{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,5]],"date-time":"2026-03-05T15:20:16Z","timestamp":1772724016622,"version":"3.50.1"},"reference-count":111,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2021,10,31]],"date-time":"2021-10-31T00:00:00Z","timestamp":1635638400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Deanship of Scientific Research (DSR) at King Abdulaziz University","award":["(FB-022-43)"],"award-info":[{"award-number":["(FB-022-43)"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Prostate cancer (PCa) represents the most commonly non-cutaneous diagnosed cancer in men worldwide and occupies a very wide area of preclinical and clinical research. Targeted therapy for any cancer depends on the understanding of the molecular bases and natural behaviour of the diseases. Despite the well-known effect of androgen deprivation on PCa, many patients develop resistance either for antiandrogen therapy or other new treatment modalities such as checkpoint inhibitors and chemotherapy. Comprehensive understanding of the development of PCa as well as of the mechanisms underlying its progression is mandatory to maximise the benefit of the current approved medications or to guide the future research for targeted therapy of PCa. The aim of this review was to provide updates on the most recent mechanisms regarding the development and the progression of PCa. According to the current understanding, future treatment strategies should include more predictive genetic and biomarker analysis to assign different patients to the expected most appropriate and effective treatment.<\/jats:p>","DOI":"10.3390\/jcm10215127","type":"journal-article","created":{"date-parts":[[2021,11,1]],"date-time":"2021-11-01T22:21:34Z","timestamp":1635805294000},"page":"5127","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Updates on Molecular and Biochemical Development and Progression of Prostate Cancer"],"prefix":"10.3390","volume":"10","author":[{"given":"Omar","family":"Fahmy","sequence":"first","affiliation":[{"name":"Department of Urology, Universiti Putra Malaysia, Serdang 43400, Malaysia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3826-1519","authenticated-orcid":false,"given":"Nabil A.","family":"Alhakamy","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia"},{"name":"Advanced Drug Delivery Research Group, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia"},{"name":"Center of Excellence for Drug Research and Pharmaceutical Industries, King Abdulaziz University, Jeddah 21589, Saudi Arabia"},{"name":"Mohamed Saeed Tamer Chair for Pharmaceutical Industries, King Abdulaziz University, Jeddah 21589, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3088-4084","authenticated-orcid":false,"given":"Waleed Y.","family":"Rizg","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia"},{"name":"Advanced Drug Delivery Research Group, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alaa","family":"Bagalagel","sequence":"additional","affiliation":[{"name":"Department of Pharmacy Practice, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9028-8225","authenticated-orcid":false,"given":"Abdulmohsin J.","family":"Alamoudi","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9067-8565","authenticated-orcid":false,"given":"Hibah M.","family":"Aldawsari","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia"},{"name":"Advanced Drug Delivery Research Group, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aiah M.","family":"Khateb","sequence":"additional","affiliation":[{"name":"Medical Laboratory Technology Department, College of Applied Medical Sciences, Taibah University, Madinah 42224, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6962-5848","authenticated-orcid":false,"given":"Basmah M.","family":"Eldakhakhny","sequence":"additional","affiliation":[{"name":"Department of Clinical Biochemistry, Faculty of Medicine, King Abdulaziz University, Jeddah 21555, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6094-5570","authenticated-orcid":false,"given":"Usama A.","family":"Fahmy","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia"},{"name":"Advanced Drug Delivery Research Group, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2510-1946","authenticated-orcid":false,"given":"Wesam H.","family":"Abdulaal","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Faculty of Science, Cancer and Mutagenesis Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah 21555, Saudi Arabia"},{"name":"Centre