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Cancer  \nProgression to Metastatic Disease and Therapeutic Resistance  \nMartina Bedeschi 1, *, Noemi Marino 1, Elena Cavassi 1, Filippo Piccinini 1,2 and Anna Tesei 1, *  \nCitation: Bedeschi, M.; Marino, N.; Cavassi, E.; Piccinini, F.; Tesei, A. Cancer-Associated Fibroblast: Role in Prostate Cancer Progression to Metastatic Disease and Therapeutic Resistance. Cells 2023, 12, 802 . [https://doi.org/10.3390/](https://doi.org/10.3390/)[ ](https://doi.org/10.3390/)cells12050802  \nAcademic Editor: Claudio Festuccia  \nReceived: 30 January 2023  \nRevised: 24 February 2023  \nAccepted: 3 March 2023  \nPublished: 4 March 2023  \nCopyright: © 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ([https://](https://)[ ](https://)[creativecommons.org/licenses/by/](creativecommons.org/licenses/by/)[ ](creativecommons.org/licenses/by/)[4.0/](4.0/)) .  \n1 BioScience Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST)“Dino Amadori”,  \n47014 Meldola, Italy  \n2 Department of Medical and Surgical Sciences (DIMEC), University of Bologna, 40126 Bologna, Italy  \n* [Correspondence: martina.bedeschi@irst.emr.it](Correspondence: martina.bedeschi@irst.emr.it) (M.B.); [anna.tesei@irst.emr.it](anna.tesei@irst.emr.it) (A.T.); Tel.: +39-0543739932 (A.T.)  \nAbstract: Prostate cancer (PCa) is one of the most common cancers in European males. Although therapeutic approaches have changed in recent years, and several new drugs have been approved by the Food and Drug Administration (FDA), androgen deprivation therapy (ADT) remains the standard of care. Currently, PCa represents a clinical and economic burden due to the development of resistance to ADT, paving the way to cancer progression, metastasis, and to long-term side effects induced by ADT and radio-chemotherapeutic regimens. In light of this, a growing number of studies are focusing on the tumor microenvironment (TME) because of its role in supporting tumor growth. Cancer-associated fibroblasts (CAFs) have a central function in the TME because they communicate with prostate cancer cells, altering their metabolism and sensitivity to drugs; hence, targeted therapy against the TME, and, in particular, CAFs, could represent an alternative therapeutic approach to defeat therapy resistance in PCa. In this review, we focus on different CAF origins, subsets, and functions to highlight their potential in future therapeutic strategies for prostate cancer.  \nKeywords: cancer-associated fibroblasts; prostatic neoplasm; tumor microenvironment; fibroblasts; reactive stroma; targeted therapy  \n1. Introduction  \nProstate cancer (PCa) is the second most prevalent malignancy in men worldwide, accounting for 7.8% of all cancers. Despite death rates declining since the 1990s due to early detection and advances in treatment [1], it is estimated that in 2020 there were around 1.41 million new cases globally [2] . Incidences vary considerably worldwide, but Northern Europe accounts for the highest number of cases with 83 per 100,000 males [2] . PCa is strongly associated with age, and the incidence increases sharply after the age of 50 [3] . Many patients present a slow development without any threat to mortality; yet, in several cases, PCa displays metastasis, develops aggressive subtypes, and carries a high mortality risk [4,5] . In 2020, PCa was the fifth most common cause of cancer death [2] .  \nAndrogen deprivation therapy (ADT), aimed at suppressing the aberrant activation of androgen receptor (AR) signaling, remains the standard of care for advanced prostate cancer [6–8]; instead, the treatment for metastatic castration-resistant prostate cancer (mCRPC) patients is based on chemo-radiotherapy regimens. Over the years, several drugs aimed at inhibiting circulating testosterone synthesis (abiraterone acetate), inact","cbCaiuk6zQFPoTwH","https://ap.wps.com/l/cbCaiuk6zQFPoTwH","pdf",1604425,15,"English","# Abstract\n# Keywords\n# 1. Introduction","[{\"question\":\"Why does prostate cancer treatment often face progression after ADT?\",\"answer\":\"Resistance to ADT drives cancer progression and can contribute to metastasis and long-term side effects from subsequent regimens.\"},{\"question\":\"What role do cancer-associated fibroblasts play in the tumor microenvironment?\",\"answer\":\"CAFs communicate with prostate cancer cells, altering cancer metabolism and sensitivity to drugs, which supports tumor growth and treatment resistance.\"},{\"question\":\"What does this review focus on regarding CAFs?\",\"answer\":\"It highlights different CAF origins, subsets, and functions to clarify their potential in future therapeutic strategies for prostate cancer.\"}]","Cancer-Associated Fibroblast: Role in Prostate Cancer Progression to Metastatic Disease and Therapeutic Resistance | PDF",1790226430,38]