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Prognostic and therapeutic potential of senescent stromal fibroblasts in prostate cancer

Nature Reviews Urology (2023)Cite this article

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Abstract

The stromal component of the tumour microenvironment in primary and metastatic prostate cancer can influence and promote disease progression. Within the prostatic stroma, fibroblasts are one of the most prevalent cell types associated with precancerous and cancerous lesions; they have a vital role in the structural composition, organization and integrity of the extracellular matrix. Fibroblasts within the tumour microenvironment can undergo cellular senescence, which is a stable arrest of cell growth and a phenomenon that is emerging as a recognized hallmark of cancer. Supporting the idea that cellular senescence has a pro-tumorigenic role, a subset of senescent cells exhibits a senescence-associated secretory phenotype (SASP), which, along with increased inflammation, can promote prostate cancer cell growth and survival. These cellular characteristics make targeting senescent cells and/or modulating SASP attractive as a potential preventive or therapeutic option for prostate cancer.

Key points

  • Cellular senescence is a stable arrest of cell growth and is emerging as a recognized hallmark of cancer.

  • Senescent fibroblasts in the prostatic stroma can exhibit a senescence-associated secretory phenotype (SASP) in the tumour microenvironment, which can contribute to increased local inflammation, thereby promoting prostate cancer development, progression and resistance to therapy.

  • To eliminate the ability of senescent cells to produce factors that promote cancer cell growth and survival, specifically targeting the senescent cells with senotherapeutics would be an attractive option in prostate cancer treatment.

  • The preventive or therapeutic potential of using senotherapeutics could most benefit those disproportionately affected by prostate cancer (such as Black men and men with considerable comorbidities) or men with prostate cancer who are at high risk of disease progression.

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Fig. 1: Conceptual illustration of factors influencing the accumulation of senescent cells and SASP.
Fig. 2: Conceptual illustration of a feedback loop involving prostate cancer cells, inflammation and cellular senescence.
Fig. 3: Conceptual illustration of the potential benefits of targeting senescent stromal fibroblasts and SASP in prostate cancer.
Fig. 4: Potential therapeutic targets for senescent stromal fibroblasts and SASP in the prostate cancer TME.

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Acknowledgements

E.A.P. and A.K.M. received support for this research from the National Cancer Institute (R01CA255349) and the Department of Defense Prostate Cancer Research Program (W81XWH-20-1-0264). W.N.B. received support for the research of this work from the National Cancer Institute (R01CA255259). A.M.D.M. received support for the research of this work from the National Cancer Institute (U01CA196390). S.Y., A.M.D.M. and W.N.B. received support for the research of this work from the National Cancer Institute (U54CA274370). S.R.D. received support for the research of this work from the National Cancer Institute (P50CA058236). The content of this work is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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Authors and Affiliations

  1. Department of Medicine, Boston University Chobanian & Avedisian School of Medicine and Boston Medical Center, Boston, MA, USA

    Joakin O. Mori, Gerald V. Denis & Christopher M. Heaphy

  2. Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Isra Elhussin, W. Nathaniel Brennen, Mindy K. Graham, Tamara L. Lotan, Clayton C. Yates, Angelo M. De Marzo, Samuel R. Denmeade, Srinivasan Yegnasubramanian, William G. Nelson, Elizabeth A. Platz & Alan K. Meeker

  3. Department of Urology and the James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Isra Elhussin, W. Nathaniel Brennen, Tamara L. Lotan, Clayton C. Yates, Angelo M. De Marzo, Samuel R. Denmeade, Srinivasan Yegnasubramanian, William G. Nelson, Elizabeth A. Platz & Alan K. Meeker

  4. Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Isra Elhussin, Tamara L. Lotan, Clayton C. Yates, Angelo M. De Marzo, Srinivasan Yegnasubramanian, William G. Nelson & Alan K. Meeker

  5. Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Mindy K. Graham & William G. Nelson

  6. Department of Pharmacology and Experimental Therapeutics, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA

    Gerald V. Denis

  7. Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA

    Elizabeth A. Platz

  8. Department of Pathology and Laboratory Medicine, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA

    Christopher M. Heaphy

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  1. Joakin O. Mori
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Contributions

J.O.M., I.E. and C.M.H. researched data for the article. J.O.M., W.N.B., M.K.G., T.L.L., A.M.D.M., S.R.D., S.Y., W.G.N., G.V.D., E.A.P., A.K.M., C.C.Y. and C.M.H. contributed substantially to discussion of the content. J.O.M., I.E., W.N.B., M.K.G., E.A.P., A.K.M. and C.M.H. wrote the article. All authors reviewed and/or edited the manuscript before submission.

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Correspondence to Christopher M. Heaphy.

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T.L.L. has received research support from Roche/Ventana, AIRA Matrix, DeepBio and Myriad Genetics for other studies. C.C.Y. received honorarium or consultant fees from PreludeDx, QED Therapeutics, Amgen, Regeneron and Riptide Bioscience. C.C.Y. is a shareholder in Riptide Bioscience. A.M.D.M. has served as a Consultant for Merck and Cepheid and has received research grant funding from Janssen R&D. S.R.D. has received research funding for his institution from Astellas and Bayer. S.Y. has received grant support to his institution from Janssen, Bristol Myers Squibb and Cepheid. He has also previously served as a consultant to Cepheid. W.G.N. is a member of the Scientific Advisory Board for Cepheid and has received funding support from Bristol Myers Squibb. G.V.D. is a member of the scientific advisory board of Vyne Therapeutics. The other authors declare no competing interests.

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Mori, J.O., Elhussin, I., Brennen, W.N. et al. Prognostic and therapeutic potential of senescent stromal fibroblasts in prostate cancer. Nat Rev Urol (2023). https://doi.org/10.1038/s41585-023-00827-x

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