine prostate. PLoS ONE 10, e0128489 (2015).

    PubMed  PubMed Central  Google Scholar 

  82. Shivdasani, R. A., Clevers, H. & de Sauvage, F. J. Tissue regeneration: reserve or reverse? Science 371, 784–786 (2021).

    CAS  PubMed  Google Scholar 

  83. Brennen, W. N. & Isaacs, J. T. Mesenchymal stem cells and the embryonic reawakening theory of BPH. Nat. Rev. Urol. 15, 703–715 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Claus, S., Wrenger, M., Senge, T. & Schulze, H. Immunohistochemical determination of age related proliferation rates in normal and benign hyperplastic human prostates. Urol. Res. 21, 305–308 (1993).

    CAS  PubMed  Google Scholar 

  85. Izumi, K., Li, L. & Chang, C. Androgen receptor and immune inflammation in benign prostatic hyperplasia and prostate cancer. Clin. Investig. 4, 935–950 (2014).

    CAS  Google Scholar 

  86. Roehrborn, C. G. et al. The effects of combination therapy with dutasteride and tamsulosin on clinical outcomes in men with symptomatic benign prostatic hyperplasia: 4-year results from the CombAT study. Eur. Urol. 57, 123–131 (2010).

    CAS  PubMed  Google Scholar 

  87. McConnell, J. D. et al. The long-term effect of doxazosin, finasteride, and combination therapy on the clinical progression of benign prostatic hyperplasia. N. Engl. J. Med. 349, 2387–2398 (2003).

    CAS  PubMed  Google Scholar 

  88. Cornu, J. N. et al. A systematic review and meta-analysis of functional outcomes and complications following transurethral procedures for lower urinary tract symptoms resulting from benign prostatic obstruction: an update. Eur. Urol. 67, 1066–1096 (2015).

    PubMed  Google Scholar 

  89. Kindblom, J. et al. Prostate hyperplasia in a transgenic mouse with prostate-specific expression of prolactin. Endocrinology 144, 2269–2278 (2003).

    CAS  PubMed  Google Scholar 

  90. Nevalainen, M. T. et al. Prolactin and prolactin receptors are expressed and functioning in human prostate. J. Clin. Invest. 99, 618–627 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Pigat, N. et al. Combined Sabal and Urtica extracts (WS® 1541) exert anti-proliferative and anti-inflammatory effects in a mouse model of benign prostate hyperplasia. Front. Pharmacol. 10, 311 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Bernichtein, S. et al. Anti-inflammatory properties of Lipidosterolic extract of Serenoa repens (Permixon®) in a mouse model of prostate hyperplasia. Prostate 75, 706–722 (2015).

    PubMed  Google Scholar 

  93. Lai, K. P. et al. Targeting stromal androgen receptor suppresses prolactin-driven benign prostatic hyperplasia (BPH). Mol. Endocrinol. 27, 1617–1631 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Isaacs, J. T. & Coffey, D. S. Etiology and disease process of benign prostatic hyperplasia. Prostate Suppl. 2, 33–50 (1989).

    CAS  PubMed  Google Scholar 

  95. Kwon, O. J., Zhang, L., Ittmann, M. M. & Xin, L. Prostatic inflammation enhances basal-to-luminal differentiation and accelerates initiation of prostate cancer with a basal cell origin. Proc. Natl Acad. Sci. USA 111, E592–E600 (2014).

    CAS  PubMed  Google Scholar 

  96. Schalken, J. A. Inflammation in the pathophysiology of benign prostatic hypertrophy. Eur. Urol. Suppl. 14, e1455–e1458 (2015).

    Google Scholar 

  97. McNeal, J. E. Origin and evolution of benign prostatic enlargement. Invest. Urol. 15, 340–345 (1978).

    CAS  PubMed  Google Scholar 

  98. De Nunzio, C., Presicce, F. & Tubaro, A. Inflammatory mediators in the development and progression of benign prostatic hyperplasia. Nat. Rev. Urol. 13, 613–626 (2016).

    PubMed  Google Scholar 

  99. Bushman, W. A. & Jerde, T. J. The role of prostate inflammation and fibrosis in lower urinary tract symptoms. Am. J. Physiol. Renal Physiol. 311, F817–F821 (2016).

