Prostate Cancer—from Molecular Mechanisms to Clinical Care

A topical collection in Cancers (ISSN 2072-6694). This collection belongs to the section "Molecular Cancer Biology".

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Editors


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Collection Editor
Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, 0424 Oslo, Norway
Interests: precision medicine; patients stratification; prostate cancer; molecular signatures; androgen receptor; MYC; bromodomain; chromatin; transcriptomics; single cell; gene regulation; radiobiology
Special Issues, Collections and Topics in MDPI journals

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Collection Editor
Sahlgrenska Cancer Center, Institute of clinical studies, University of Gothenburg, Gothenburg, Sweden
Interests: prostate cancer; personalized medicine; molecular medicine; liquid biopsies; cfDNA; cancer biomarkers; cancer genomics

Topical Collection Information

Dear Colleagues,

Prostate cancer is the second leading cause of cancer-related death in men worldwide.

The treatment options for men with advanced form of the disease have been focused on targeting the androgen receptor signaling axes for decades. Recent technical developments that allow better resolution have increased our understanding of the molecular mechanisms that are important for prostate cancer biology and disease evolution.

As new, possibly druggable, targets are discovered and novel treatment options enter clinical trials, the need to improve the link between molecular discoveries and clinical management also increases.

This Collection will focus on the current status and challenges in treating early and progressive prostate cancer, covering topics from basic research and technical developments to specific new and emerging targets, and the clinical management of prostate cancer patients.

Dr. Alfonso Urbanucci
Dr. Delila Gasi Tandefelt
Collection Editors

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Keywords

  • prostate cancer
  • castration resistance
  • neuroendocrine prostate cancer
  • personalized medicine
  • precision medicine
  • molecular medicine
  • liquid biopsies
  • cancer biomarkers
  • cancer screening
  • PSA
  • androgens
  • androgen receptor

Published Papers (36 papers)