for Artificial Intelligence in Precision Medicines, King Abdulaziz University, Jeddah 21555, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Claudia G.","family":"Fresta","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Biotechnological Sciences, University of Catania, 95125 Catania, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1571-5327","authenticated-orcid":false,"given":"Giuseppe","family":"Caruso","sequence":"additional","affiliation":[{"name":"Department of Drug and Health Sciences, University of Catania, 95125 Catania, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,10,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"7","DOI":"10.3322\/caac.21654","article-title":"Cancer statistics, 2021","volume":"71","author":"Siegel","year":"2021","journal-title":"CA Cancer J. Clin."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"7","DOI":"10.3322\/caac.21551","article-title":"Cancer statistics, 2019","volume":"69","author":"Siegel","year":"2019","journal-title":"CA Cancer J. Clin."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1158\/1055-9965.EPI-15-0578","article-title":"Global cancer incidence and mortality rates and trends--an update","volume":"25","author":"Torre","year":"2016","journal-title":"Cancer Epidemiol. Biomarkers Prev."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1097\/PPO.0b013e31823b042c","article-title":"Prognostic determinants in prostate cancer","volume":"17","author":"Martin","year":"2011","journal-title":"Cancer J."},{"key":"ref_5","first-page":"265","article-title":"Nccn prostate cancer practice guidelines. The national comprehensive cancer network","volume":"10","author":"Baker","year":"1996","journal-title":"Oncology"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"e331","DOI":"10.1016\/j.urolonc.2015.05.003","article-title":"Shifting paradigms in the estimation of survival for castration-resistant prostate cancer: A tertiary academic center experience","volume":"33","author":"Afshar","year":"2015","journal-title":"Urol. Oncol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1091","DOI":"10.2217\/fon-2016-0464","article-title":"The evolving role of chemotherapy in prostate cancer","volume":"13","author":"Boulos","year":"2017","journal-title":"Future Oncol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1080","DOI":"10.1200\/JCO.2017.75.3657","article-title":"Chemohormonal therapy in metastatic hormone-sensitive prostate cancer: Long-term survival analysis of the randomized phase iii e3805 chaarted trial","volume":"36","author":"Kyriakopoulos","year":"2018","journal-title":"J. Clin. Oncol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1992","DOI":"10.1093\/annonc\/mdz396","article-title":"Addition of docetaxel to hormonal therapy in low- and high-burden metastatic hormone sensitive prostate cancer: Long-term survival results from the stampede trial","volume":"30","author":"Clarke","year":"2019","journal-title":"Ann. Oncol."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Ruiz de Porras, V., Pardo, J.C., Notario, L., Etxaniz, O., and Font, A. (2021). Immune checkpoint inhibitors: A promising treatment option for metastatic castration-resistant prostate cancer?. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22094712"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1097\/00000478-198808000-00003","article-title":"Normal histology of the prostate","volume":"12","author":"McNeal","year":"1988","journal-title":"Am. J. Surg. Pathol."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Ittmann, M. (2018). Anatomy and histology of the human and murine prostate. Cold Spring Harb. Perspect. Med., 8.","DOI":"10.1101\/cshperspect.a030346"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"20111","DOI":"10.1073\/pnas.1320565110","article-title":"Prostate cancer originating in basal cells progresses to adenocarcinoma propagated by luminal-like cells","volume":"110","author":"Stoyanova","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1016\/j.cyto.2016.08.008","article-title":"Expression of several cytokines in prostate cancer: Correlation with clinical variables of patients. Relationship with biochemical progression of the malignance","volume":"89","author":"Torrealba","year":"2017","journal-title":"Cytokine"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"500","DOI":"10.1002\/path.1427","article-title":"The myofibroblast in wound healing and fibrocontractive