    CAS  PubMed  Google Scholar 

  100. Wang, H. H. et al. Characterization of autoimmune inflammation induced prostate stem cell expansion. Prostate 75, 1620–1631 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Zhang, B. et al. Non-cell-autonomous regulation of prostate epithelial homeostasis by androgen receptor. Mol. Cell 63, 976–989 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Yu, Y. et al. Mesenchymal stem cells recruited by castration-induced inflammation activation accelerate prostate cancer hormone resistance via chemokine ligand 5 secretion. Stem Cell Res. Ther. 9, 242 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Shi, X., Gipp, J., Dries, M. & Bushman, W. Prostate progenitor cells proliferate in response to castration. Stem Cell Res. 13, 154–163 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. Spehar, K., Pan, A. & Beerman, I. Restoring aged stem cell functionality: current progress and future directions. Stem Cell 38, 1060–1077 (2020).

    Google Scholar 

  105. Stoyanova, T. et al. Prostate cancer originating in basal cells progresses to adenocarcinoma propagated by luminal-like cells. Proc. Natl Acad. Sci. USA 110, 20111–20116 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Goldstein, A. S. et al. Purification and direct transformation of epithelial progenitor cells from primary human prostate. Nat. Protoc. 6, 656–667 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Wang, Z. A., Toivanen, R., Bergren, S. K., Chambon, P. & Shen, M. M. Luminal cells are favored as the cell of origin for prostate cancer. Cell Rep. 8, 1339–1346 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Goldstein, A. S., Huang, J., Guo, C., Garraway, I. P. & Witte, O. N. Identification of a cell of origin for human prostate cancer. Science 329, 568–571 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Lu, T. L. et al. Conditionally ablated Pten in prostate basal cells promotes basal-to-luminal differentiation and causes invasive prostate cancer in mice. Am. J. Pathol. 182, 975–991 (2013).

    CAS  PubMed  Google Scholar 

  110. Taylor, B. S. et al. Integrative genomic profiling of human prostate cancer. Cancer Cell 18, 11–22 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. 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).

    CAS  PubMed  Google Scholar 

  112. Parisotto, M. et al. PTEN deletion in luminal cells of mature prostate induces replication stress and senescence in vivo. J. Exp. Med. 215, 1749–1763 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Ratnacaram, C. K. et al. Temporally controlled ablation of PTEN in adult mouse prostate epithelium generates a model of invasive prostatic adenocarcinoma. Proc. Natl Acad. Sci. USA 105, 2521–2526 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Zhang, J. et al. Proteomic and transcriptomic profiling of Pten gene-knockout mouse model of prostate cancer. Prostate 80, 588–605 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Abu El Maaty, M. A. et al. Single-cell analyses unravel cell type-specific responses to a vitamin D analog in prostatic precancerous lesions. Sci. Adv. 7, eabg5982 (2021).

    PubMed  PubMed Central  Google Scholar 

  117. Humphrey, P. A. Diagnosis of adenocarcinoma in prostate needle biopsy tissue. J. Clin. Pathol. 60, 35–42 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. Shah, R. B., Zhou, M., LeBlanc, M., Snyder, M. & Rubin, M. A. Comparison of the basal cell-specific markers, 34βE12 and p63, in the diagnosis of prostate cancer. Am. J. Surg. Pathol. 26, 1161–1168 (2002).

    PubMed  Google Scholar 

  119. Toivanen, R. et al. A preclinical xenograft model identifies castration-tolerant cancer-repopulating cells in localized prostate tumors. Sci. Transl. Med. 5, 187ra171 (2013).

    Google Scholar 

  120. Scher, H. I. et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. N. Engl. J. Med. 367, 1187–1197 (2012).

    CAS  PubMed  Google Scholar 

  121. Ryan, C. J. et al. Abiraterone in metastatic prostate cancer without previous chemotherapy. N. Engl. J. Med. 368, 138–148 (2013).

    CAS  PubMed  Google Scholar 

  122. Fizazi, K. et al. Abiraterone plus prednisone in metastatic, castration-sensitive prostate cancer. N. Engl. J. Med. 377, 352–360 (2017).

    CAS  PubMed  Google Scholar 

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

    PubMed  PubMed Central  Google Scholar 

  124. Fizazi, K. et al. Nonmetastatic, castration-resistant prostate cancer and survival with darolutamide. N. Engl. J. Med. 383, 1040–1049 (2020).

    CAS  PubMed  Google Scholar 

  125. Smith, M. R. et al. Apalutamide treatment and metastasis-free survival in prostate cancer. N. Engl. J. Med. 378, 1408–1418 (2018).

    CAS  PubMed  Google Scholar 

  126. Davies, A. H., Beltran, H. & Zoubeidi, A. Cellular plasticity and the neuroendocrine phenotype in prostate cancer. Nat. Rev. Urol. 15, 271–286 (2018).