2024

Jump to: 2023, 2022, 2021, 2020

20 pages, 15912 KiB  
Article
Liver X Receptors Enhance Epithelial to Mesenchymal Transition in Metastatic Prostate Cancer Cells
by Erwan Bouchareb, Sarah Dallel, Angélique De Haze, Christelle Damon-Soubeyrand, Yoan Renaud, Elissa Baabdaty, Marine Vialat, Julien Fabre, Pierre Pouchin, Cyrille De Joussineau, Françoise Degoul, Swapnil Sanmukh, Juliette Gendronneau, Phelipe Sanchez, Céline Gonthier-Gueret, Amalia Trousson, Laurent Morel, Jean Marc Lobaccaro, Ayhan Kocer and Silvère Baron
Cancers 2024, 16(16), 2776; https://doi.org/10.3390/cancers16162776 - 6 Aug 2024
Viewed by 839
Abstract
Prostate cancer (PCa) is one of the most common cancers in men. Metastasis is the leading cause of death in prostate cancer patients. One of the crucial processes involved in metastatic spread is the “epithelial–mesenchymal transition” (EMT), which allows cells to acquire the [...] Read more.
Prostate cancer (PCa) is one of the most common cancers in men. Metastasis is the leading cause of death in prostate cancer patients. One of the crucial processes involved in metastatic spread is the “epithelial–mesenchymal transition” (EMT), which allows cells to acquire the ability to invade distant organs. Liver X Receptors (LXRs) are nuclear receptors that have been demonstrated to regulate EMT in various cancers, including hepatic cancer. Our study reveals that the LXR pathway can control pro-invasive cell capacities through EMT in prostate cancer, employing ex vivo and in vivo approaches. We characterized the EMT status of the commonly used LNCaP, DU145, and PC3 prostate cancer cell lines through molecular and immunohistochemistry experiments. The impact of LXR activation on EMT function was also assessed by analyzing the migration and invasion of these cell lines in the absence or presence of an LXR agonist. Using in vivo experiments involving NSG-immunodeficient mice xenografted with PC3-GFP cells, we were able to study metastatic spread and the effect of LXRs on this process. LXR activation led to an increase in the accumulation of Vimentin and Amphiregulin in PC3. Furthermore, the migration of PC3 cells significantly increased in the presence of the LXR agonist, correlating with an upregulation of EMT. Interestingly, LXR activation significantly increased metastatic spread in an NSG mouse model. Overall, this work identifies a promoting effect of LXRs on EMT in the PC3 model of advanced prostate cancer. Full article
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19 pages, 1460 KiB  
Article
Transcript Markers from Urinary Extracellular Vesicles for Predicting Risk Reclassification of Prostate Cancer Patients on Active Surveillance
by Kati Erdmann, Florian Distler, Sebastian Gräfe, Jeremy Kwe, Holger H. H. Erb, Susanne Fuessel, Sascha Pahernik, Christian Thomas and Angelika Borkowetz
Cancers 2024, 16(13), 2453; https://doi.org/10.3390/cancers16132453 - 4 Jul 2024
Viewed by 1103
Abstract
Serum prostate-specific antigen (PSA), its derivatives, and magnetic resonance tomography (MRI) lack sufficient specificity and sensitivity for the prediction of risk reclassification of prostate cancer (PCa) patients on active surveillance (AS). We investigated selected transcripts in urinary extracellular vesicles (uEV) from PCa patients [...] Read more.
Serum prostate-specific antigen (PSA), its derivatives, and magnetic resonance tomography (MRI) lack sufficient specificity and sensitivity for the prediction of risk reclassification of prostate cancer (PCa) patients on active surveillance (AS). We investigated selected transcripts in urinary extracellular vesicles (uEV) from PCa patients on AS to predict PCa risk reclassification (defined by ISUP 1 with PSA > 10 ng/mL or ISUP 2-5 with any PSA level) in control biopsy. Before the control biopsy, urine samples were prospectively collected from 72 patients, of whom 43% were reclassified during AS. Following RNA isolation from uEV, multiplexed reverse transcription, and pre-amplification, 29 PCa-associated transcripts were quantified by quantitative PCR. The predictive ability of the transcripts to indicate PCa risk reclassification was assessed by receiver operating characteristic (ROC) curve analyses via calculation of the area under the curve (AUC) and was then compared to clinical parameters followed by multivariate regression analysis. ROC curve analyses revealed a predictive potential for AMACR, HPN, MALAT1, PCA3, and PCAT29 (AUC = 0.614–0.655, p < 0.1). PSA, PSA density, PSA velocity, and MRI maxPI-RADS showed AUC values of 0.681–0.747 (p < 0.05), with accuracies for indicating a PCa risk reclassification of 64–68%. A model including AMACR, MALAT1, PCAT29, PSA density, and MRI maxPI-RADS resulted in an AUC of 0.867 (p < 0.001) with a sensitivity, specificity, and accuracy of 87%, 83%, and 85%, respectively, thus surpassing the predictive power of the individual markers. These findings highlight the potential of uEV transcripts in combination with clinical parameters as monitoring markers during the AS of PCa. Full article