diseases","volume":"200","author":"Gabbiani","year":"2003","journal-title":"J. Pathol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"531","DOI":"10.3390\/cancers4020531","article-title":"The stroma-a key regulator in prostate function and malignancy","volume":"4","author":"Bergh","year":"2012","journal-title":"Cancers"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Levesque, C., and Nelson, P.S. (2018). Cellular constituents of the prostate stroma: Key contributors to prostate cancer progression and therapy resistance. Cold Spring Harb. Perspect. Med., 8.","DOI":"10.1101\/cshperspect.a030510"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1038\/s41568-019-0238-1","article-title":"A framework for advancing our understanding of cancer-associated fibroblasts","volume":"20","author":"Sahai","year":"2020","journal-title":"Nat. Rev. Cancer"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1080\/17446651.2020.1764844","article-title":"The role of insulin-like growth factors in the development of prostate cancer","volume":"15","author":"Holly","year":"2020","journal-title":"Expert Rev. Endocrinol. Metab."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1007\/s10552-017-0883-1","article-title":"Does milk intake promote prostate cancer initiation or progression via effects on insulin-like growth factors (igfs)? A systematic review and meta-analysis","volume":"28","author":"Harrison","year":"2017","journal-title":"Cancer Causes Control."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Mancarella, C., Casanova-Salas, I., Calatrava, A., Garc\u00eda-Flores, M., Garofalo, C., Grilli, A., Rubio-Briones, J., Scotlandi, K., and L\u00f3pez-Guerrero, J.A. (2017). Insulin-like growth factor 1 receptor affects the survival of primary prostate cancer patients depending on tmprss2-erg status. BMC Cancer, 17.","DOI":"10.1186\/s12885-017-3356-8"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Melegh, Z., and Oltean, S. (2019). Targeting angiogenesis in prostate cancer. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20112676"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"567","DOI":"10.1016\/S0090-4295(99)00156-9","article-title":"Expression of vascular endothelial growth factor receptors in human prostate cancer","volume":"54","author":"Ferrer","year":"1999","journal-title":"Urology"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"821","DOI":"10.1016\/S0090-4295(00)01044-X","article-title":"Increased hypoxia correlates with increased expression of the angiogenesis marker vascular endothelial growth factor in human prostate cancer","volume":"57","author":"Cvetkovic","year":"2001","journal-title":"Urology"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"282","DOI":"10.1002\/(SICI)1097-0045(199611)29:5<282::AID-PROS2>3.0.CO;2-C","article-title":"Platelet-derived growth factor a and b chains and the \u03b1 and \u03b2 receptors in prostatic intraepithelial neoplasia","volume":"29","author":"Fudge","year":"1996","journal-title":"Prostate"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1271","DOI":"10.1016\/S0002-9440(10)65229-7","article-title":"Tyrosine kinases expressed in vivo by human prostate cancer bone marrow metastases and loss of the type 1 insulin-like growth factor receptor","volume":"155","author":"Chott","year":"1999","journal-title":"Am. J. Pathol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"412","DOI":"10.1038\/onc.2008.390","article-title":"The alpha-receptor for platelet-derived growth factor as a target for antibody-mediated inhibition of skeletal metastases from prostate cancer cells","volume":"28","author":"Russell","year":"2009","journal-title":"Oncogene"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"787","DOI":"10.1517\/13543784.2013.787409","article-title":"Imatinib and prostate cancer: Lessons learned from targeting the platelet-derived growth factor receptor","volume":"22","author":"Rosenberg","year":"2013","journal-title":"Expert Opin. Investig. Drugs"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1146\/annurev.bi.58.070189.003043","article-title":"The heparin-binding (fibroblast) growth factor family of proteins","volume":"58","author":"Burgess","year":"1989","journal-title":"Annu. Rev. Biochem."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Teishima, J., Hayashi, T., Nagamatsu, H., Shoji, K., Shikuma, H., Yamanaka, R., Sekino, Y., Goto, K., Inoue, S., and Matsubara, A. (2019). Fibroblast growth factor family in the progression of prostate cancer. J. Clin. Med., 8.","DOI":"10.3390\/jcm8020183"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"65","DOI":"10.3892\/or.2014.3200","article-title":"Restoration of fibroblast growth factor receptor 2iiib enhances the chemosensitivity of human prostate cancer cells","volume":"32","author":"Shoji","year":"2014","journal-title":"Oncol. Rep."