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Prostate carcinogenesis: inflammatory storms

Nature Reviews Cancer volume 20, pages 455–469 (2020)Cite this article

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Abstract

Prostate cancer is a major cause of cancer morbidity and mortality. Intra-prostatic inflammation is a risk factor for prostate carcinogenesis, with diet, chemical injury and an altered microbiome being causally implicated. Intra-prostatic inflammatory cell recruitment and expansion can ultimately promote DNA double-strand breaks and androgen receptor activation in prostate epithelial cells. The activation of the senescence-associated secretory phenotype fuels further ‘inflammatory storms’, with free radicals leading to further DNA damage. This drives the overexpression of DNA repair and tumour suppressor genes, rendering these genes susceptible to mutagenic insults, with carcinogenesis accelerated by germline DNA repair gene defects. We provide updates on recent advances in elucidating prostate carcinogenesis and explore novel therapeutic and prevention strategies harnessing these discoveries.

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Fig. 1: Overview of the vicious cycle of ‘inflammatory storms’ driving prostate carcinogenesis.
Fig. 2: Prostate inflammation: external cues.
Fig. 3: Androgen receptor signalling, inflammation and defective DNA repair create the perfect storm for prostate carcinogenesis.
Fig. 4: Potential therapeutic targets in lethal prostate cancer.

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Acknowledgements

J.S.d.B. acknowledges funding from Movember, Prostate Cancer UK, the Prostate Cancer Foundation, Cancer Research UK and the Medical Research Council. J.S.d.B. is a National Institutes of Health Research (NIHR) Senior Investigator. The views expressed in this article are those of the author(s) and not necessarily those of the National Health Service, the NIHR or the Department of Health. K.S.S. acknowledges support from the Prostate Cancer Foundation. R.S.M. acknowledges funding from an NIH/NCI R01 grant (R01CA245294), the CPRIT Individual Investigator Research Award (RP190454) and an Impact Award from the U.S. Department of Defense Prostate Cancer Research Program (W81XWH-17-1-0675). C.G.D. was supported by the Prostate Cancer Foundation, U.S. Department of Defense grant W81XWH-13-1-0369 and the Patrick C. Walsh Fund. A.A. was supported by European Research Council Consolidator grant 683136, Swiss Cancer League grant KFS4267-08-2017, SNSF grant 310030_176045, Prostate Cancer Foundation grant 19CHAL08 and a Fondazione Italiana per la ricerca sul Cancro (AIRC) Investigator Grant (22030).

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  1. These authors contributed equally: Johann S. de Bono, Christina Guo

Authors and Affiliations

  1. The Institute of Cancer Research, London, UK

    Johann S. de Bono, Christina Guo & Bora Gurel

  2. The Royal Marsden NHS Foundation Trust, Sutton, UK

    Johann S. de Bono & Christina Guo

  3. Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Angelo M. De Marzo & Karen S. Sfanos

  4. Department of Pathology, UT Southwestern Medical Center, Dallas, TX, USA

    Ram S. Mani

  5. MRC London Institute of Medical Sciences (LMS), London, UK

    Jesús Gil

  6. Institute of Clinical Sciences (ICS), Faculty of Medicine, Imperial College London, London, UK

    Jesús Gil

  7. Columbia University Medical Center, New York, NY, USA

    Charles G. Drake

  8. Institute of Oncology Research, Bellinzona, Switzerland

    Andrea Alimonti

  9. Faculty of Biomedical Sciences, Università della Svizzera Italiana, Lugano, Switzerland

    Andrea Alimonti

  10. Department of Medicine, University of Padova, Padova, Italy

    Andrea Alimonti

  11. Veneto Institute of Molecular Medicine, Padova, Italy

    Andrea Alimonti

  12. Department of Health Sciences and Technology, ETH Zürich, Zurich, Switzerland

    Andrea Alimonti

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Contributions

All authors researched data for the article and made substantial contributions to the discussion of the content. J.S.d.B. and C.G. wrote the manuscript. B.G., A.M.D.M., K.S.S., R.S.M., J.G., C.G.D. and A.A. reviewed and edited the manuscript before submission.