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26 pages, 6732 KiB  
Review
Casein Kinase 1α—A Target for Prostate Cancer Therapy?
by Emma Lishman-Walker and Kelly Coffey
Cancers 2024, 16(13), 2436; https://doi.org/10.3390/cancers16132436 - 2 Jul 2024
Viewed by 1452
Abstract
The androgen receptor (AR) is a key driver of prostate cancer (PCa) and, as such, current mainstay treatments target this molecule. However, resistance commonly arises to these therapies and, therefore, additional targets must be evaluated to improve patient outcomes. Consequently, alternative approaches for [...] Read more.
The androgen receptor (AR) is a key driver of prostate cancer (PCa) and, as such, current mainstay treatments target this molecule. However, resistance commonly arises to these therapies and, therefore, additional targets must be evaluated to improve patient outcomes. Consequently, alternative approaches for indirectly targeting the AR are sought. AR crosstalk with other signalling pathways, including several protein kinase signalling cascades, has been identified as a potential route to combat therapy resistance. The casein kinase 1 (CK1) family of protein kinases phosphorylate a multitude of substrates, allowing them to regulate a diverse range of pathways from the cell cycle to DNA damage repair. As well as its role in several signalling pathways that are de-regulated in PCa, mutational data suggest its potential to promote prostate carcinogenesis. CK1α is one isoform predicted to regulate AR activity via phosphorylation and has been implicated in the progression of several other cancer types. In this review, we explore how the normal biological function of CK1 is de-regulated in cancer, the impact on signalling pathways and how this contributes towards prostate tumourigenesis, with a particular focus on the CK1α isoform as a novel therapeutic target for PCa. Full article
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11 pages, 1314 KiB  
Article
Histologically Overt Stromal Response and the Risk of Progression after Radical Prostatectomy for Prostate Cancer
by Mutlay Sayan, Yetkin Tuac, Samet Kucukcolak, Mary D. Rowan, Grace K. Pratt, Cagdas Aktan, Elza Tjio, Dilara Akbulut, Shalini Moningi, Jonathan E. Leeman, Peter F. Orio, Paul L. Nguyen, Anthony V. D’Amico and Mahmut Akgul
Cancers 2024, 16(10), 1871; https://doi.org/10.3390/cancers16101871 - 14 May 2024
Cited by 1 | Viewed by 894
Abstract
Purpose: Given the variable clinical course of prostate cancer and the limitations of current prognostic factors, this study was conducted to investigate the impact of a histologically overt stromal response (HOST-response) to prostate cancer on clinical outcomes after radical prostatectomy. Methods: This retrospective [...] Read more.
Purpose: Given the variable clinical course of prostate cancer and the limitations of current prognostic factors, this study was conducted to investigate the impact of a histologically overt stromal response (HOST-response) to prostate cancer on clinical outcomes after radical prostatectomy. Methods: This retrospective analysis utilized The Cancer Genome Atlas (TCGA) to evaluate data from individuals with a confirmed diagnosis of prostate cancer who underwent radical prostatectomy and had available pathology slides. These slides were assessed for the presence of a HOST-response, similar to desmoplasia. The primary endpoint was progression-free survival (PFS). A multivariable competing risk regression analysis was used to assess whether a significant association existed between HOST-response and PFS, adjusting for known prostate cancer prognostic factors. Results: Among the 348 patients analyzed, 166 (47.70%) demonstrated a HOST-response. After a median follow-up of 37.87 months (IQR: 21.20, 65.50), the presence of a HOST-response was significantly associated with a shorter PFS (SDHR, 2.10; 95% CI, 1.26 to 3.50; p = 0.004), after adjusting for covariates. Conclusions: HOST-response in prostate cancer patients treated with radical prostatectomy is significantly associated with reduced PFS, suggesting a potential benefit from adjuvant therapy and highlighting the need for further investigation in a prospective randomized clinical trial. Full article
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2023