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"5856","DOI":"10.1158\/1078-0432.CCR-13-1550","article-title":"Targeting fibroblast growth factor pathways in prostate cancer","volume":"19","author":"Corn","year":"2013","journal-title":"Clin. Cancer Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"374","DOI":"10.1016\/j.phrs.2018.02.007","article-title":"Neurobiological links between depression and ad: The role of tgf-\u03b21 signaling as a new pharmacological target","volume":"130","author":"Caraci","year":"2018","journal-title":"Pharmacol. Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"693","DOI":"10.3389\/fphar.2019.00693","article-title":"Fluoxetine and vortioxetine reverse depressive-like phenotype and memory deficits induced by a\u03b2(1-42) oligomers in mice: A key role of transforming growth factor-\u03b21","volume":"10","author":"Torrisi","year":"2019","journal-title":"Front. Pharmacol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1038\/nrneph.2016.48","article-title":"Tgf-\u03b2: The master regulator of fibrosis","volume":"12","author":"Meng","year":"2016","journal-title":"Nat. Rev. Nephrol."},{"key":"ref_36","first-page":"1255","article-title":"Loss of expression of transforming growth factor beta type I and type II receptors correlates with tumor grade in human prostate cancer tissues","volume":"2","author":"Kim","year":"1996","journal-title":"Clin. Cancer Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1038\/cr.2014.141","article-title":"Egf promotes mammalian cell growth by suppressing cellular senescence","volume":"25","author":"Alexander","year":"2015","journal-title":"Cell Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.canlet.2016.10.014","article-title":"Epidermal growth factor receptor signaling promotes metastatic prostate cancer through microrna-96-mediated downregulation of the tumor suppressor etv6","volume":"384","author":"Tsai","year":"2017","journal-title":"Cancer Lett."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1186\/s12943-018-0785-1","article-title":"Disruption of etv6 leads to twist1-dependent progression and resistance to epidermal growth factor receptor tyrosine kinase inhibitors in prostate cancer","volume":"17","author":"Tsai","year":"2018","journal-title":"Mol. Cancer"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1782","DOI":"10.2174\/0929867326666190712091515","article-title":"Inflammation as the common biological link between depression and cardiovascular diseases: Can carnosine exert a protective role?","volume":"27","author":"Caruso","year":"2020","journal-title":"Curr. Med. Chem."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1038\/nrc2067","article-title":"The tumour microenvironment as a target for chemoprevention","volume":"7","author":"Albini","year":"2007","journal-title":"Nat. Rev. Cancer"},{"key":"ref_42","first-page":"1398","article-title":"Centrosome abnormalities and chromosome instability occur together in pre-invasive carcinomas","volume":"63","author":"Pihan","year":"2003","journal-title":"Cancer Res."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Fujita, K., Hayashi, T., Matsushita, M., Uemura, M., and Nonomura, N. (2019). Obesity, inflammation, and prostate cancer. J. Clin. Med., 8.","DOI":"10.3390\/jcm8020201"},{"key":"ref_44","first-page":"455","article-title":"Inflammation in prostate cancer progression and therapeutic targeting","volume":"4","author":"Stark","year":"2015","journal-title":"Transl. Androl. Urol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1007\/978-3-319-95693-0_3","article-title":"Inflammation and prostate cancer","volume":"1095","author":"Tewari","year":"2018","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1590\/S1677-55382007000300008","article-title":"Inflammatory atrophy on prostate needle biopsies: Is there topographic relationship to cancer?","volume":"33","author":"Billis","year":"2007","journal-title":"Int. Braz. J. Urol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1378","DOI":"10.1002\/pros.20992","article-title":"Morphological transition of proliferative inflammatory atrophy to high-grade intraepithelial neoplasia and cancer in human prostate","volume":"69","author":"Wang","year":"2009","journal-title":"Prostate"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1016\/j.eururo.2006.06.001","article-title":"Different types of atrophy in the prostate with and without adenocarcinoma","volume":"51","author":"Tomas","year":"2007","journal-title":"Eur. Urol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"756","DOI":"10.1158\/1078-0432.CCR-14-2235","article-title":"Aspirin, nsaids, and risk of prostate cancer: Results from the reduce study","volume":"21","author":"Vidal","year":"2015","journal-title":"Clin. Cancer Res."