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Mesenchymal stem cells and the embryonic reawakening theory of BPH

Nature Reviews Urology volume 15, pages 703–715 (2018)Cite this article

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Abstract

The prostate is the only organ in a man that continues to grow with age. John McNeal proposed, 40 years ago, that this BPH is characterized by an age-related reinitiation of benign neoplastic growth selectively in developmentally abortive distal ducts within the prostate transition–periurethral zone (TPZ), owing to a reawakening of inductive stroma selectively within these zones. An innovative variant of this hypothesis is that, owing to its location, the TPZ is continuously exposed to urinary components and/or autoantigens, which produces an inflammatory TPZ microenvironment that promotes recruitment of bone marrow-derived mesenchymal stem cells (MSCs) and generates a paracrine-inductive stroma that reinitiates benign neoplastic nodular growth. In support of this hypothesis, MSCs infiltrate human BPH tissue and have the ability to stimulate epithelial stem cell growth. These results provide a framework for defining both the aetiology of BPH in ageing men and insights into new therapeutic approaches.

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Fig. 1: Anatomical changes to the prostate with age.
Fig. 2: Embryonic development of the human prostate.
Fig. 3: Reciprocal crosstalk between epithelium and stroma in the human prostate.
Fig. 4: Reciprocal hierarchical expansion of human epithelial and stromal adult stem cells in the prostate.
Fig. 5: Mesenchymal stem cells infiltrate BPH nodules along with other immune cells.
Fig. 6: Heuristic model of mesenchymal stem cell-dependent episodic inductive reawakening in BPH pathogenesis.

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Acknowledgements

The authors thank B. Zhang and I. P. Garraway (University of California–Los Angeles) for generously providing urogenital sinus tissue, A. Meeker for his assistance in developing the immunofluorescence assays, and the Sidney Kimmel Comprehensive Cancer Center (SKCCC) Immunohistochemistry Core supported by the SKCCC Cancer Center Support Grant (CCSG; P30 CA006973). The authors also acknowledge the following sources of financial support: the Prostate Cancer Foundation Young Investigator Award (W.N.B.), SKCCC CCSG developmental funds (P30 CA006973 (W.N.B.)), the U.S. Department of Defense (W81XWH-17-1-0528 (W.N.B.)), and the US NIH Prostate SPORE Grant (P50 CA058236 (J.T.I.)).

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Nature Reviews Urology thanks W. -J. Lin and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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  1. Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins Hospital, Baltimore, MD, USA

    W. Nathaniel Brennen & John T. Isaacs

  2. Brady Urological Institute, Johns Hopkins School of Medicine, Baltimore, MD, USA

    John T. Isaacs

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W.N.B. and J.T.I. researched data for the article, substantially contributed to discussion of content, and wrote, reviewed, and edited the article.

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Correspondence to W. Nathaniel Brennen or John T. Isaacs.

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J.T.I. declares financial interest with Sophiris Bio related to topsalysin (also known as PRX302). W.N.B. declares no competing interests.

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Brennen, W.N., Isaacs, J.T. Mesenchymal stem cells and the embryonic reawakening theory of BPH. Nat Rev Urol 15, 703–715 (2018). https://doi.org/10.1038/s41585-018-0087-9

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