Jump to: 2024, 2022, 2021, 2020

4 pages, 189 KiB  
Editorial
Role of Chromatin and Epigenetic Dysregulation in Prostate Cancer: From Development to Progression and Therapeutic Response
by Nikhila Paleati and Gnanasekar Munirathinam
Cancers 2023, 15(23), 5638; https://doi.org/10.3390/cancers15235638 - 29 Nov 2023
Cited by 1 | Viewed by 875
Abstract
A multitude of epigenetic modifications and genetic mutations have been found to play pivotal roles in the development and progression of prostate cancer (PCa) [...] Full article

2022

Jump to: 2024, 2023, 2021, 2020

9 pages, 605 KiB  
Article
Multiparametric Magnetic Resonance Imaging Grades the Aggressiveness of Prostate Cancer
by Juan Morote, Angel Borque-Fernando, Marina Triquell, Anna Celma, Lucas Regis, Richard Mast, Inés M. de Torres, María E. Semidey, Anna Santamaría, Jacques Planas, Luis M. Esteban and Enrique Trilla
Cancers 2022, 14(7), 1828; https://doi.org/10.3390/cancers14071828 - 5 Apr 2022
Cited by 7 | Viewed by 1990
Abstract
We sought to find further evidence showing the increase in PCa aggressiveness as PI-RADS score increases from four surrogates of PCa aggressiveness: i. prostate biopsy GG (≤3 vs. >3), ii. type of pathology in surgical specimens (favourable vs. unfavourable), iii. clinical stage (localised [...] Read more.
We sought to find further evidence showing the increase in PCa aggressiveness as PI-RADS score increases from four surrogates of PCa aggressiveness: i. prostate biopsy GG (≤3 vs. >3), ii. type of pathology in surgical specimens (favourable vs. unfavourable), iii. clinical stage (localised vs. advanced), and risk of recurrence of localised PCa after primary treatment (low-intermediate vs. high). A group of 692 PCa patients were diagnosed after 3-T multiparametric MRI (mpMRI) and guided and/or systematic biopsies, showing csPCa (GG ≥ 2) in 547 patients (79%) and insignificant PCa (iPCa) in 145 (21%). The csPCa rate increased from 32.4% in PI-RADS < 3 to 95.5% in PI-RADS 5 (p < 0.001). GG ≥ 3 was observed in 7.6% of PCa with PI-RADS < 3 and 32.6% in those with PI-RADS > 3 (p < 0.001). Unfavourable pathology was observed in 38.9% of PCa with PI-RAD < 3 and 68.3% in those with PI-RADS > 3 (p = 0.030). Advanced disease was not observed in PCa with PI-RADS ≤ 3, while it existed in 12.7% of those with PI-RADS > 3 (p < 0.001). High-risk recurrence localised PCa was observed in 9.5% of PCa with PI-RADS < 3 and 35% in those with PI-RADS > 3 (p = 0.001). The PI-RADS score was an independent predictor of all surrogates of PCa aggressiveness as PSA density. We confirmed that mpMRI grades PCa aggressiveness. Full article
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16 pages, 777 KiB  
Review
Unravelling Prostate Cancer Heterogeneity Using Spatial Approaches to Lipidomics and Transcriptomics
by Shadrack M. Mutuku, Xander Spotbeen, Paul J. Trim, Marten F. Snel, Lisa M. Butler and Johannes V. Swinnen
Cancers 2022, 14(7), 1702; https://doi.org/10.3390/cancers14071702 - 27 Mar 2022
Cited by 11 | Viewed by 4677
Abstract
Due to advances in the detection and management of prostate cancer over the past 20 years, most cases of localised disease are now potentially curable by surgery or radiotherapy, or amenable to active surveillance without treatment. However, this has given rise to a [...] Read more.
Due to advances in the detection and management of prostate cancer over the past 20 years, most cases of localised disease are now potentially curable by surgery or radiotherapy, or amenable to active surveillance without treatment. However, this has given rise to a new dilemma for disease management; the inability to distinguish indolent from lethal, aggressive forms of prostate cancer, leading to substantial overtreatment of some patients and delayed intervention for others. Driving this uncertainty is the critical deficit of novel targets for systemic therapy and of validated biomarkers that can inform treatment decision-making and to select and monitor therapy. In part, this lack of progress reflects the inherent challenge of undertaking target and biomarker discovery in clinical prostate tumours, which are cellularly heterogeneous and multifocal, necessitating the use of spatial analytical approaches. In this review, the principles of mass spectrometry-based lipid imaging and complementary gene-based spatial omics technologies, their application to prostate cancer and recent advancements in these technologies are considered. We put in perspective studies that describe spatially-resolved lipid maps and metabolic genes that are associated with prostate tumours compared to benign tissue and increased risk of disease progression, with the aim of evaluating the future implementation of spatial lipidomics and complementary transcriptomics for prognostication, target identification and treatment decision-making for prostate cancer. Full article
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30 pages, 1218 KiB  
Review
Crosstalk between Long Non Coding RNAs, microRNAs and DNA Damage Repair in Prostate Cancer: New Therapeutic Opportunities?
by Folake Orafidiya, Lin Deng, Charlotte Lynne Bevan and Claire Emily Fletcher
Cancers 2022, 14(3), 755; https://doi.org/10.3390/cancers14030755 - 31 Jan 2022
Cited by 15 | Viewed by 3736
Abstract
It is increasingly appreciated that transcripts derived from non-coding parts of the human genome, such as long non-coding RNAs (lncRNAs) and microRNAs (miRNAs), are key regulators of biological processes both in normal physiology and disease. Their dysregulation during tumourigenesis has attracted significant interest [...] Read more.
It is increasingly appreciated that transcripts derived from non-coding parts of the human genome, such as long non-coding RNAs (lncRNAs) and microRNAs (miRNAs), are key regulators of biological processes both in normal physiology and disease. Their dysregulation during tumourigenesis has attracted significant interest in their exploitation as novel cancer therapeutics. Prostate cancer (PCa), as one of the most diagnosed malignancies and a leading cause of cancer-related death in men, continues to pose a major public health problem. In particular, survival of men with metastatic disease is very poor. Defects in DNA damage response (DDR) pathways culminate in genomic instability in PCa, which is associated with aggressive disease and poor patient outcome. Treatment options for metastatic PCa remain limited. Thus, researchers are increasingly targeting ncRNAs and DDR pathways to develop new biomarkers and therapeutics for PCa. Increasing evidence points to a widespread and biologically-relevant regulatory network of interactions between lncRNAs and miRNAs, with implications for major biological and pathological processes. This review summarises the current state of knowledge surrounding the roles of the lncRNA:miRNA interactions in PCa DDR, and their emerging potential as predictive and diagnostic biomarkers. We also discuss their therapeutic promise for the clinical management of PCa. Full article
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2021