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"603","DOI":"10.1517\/14740331003662620","article-title":"Statin use and cancer risk: A comprehensive review","volume":"9","author":"Boudreau","year":"2010","journal-title":"Expert Opin. Drug Saf."},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Caruso, G., Torrisi, S.A., Mogavero, P., Currenti, W., Castellano, S., Godos, J., Ferri, R., Galvano, F., Leggio, G.M., and Grosso, G. (2021). Polyphenols and neuroprotection: Therapeutic implications for cognitive decline. Pharmacol. Ther., 108013.","DOI":"10.1016\/j.pharmthera.2021.108013"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1111\/j.1365-2559.2011.04033.x","article-title":"Prostate cancer and inflammation: The evidence","volume":"60","author":"Sfanos","year":"2012","journal-title":"Histopathology"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1817","DOI":"10.1093\/humrep\/dey279","article-title":"Low-molecular weight compounds in human seminal plasma as potential biomarkers of male infertility","volume":"33","author":"Lazzarino","year":"2018","journal-title":"Hum. Reprod."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1038\/pcan.2013.13","article-title":"Oxidative stress in prostate cancer: Changing research concepts towards a novel paradigm for prevention and therapeutics","volume":"16","author":"Paschos","year":"2013","journal-title":"Prostate Cancer Prostatic Dis."},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Caruso, G., Godos, J., Castellano, S., Micek, A., Murabito, P., Galvano, F., Ferri, R., Grosso, G., and Caraci, F. (2021). The therapeutic potential of carnosine\/anserine supplementation against cognitive decline: A systematic review with meta-analysis. Biomedicines, 9.","DOI":"10.3390\/biomedicines9030253"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1777","DOI":"10.1158\/0008-5472.CAN-07-5259","article-title":"Oxidative stress is inherent in prostate cancer cells and is required for aggressive phenotype","volume":"68","author":"Kumar","year":"2008","journal-title":"Cancer Res."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"3406","DOI":"10.2741\/2322","article-title":"Nitrosative stress in cancer therapy","volume":"12","author":"Hirst","year":"2007","journal-title":"Front. Biosci."},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Caruso, G., Benatti, C., Musso, N., Fresta, C.G., Fidilio, A., Spampinato, G., Brunello, N., Bucolo, C., Drago, F., and Lunte, S.M. (2021). Carnosine protects macrophages against the toxicity of a\u03b21-42 oligomers by decreasing oxidative stress. Biomedicines, 9.","DOI":"10.3390\/biomedicines9050477"},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Fresta, C.G., Fidilio, A., Lazzarino, G., Musso, N., Grasso, M., Merlo, S., Amorini, A.M., Bucolo, C., Tavazzi, B., and Lazzarino, G. (2020). Modulation of pro-oxidant and pro-inflammatory activities of m1 macrophages by the natural dipeptide carnosine. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21030776"},{"key":"ref_60","first-page":"8611","article-title":"Reversal of gstp1 cpg island hypermethylation and reactivation of pi-class glutathione s-transferase (gstp1) expression in human prostate cancer cells by treatment with procainamide","volume":"61","author":"Lin","year":"2001","journal-title":"Cancer Res."},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Whelan, K.F., Lu, J.P., Fridman, E., Wolf, A., Honig, A., Paulin, G., Klotz, L., and Pinthus, J.H. (2010). What can surrogate tissues tell us about the oxidative stress status of the prostate? A hypothesis-generating in-vivo study. PLoS One, 5.","DOI":"10.1371\/journal.pone.0015880"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1093\/jnci\/89.1.40","article-title":"Prooxidant-antioxidant shift induced by androgen treatment of human prostate carcinoma cells","volume":"89","author":"Ripple","year":"1997","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"603","DOI":"10.3389\/fimmu.2019.00603","article-title":"The tumor immune contexture of prostate cancer","volume":"10","author":"Vitkin","year":"2019","journal-title":"Front. Immunol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1038\/nri3581","article-title":"Regulation of type i interferon responses","volume":"14","author":"Ivashkiv","year":"2014","journal-title":"Nat. Rev. Immunol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"7736","DOI":"10.1038\/ncomms8736","article-title":"Stat3 regulated arf expression suppresses prostate cancer metastasis","volume":"6","author":"Pencik","year":"2015","journal-title":"Nat. Commun."