    CAS  PubMed  Google Scholar 

  127. Mu, P. et al. SOX2 promotes lineage plasticity and antiandrogen resistance in TP53- and RB1-deficient prostate cancer. Science 355, 84–88 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  129. Kwon, O. J. et al. De novo induction of lineage plasticity from human prostate luminal epithelial cells by activated AKT1 and c-Myc. Oncogene 39, 7142–7151 (2020).

    PubMed  PubMed Central  Google Scholar 

  130. Hsu, E. C. et al. Trop2 is a driver of metastatic prostate cancer with neuroendocrine phenotype via PARP1. Proc. Natl Acad. Sci. USA 117, 2032–2042 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  131. Mottahedeh, J. et al. CD38 is methylated in prostate cancer and regulates extracellular NAD+. Cancer Metab. 6, 13 (2018).

    PubMed  PubMed Central  Google Scholar 

  132. Chung, J. S. et al. Circulating tumor cell-based molecular classifier for predicting resistance to abiraterone and enzalutamide in metastatic castration-resistant prostate cancer. Neoplasia 21, 802–809 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  133. Blanpain, C. & Simons, B. D. Unravelling stem cell dynamics by lineage tracing. Nat. Rev. Mol. Cell Biol. 14, 489–502 (2013).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

V.G. and J.-E.G. are grateful to L. Sackmann Sala for her pioneering work that led to the discovery of LSCmed cells. The authors thank the following sources of financial support: Ligue contre le cancer (RS16/75-18, RS17/75-1, RS18/75-48, RS19/75-63, RS20/75-93 and RS21 /75-35), FONCER contre le cancer, Association pour la recherche sur les tumeurs de la prostate (ARTP), Cancéropôle Ile-de-France and Institut National du Cancer (INCa_6672), Inserm and the Université de Paris. M.B. is supported by a fellowship from the Ministry of Research, C.D. by research/mobility fellowships from Inserm, the Association Française d’Urologie and Assistance Publique Hôpitaux de Paris (APHP), and E.T. by a Fonds de la Recherche Scientific (FNRS) fellowship. C.B. is an investigator of WELBIO.

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Authors and Affiliations

  1. Inserm U1151/Institut Necker Enfants Malades (INEM), Université de Paris, Paris, France

    Manon Baures, Charles Dariane, Nicolas Barry Delongchamps, Jacques-Emmanuel Guidotti & Vincent Goffin

  2. Urology Department, Hôpital européen Georges-Pompidou, Assistance Publique Hôpitaux de Paris, Paris, France

    Charles Dariane

  3. Laboratory of Stem Cells and Cancer, Université Libre de Bruxelles (ULB), Brussels, Belgium

    Elisavet Tika & Cedric Blanpain

  4. Bioinformatics Core Platform, INSERM UMR1163, Imagine Institute/Paris Descartes University, Paris, France

    Emilia Puig Lombardi

  5. Urology Department, Hôpital Cochin, Assistance Publique Hôpitaux de Paris, Paris, France

    Nicolas Barry Delongchamps

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  1. Manon Baures
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Contributions

V.G., M.B., C.D., E.P.L. and J.-E.G. researched data for the article. V.G., M.B., C.D., E.T., E.P.L., C.B. and J.-E.G. wrote the article. V.G., M.B., C.D., N.B.D., C.B. and J.-E.G. reviewed/edited the manuscript before submission. All authors made a substantial contribution to discussion of content.

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Correspondence to Vincent Goffin.

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Competing interests

C.D. is a consultant for Janssen, Astellas and Bayer. C.B. is a consultant for Genentech, Nestlé and Chromacure. N.B.D. is a consultant for Koelis and Affluent Medical. The other authors declare no competing interests.

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Review criteria

Most references were retrieved from our personal collection of references, and some were suggested by the peer reviewers. We also searched for original and review articles in PubMed using the following search terms, alone or in combination: prostate, progenitor, stem cells, luminal cells, neuroendocrine, CARN, CARB, Sox2, organoid, lineage-tracing, castration, treatment resistance, recurrence, 5α-reductase, cancer, benign prostate hyperplasia, inflammation, development, single cell, RNA-seq, and biomarkers. All papers identified were full text papers in English. We also searched the reference lists of identified articles for further relevant papers.

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Baures, M., Dariane, C., Tika, E. et al. Prostate luminal progenitor cells: from mouse to human, from health to disease. Nat Rev Urol 19, 201–218 (2022). https://doi.org/10.1038/s41585-021-00561-2

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