Jump to: 2024, 2023, 2022, 2020

28 pages, 1444 KiB  
Review
Proteomic Landscape of Prostate Cancer: The View Provided by Quantitative Proteomics, Integrative Analyses, and Protein Interactomes
by Nithin Sadeesh, Mauro Scaravilli and Leena Latonen
Cancers 2021, 13(19), 4829; https://doi.org/10.3390/cancers13194829 - 27 Sep 2021
Cited by 9 | Viewed by 4661
Abstract
Prostate cancer is the second most frequent cancer of men worldwide. While the genetic landscapes and heterogeneity of prostate cancer are relatively well-known already, methodological developments now allow for studying basic and dynamic proteomes on a large scale and in a quantitative fashion. [...] Read more.
Prostate cancer is the second most frequent cancer of men worldwide. While the genetic landscapes and heterogeneity of prostate cancer are relatively well-known already, methodological developments now allow for studying basic and dynamic proteomes on a large scale and in a quantitative fashion. This aids in revealing the functional output of cancer genomes. It has become evident that not all aberrations at the genetic and transcriptional level are translated to the proteome. In addition, the proteomic level contains heterogeneity, which increases as the cancer progresses from primary prostate cancer (PCa) to metastatic and castration-resistant prostate cancer (CRPC). While multiple aspects of prostate adenocarcinoma proteomes have been studied, less is known about proteomes of neuroendocrine prostate cancer (NEPC). In this review, we summarize recent developments in prostate cancer proteomics, concentrating on the proteomic landscapes of clinical prostate cancer, cell line and mouse model proteomes interrogating prostate cancer-relevant signaling and alterations, and key prostate cancer regulator interactomes, such as those of the androgen receptor (AR). Compared to genomic and transcriptomic analyses, the view provided by proteomics brings forward changes in prostate cancer metabolism, post-transcriptional RNA regulation, and post-translational protein regulatory pathways, requiring the full attention of studies in the future. Full article
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20 pages, 2976 KiB  
Article
Androgen Receptor-Mediated Nuclear Transport of NRDP1 in Prostate Cancer Cells Is Associated with Worse Patient Outcomes
by Thomas Steele, Anhao Sam, Shawna Evans, Elizabeth Browning, Sheryl Krig, Katelyn Macias, Adarsh Konda, Salma Siddiqui, Blythe Durbin-Johnson, Paramita Ghosh and Ruth Vinall
Cancers 2021, 13(17), 4425; https://doi.org/10.3390/cancers13174425 - 2 Sep 2021
Cited by 1 | Viewed by 2740
Abstract
To our knowledge, our group is the first to demonstrate that NRDP1 is located in the nucleus as well as the cytoplasm of CaP cells. Subcellular fractionation, immunohistochemistry, and immunofluorescence analysis combined with confocal microscopy were used to validate this finding. Subcellular fractionation [...] Read more.
To our knowledge, our group is the first to demonstrate that NRDP1 is located in the nucleus as well as the cytoplasm of CaP cells. Subcellular fractionation, immunohistochemistry, and immunofluorescence analysis combined with confocal microscopy were used to validate this finding. Subcellular fractionation followed by western blot analysis revealed a strong association between AR and NRDP1 localization when AR expression and/or cellular localization was manipulated via treatment with R1881, AR-specific siRNA, or enzalutamide. Transfection of LNCaP with various NRDP1 and AR constructs followed by immunoprecipitation confirmed binding of NRDP1 to AR is possible and determined that binding requires the hinge region of AR. Co-transfection with NRDP1 constructs and HA-ubiquitin followed by subcellular fractionation confirmed that nuclear NRDP1 retains its ubiquitin ligase activity. We also show that increased nuclear NRDP1 is associated with PSA recurrence in CaP patients (n = 162, odds ratio; 1.238, p = 0.007) and that higher levels of nuclear NRDP1 are found in castration resistant cell lines (CWR22Rv1 and PC3) compared to androgen sensitive cell lines (LNCaP and MDA-PCa-3B). The combined data indicate that NRDP1 plays a role in mediating CaP progression and supports further investigation of both the mechanism by which nuclear transport occurs and the identification of specific nuclear targets. Full article