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"901","DOI":"10.1111\/j.1600-0463.2012.02924.x","article-title":"Intratumoral t but not b lymphocytes are related to clinical outcome in prostate cancer","volume":"120","author":"Flammiger","year":"2012","journal-title":"Apmis"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"1031","DOI":"10.2353\/ajpath.2010.100070","article-title":"Mast cells are novel independent prognostic markers in prostate cancer and represent a target for therapy","volume":"177","author":"Johansson","year":"2010","journal-title":"Am. J. Pathol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"952","DOI":"10.1038\/sj.bjc.6603962","article-title":"Decreased number of mast cells infiltrating into needle biopsy specimens leads to a better prognosis of prostate cancer","volume":"97","author":"Nonomura","year":"2007","journal-title":"Br. J. Cancer"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1007\/s10555-011-9286-z","article-title":"The significant role of mast cells in cancer","volume":"30","author":"Khazaie","year":"2011","journal-title":"Cancer Metastasis Rev."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"302","DOI":"10.1038\/nature08782","article-title":"B-cell-derived lymphotoxin promotes castration-resistant prostate cancer","volume":"464","author":"Ammirante","year":"2010","journal-title":"Nature"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"1069","DOI":"10.1158\/2159-8290.CD-18-0367","article-title":"Fundamental mechanisms of immune checkpoint blockade therapy","volume":"8","author":"Wei","year":"2018","journal-title":"Cancer Discov."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"234","DOI":"10.18632\/oncotarget.2703","article-title":"Pd-l1 is highly expressed in enzalutamide resistant prostate cancer","volume":"6","author":"Bishop","year":"2015","journal-title":"Oncotarget"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"831","DOI":"10.1016\/j.eururo.2020.08.040","article-title":"A \u201ctail\u201d of immunotherapy in metastatic prostate cancer","volume":"78","author":"Pachynski","year":"2020","journal-title":"Eur. Urol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"1810","DOI":"10.1158\/1078-0432.CCR-06-2318","article-title":"A pilot trial of ctla-4 blockade with human anti-ctla-4 in patients with hormone-refractory prostate cancer","volume":"13","author":"Small","year":"2007","journal-title":"Clin. Cancer Res."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"e261","DOI":"10.1016\/j.juro.2010.02.1055","article-title":"668 a randomized phase ii study of ipilimumab with androgen ablation compared with androgen ablation alone in patients with advanced prostate cancer","volume":"183","author":"Tollefson","year":"2010","journal-title":"J. Urol."},{"key":"ref_76","doi-asserted-by":"crossref","unstructured":"Lange, E.M. (2010). Identification of genetic risk factors for prostate cancer: Analytic approaches using hereditary prostate cancer families. Male Reproductive Cancers, Springer.","DOI":"10.1007\/978-1-4419-0449-2_7"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"845","DOI":"10.1158\/1055-9965.EPI-16-1046","article-title":"A review of prostate cancer genome-wide association studies (gwas)","volume":"27","author":"Benafif","year":"2018","journal-title":"Cancer Epidemiol. Biomarkers Prev."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1016\/0140-6736(91)90076-2","article-title":"Familial breast-ovarian cancer locus on chromosome 17q12-q23","volume":"338","author":"Narod","year":"1991","journal-title":"Lancet"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"1358","DOI":"10.1093\/jnci\/94.18.1358","article-title":"Cancer incidence in brca1 mutation carriers","volume":"94","author":"Thompson","year":"2002","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"639","DOI":"10.1038\/s41585-019-0249-4","article-title":"The impact of brca2 in prostate cancer","volume":"16","author":"Stone","year":"2019","journal-title":"Nat. Rev. Urol."