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Competing interests

J.S.d.B., B.G. and C.G. are employed by the Institute of Cancer Research, which has commercial interests in abiraterone, in the use of PARP inhibitors in DNA repair-defective cancers and in IL-23 driving AR signalling in prostate cancer. J.S.d.B. has served on advisory boards for companies, including AstraZeneca (AZ), Astellas, Bayer, Boehringer Ingelheim, Cellcentric, Daiichi Sankyo, Genentech/Roche, Genmab, GSK, Janssen, Merck Serono, Merck Sharp & Dohme (MSD), Menarini/Silicon Biosystems, Orion, Pfizer, Qiagen, Sanofi Aventis, Sierra Oncology and Taiho. His institution has received funding or other support for his research work from AZ, Astellas, Bayer, Cellcentric, Daiichi Sankyo, Genentech, Genmab, GSK, Janssen, Merck Serono, MSD, Menarini/Silicon Biosystems, Orion, Pfizer, Sanofi Aventis, Sierra Oncology and Taiho. He has been the CI/PI of many industry-sponsored clinical trials. A.M.D.M. has served as a sponsored research recipient from Janssen R&D and Myriad Genetics, and currently he serves as a consultant for Cepheid Inc. J.G. owns equity and has acted as a consultant for Unity Biotechnology and Geras Bio. J.G. is an inventor in a Medical Research Council patent related to senolytic therapies (PCT/GB2018/051437). C.G.D. has served on advisory boards for AZ Medimmune, Bristol Myers Squibb (BMS), F-Star, Genocea, Janssen, Merck, Pfizer, Pierre Fabre, Genentech/Roche and Sanofi Aventis. His institution holds AZ Medimmune, BMS and Janssen patents, and he has interests in Harpoon, Kleo, Shattuck Labs, Tizona and Werewolf. A.A. is a cofounder and shareholder of Oncosence; he is inventor of the following patents: WO2019142095A1, WO2019142097A1, WO2019180636A1 and US20200095314A1. No relevant conflicts of interest were disclosed by other authors.

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Glossary

Metastatic castration-resistant prostate cancer

(mCRPC). Prostate cancer that has spread to sites of the body beyond the prostate and continues to progress despite androgen deprivation therapy.

Infection

Invasion of a host organism’s bodily tissue by disease-causing organisms. This is different from colonization, which is the presence of bacteria on a body surface without causing disease (or infection).

Myeloid-derived suppressor cells

(MDSCs). A heterogeneous group of immature myeloid cells that deviate from the standard path of differentiation during pathologic states, such as cancer, chronic infection or tissue damage, resulting in emergency myelopoiesis. These cells are generally defined by their phenotypic, functional and molecular characteristics.

Senescence

A state in which cells enter cell cycle arrest without undergoing cell death.

Senescence-associated secretory phenotype

(SASP). Secretory phenotype of senescent cells that leads to the expression of a spectrum of soluble factors that promote inflammation, epithelial–mesenchymal transition and immunosuppression and drive tumour progression, amongst other effects.

Androgen deprivation therapy

(ADT). Treatments (for instance, through luteinizing hormone-releasing hormone agonists or surgical castration) that significantly reduce the level of testosterones and other anti-androgens in the circulation, generally the first type of hormone therapy used to treat advanced prostate cancer.

Tumour microenvironment

(TME). The environment around a tumour, including the surrounding blood vessels, immune cells, stromal cells, signalling molecules and extracellular matrices.

Microbiome

The collective genetic material of the entire collection of microorganisms in a specific niche.

Chemical injury

Exposure of the prostatic epithelium to toxic agents proposed as aetiological agents for the development of inflammation in the prostate. For example, urine contains uric acid, which can activate innate immune responses.

Proliferative inflammatory atrophy

(PIA). Focal areas of atrophy, hyperproliferation and inflammation that occur in response to prostatic epithelial damage.

Prostatic intraepithelial neoplasia

(PIN). The earliest accepted stage in prostate carcinogenesis, with phenotypic, biochemical and genetic changes due to incipient cancer but without invasion of the basement membrane of acini.

Peri-prostatic adipose tissue

(PPAT). Fat deposits that surround the prostate gland (which can be present in either obese or non-obese individuals) that can contribute to prostate tumour growth and metastases through the secretion of hormones, growth factors, chemokines and other pro-inflammatory molecules.

Extracapsular extension

Local tumour growth beyond the fibromuscular band surrounding the prostate.

DNA repair genes

(DRGs). Genes that encode the key enzymes involved in the recognition and restoration of the normal base-pair sequence and structure of damaged DNA.

Tumour-associated macrophages

(TAMs). A class of macrophages found in abundance in some solid tumours that often contribute to tumour growth and immunosuppression in the tumour microenvironment.

DNA damage response

A network of cellular pathways and machineries that sense, signal, and repair DNA lesions to prevent the generation of potentially deleterious mutations that threaten cell viability and potentially lead to neoplasia.

Mismatch repair

A process that corrects mismatched nucleotides in otherwise complementary paired DNA strands.

Senolytics

Drugs that specifically target and induce the death of senescent cells.

Tumour mutational burden

(TMB). The total number of mutations carried by tumour cells.

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de Bono, J.S., Guo, C., Gurel, B. et al. Prostate carcinogenesis: inflammatory storms. Nat Rev Cancer 20, 455–469 (2020). https://doi.org/10.1038/s41568-020-0267-9

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