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18 pages, 3582 KiB  
Article
Identification of Androgen Receptor Metabolic Correlome Reveals the Repression of Ceramide Kinase by Androgens
by Laura Camacho, Amaia Zabala-Letona, Ana R. Cortazar, Ianire Astobiza, Asier Dominguez-Herrera, Amaia Ercilla, Jana Crespo, Cristina Viera, Sonia Fernández-Ruiz, Ainara Martinez-Gonzalez, Veronica Torrano, Natalia Martín-Martín, Antonio Gomez-Muñoz and Arkaitz Carracedo
Cancers 2021, 13(17), 4307; https://doi.org/10.3390/cancers13174307 - 26 Aug 2021
Cited by 7 | Viewed by 2938
Abstract
Prostate cancer (PCa) is one of the most prevalent cancers in men. Androgen receptor signaling plays a major role in this disease, and androgen deprivation therapy is a common therapeutic strategy in recurrent disease. Sphingolipid metabolism plays a central role in cell death, [...] Read more.
Prostate cancer (PCa) is one of the most prevalent cancers in men. Androgen receptor signaling plays a major role in this disease, and androgen deprivation therapy is a common therapeutic strategy in recurrent disease. Sphingolipid metabolism plays a central role in cell death, survival, and therapy resistance in cancer. Ceramide kinase (CERK) catalyzes the phosphorylation of ceramide to ceramide 1-phosphate, which regulates various cellular functions including cell growth and migration. Here we show that activated androgen receptor (AR) is a repressor of CERK expression. We undertook a bioinformatics strategy using PCa transcriptomics datasets to ascertain the metabolic alterations associated with AR activity. CERK was among the most prominent negatively correlated genes in our analysis. Interestingly, we demonstrated through various experimental approaches that activated AR reduces the mRNA expression of CERK: (i) expression of CERK is predominant in cell lines with low or negative AR activity; (ii) AR agonist and antagonist repress and induce CERK mRNA expression, respectively; (iii) orchiectomy in wildtype mice or mice with PCa (harboring prostate-specific Pten deletion) results in elevated Cerk mRNA levels in prostate tissue. Mechanistically, we found that AR represses CERK through interaction with its regulatory elements and that the transcriptional repressor EZH2 contributes to this process. In summary, we identify a repressive mode of AR that influences the expression of CERK in PCa. Full article
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14 pages, 974 KiB  
Article
Definition of Outcome-Based Prostate-Specific Antigen (PSA) Thresholds for Advanced Prostate Cancer Risk Prediction
by Simona Ferraro, Marco Bussetti, Niccolò Bassani, Roberta Simona Rossi, Giacomo Piero Incarbone, Filippo Bianchi, Marco Maggioni, Letterio Runza, Ferruccio Ceriotti and Mauro Panteghini
Cancers 2021, 13(14), 3381; https://doi.org/10.3390/cancers13143381 - 6 Jul 2021
Cited by 27 | Viewed by 3552
Abstract
We defined prostate-specific antigen (PSA) thresholds from a well calibrated risk prediction model for identifying and excluding advanced prostate cancer (PCa). We retrieved 902 biopsied patients with a pre-biopsy PSA determination (Roche assay). A logistic regression model predictive for PCa including the main [...] Read more.
We defined prostate-specific antigen (PSA) thresholds from a well calibrated risk prediction model for identifying and excluding advanced prostate cancer (PCa). We retrieved 902 biopsied patients with a pre-biopsy PSA determination (Roche assay). A logistic regression model predictive for PCa including the main effects [i.e., PSA, age, histological evidence of glandular inflammation (GI)] was built after testing the accuracy by calibration plots and Hosmer-Lemeshow test for goodness of fit. PSA thresholds were derived by assuming a diagnostic sensitivity of 95% (rule-out) and 80% (rule-in) for overall and advanced/poorly differentiated PCa. In patients without GI, serum PSA concentrations ≤ 4.1 (<65 years old) and ≤3.7 μg/L (≥65 years old) excluded an advanced PCa (defined as Gleason score ≥ 7 at biopsy), with a negative predictive value of 95.1% [95% confidence interval (CI): 83.0–98.7] and 88.8% (CI: 80.2–93.9), respectively, while PSA > 5.7 (<65) and >6.1 μg/L (≥65) should address biopsy referral. In presence of GI, PSA did not provide a valid estimate for risk of advanced cancer because of its higher variability and the low pre-test probability of PCa. The proposed PSA thresholds may support biopsy decision except for patients with asymptomatic prostatitis who cannot be pre-biopsy identified. Full article