},{"key":"ref_81","first-page":"3663","article-title":"High prevalence of the 999del5 mutation in icelandic breast and ovarian cancer patients","volume":"56","author":"Johannesdottir","year":"1996","journal-title":"Cancer Res."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"4986365","DOI":"10.1155\/2020\/4986365","article-title":"Brca mutations in prostate cancer: Prognostic and predictive implications","volume":"2020","author":"Messina","year":"2020","journal-title":"J. Oncol."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"530","DOI":"10.4103\/1008-682X.175785","article-title":"Hoxb13 and other high penetrant genes for prostate cancer","volume":"18","author":"Pilie","year":"2016","journal-title":"Asian J. Androl."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1056\/NEJMoa1110000","article-title":"Germline mutations in hoxb13 and prostate-cancer risk","volume":"366","author":"Ewing","year":"2012","journal-title":"N. Engl. J. Med."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"1356","DOI":"10.1038\/s41416-020-01036-8","article-title":"Germline hoxb13 g84e mutation carriers and risk to twenty common types of cancer: Results from the uk biobank","volume":"123","author":"Wei","year":"2020","journal-title":"Br. J. Cancer"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1097\/PAP.0000000000000069","article-title":"Metastatic carcinoma of unknown primary: Diagnostic approach using immunohistochemistry","volume":"22","author":"Conner","year":"2015","journal-title":"Adv. Anat. Pathol."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"1097","DOI":"10.1097\/PAS.0b013e3181e6cbf3","article-title":"Nkx3.1 as a marker of prostatic origin in metastatic tumors","volume":"34","author":"Gurel","year":"2010","journal-title":"Am. J. Surg. Pathol."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"3052","DOI":"10.1073\/pnas.85.9.3052","article-title":"Sequence analysis of the myc oncogene involved in the t(8;14)(q24;q11) chromosome translocation in a human leukemia t-cell line indicates that putative regulatory regions are not altered","volume":"85","author":"Finver","year":"1988","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1177\/1947601910379132","article-title":"Myc and prostate cancer","volume":"1","author":"Koh","year":"2010","journal-title":"Genes Cancer"},{"key":"ref_90","doi-asserted-by":"crossref","unstructured":"Rebello, R.J., Pearson, R.B., Hannan, R.D., and Furic, L. (2017). Therapeutic approaches targeting myc-driven prostate cancer. Genes, 8.","DOI":"10.3390\/genes8020071"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"4977","DOI":"10.1038\/s41388-019-0768-8","article-title":"A positive role of c-myc in regulating androgen receptor and its splice variants in prostate cancer","volume":"38","author":"Bai","year":"2019","journal-title":"Oncogene"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"24","DOI":"10.3389\/fonc.2015.00024","article-title":"Pten: Multiple functions in human malignant tumors","volume":"5","author":"Milella","year":"2015","journal-title":"Front. Oncol."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1038\/nrurol.2018.9","article-title":"Clinical implications of pten loss in prostate cancer","volume":"15","author":"Jamaspishvili","year":"2018","journal-title":"Nat. Rev. Urol."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.omtm.2020.05.013","article-title":"Airways expression of sars-cov-2 receptor, ace2, and tmprss2 is lower in children than adults and increases with smoking and copd","volume":"18","author":"Alabed","year":"2020","journal-title":"Mol. Ther. Methods Clin. Dev."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1038\/onc.2015.109","article-title":"The oncogene erg: A key factor in prostate cancer","volume":"35","author":"Adamo","year":"2016","journal-title":"Oncogene"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"5450","DOI":"10.3892\/mmr.2017.7281","article-title":"Significance of the tmprss2:Erg gene fusion in prostate cancer","volume":"16","author":"Wang","year":"2017","journal-title":"Mol. Med. Rep."},{"key":"ref_97","doi-asserted-by":"crossref","unstructured":"Semaan, L., Mander, N., Cher, M.L., and Chinni, S.R. (2019). Tmprss2-erg fusions confer efficacy of enzalutamide in an in vivo bone tumor growth model. BMC Cancer, 19.","DOI":"10.1186\/s12885-019-6185-0"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1042\/BSR20110046","article-title":"Foxa1: A transcription factor with parallel functions in development and cancer","volume":"32","author":"Bernardo","year":"2012","journal-title":"Biosci. Rep."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1007\/s13238-020-00786-8","article-title":"Pioneer of prostate cancer: Past, present and the future of foxa1","volume":"12","author":"Teng","year":"2021","journal-title":"Protein Cell"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"2115","DOI":"10.1158\/0008-5472.CAN-09-2979","article-title":"Loss of foxa1\/2 is essential for the epithelial-to-mesenchymal transition in pancreatic cancer","volume":"70","author":"Song","year":"2010","journal-title":"Cancer Res."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1038\/s41586-019-1347-4","article-title":"Distinct structural classes of activating foxa1 alterations in advanced prostate cancer","volume":"571","author":"Parolia","year":"2019","journal-title":"Nature"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"1011","DOI":"10.1038\/s41588-020-0681-7","article-title":"Chromatin binding of foxa1 is promoted by lsd1-mediated demethylation in prostate cancer","volume":"52","author":"Gao","year":"2020","journal-title":"Nat. Genet."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1016\/j.eururo.2013.11.002","article-title":"Eau guidelines on prostate cancer. Part II: Treatment of advanced, relapsing, and castration-resistant prostate cancer","volume":"65","author":"Heidenreich","year":"2014","journal-title":"Eur. Urol."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1007\/978-3-319-99286-0_7","article-title":"Castration-resistant prostate cancer: Mechanisms, targets and treatment","volume":"1096","author":"Mansinho","year":"2018","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_105","doi-asserted-by":"crossref","unstructured":"Yanagisawa, T., Kimura, T., Mori, K., Suzuki, H., Sano, T., Otsuka, T., Iwamoto, Y., Fukuokaya, W., Miyajima, K., and Enei, Y. (2021). Abiraterone acetate versus nonsteroidal antiandrogen with androgen deprivation therapy for high-risk metastatic hormone-sensitive prostate cancer. Prostate.","DOI":"10.1002\/pros.24243"},{"key":"ref_106","first-page":"726","article-title":"Overcoming the mechanisms of primary and acquired resistance to new generation hormonal therapies in advanced prostate cancer: Focus on androgen receptor independent pathways","volume":"3","author":"Bungaro","year":"2020","journal-title":"Cancer Drug Resistance"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"884","DOI":"10.1016\/j.ctrv.2015.08.002","article-title":"Understanding and overcoming the mechanisms of primary and acquired resistance to abiraterone and enzalutamide in castration resistant prostate cancer","volume":"41","author":"Buttigliero","year":"2015","journal-title":"Cancer Treat. Rev."},{"key":"ref_108","doi-asserted-by":"crossref","unstructured":"Crona, D.J., and Whang, Y.E. (2017). Androgen receptor-dependent and -independent mechanisms involved in prostate cancer therapy resistance. Cancers, 9.","DOI":"10.3390\/cancers9060067"},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"1030","DOI":"10.1158\/2159-8290.CD-13-0142","article-title":"An f876l mutation in androgen receptor confers genetic and phenotypic resistance to mdv3100 (enzalutamide)","volume":"3","author":"Korpal","year":"2013","journal-title":"Cancer Discov."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"1591","DOI":"10.1007\/s40265-019-01194-x","article-title":"Apalutamide: A review in non-metastatic castration-resistant prostate cancer","volume":"79","year":"2019","journal-title":"Drugs"},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"2141","DOI":"10.2147\/OTT.S147168","article-title":"Profile of apalutamide in the treatment of metastatic castration-resistant prostate cancer: Evidence to date","volume":"11","author":"Chong","year":"2018","journal-title":"Oncol. Targets Ther."}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/10\/21\/5127\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:23:54Z","timestamp":1760167434000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/10\/21\/5127"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,10,31]]},"references-count":111,"journal-issue":{"issue":"21","published-online":{"date-parts":[[2021,11]]}},"alternative-id":["jcm10215127"],"URL":"https:\/\/doi.org\/10.3390\/jcm10215127","relation":{},"ISSN":["2077-0383"],"issn-type":[{"value":"2077-0383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,10,31]]}}}