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31 pages, 2303 KiB  
Review
Chromatin and Epigenetic Dysregulation of Prostate Cancer Development, Progression, and Therapeutic Response
by Konsta Kukkonen, Sinja Taavitsainen, Laura Huhtala, Joonas Uusi-Makela, Kirsi J. Granberg, Matti Nykter and Alfonso Urbanucci
Cancers 2021, 13(13), 3325; https://doi.org/10.3390/cancers13133325 - 2 Jul 2021
Cited by 16 | Viewed by 7047
Abstract
The dysregulation of chromatin and epigenetics has been defined as the overarching cancer hallmark. By disrupting transcriptional regulation in normal cells and mediating tumor progression by promoting cancer cell plasticity, this process has the ability to mediate all defined hallmarks of cancer. In [...] Read more.
The dysregulation of chromatin and epigenetics has been defined as the overarching cancer hallmark. By disrupting transcriptional regulation in normal cells and mediating tumor progression by promoting cancer cell plasticity, this process has the ability to mediate all defined hallmarks of cancer. In this review, we collect and assess evidence on the contribution of chromatin and epigenetic dysregulation in prostate cancer. We highlight important mechanisms leading to prostate carcinogenesis, the emergence of castration-resistance upon treatment with androgen deprivation therapy, and resistance to antiandrogens. We examine in particular the contribution of chromatin structure and epigenetics to cell lineage commitment, which is dysregulated during tumorigenesis, and cell plasticity, which is altered during tumor progression. Full article
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8 pages, 207 KiB  
Review
Response to Androgens and Androgen Receptor Antagonists in the Presence of Cytokines in Prostate Cancer
by Zoran Culig
Cancers 2021, 13(12), 2944; https://doi.org/10.3390/cancers13122944 - 12 Jun 2021
Cited by 11 | Viewed by 2671
Abstract
Non-steroidal anti-androgens have a major role in the treatment of non-localized prostate cancer. Interleukins are involved in the regulation of many cellular functions in prostate cancer and also modify cellular response to anti-androgens. A specific role of selected IL is presented in this [...] Read more.
Non-steroidal anti-androgens have a major role in the treatment of non-localized prostate cancer. Interleukins are involved in the regulation of many cellular functions in prostate cancer and also modify cellular response to anti-androgens. A specific role of selected IL is presented in this review. IL-8 is a cytokine expressed in prostate cancer tissue and microenvironment and promotes proliferation and androgen receptor-mediated transcription. In contrast, IL-1 displays negative effects on expression of androgen receptor and its target genes. A subgroup of prostate cancers show neuroendocrine differentiation, which may be in part stimulated by androgen ablation. A similar effect was observed after treatment of cells with IL-10. Another cytokine which is implicated in regulation of androgenic response is IL-23, secreted by myeloid cells. Most studies on androgens and IL were carried out with IL-6, which acts through the signal transducer and activator of the transcription (STAT) factor pathway. IL-6 is implicated in resistance to enzalutamide. Activation of the STAT-3 pathway is associated with increased cellular stemness. IL-6 activation of the androgen receptor in some prostate cancers is associated with increased growth in vitro and in vivo. Molecules such as galiellalactone or niclosamide have an inhibitory effect on both androgen receptor and STAT-3 pathways. Full article
12 pages, 1985 KiB  
Commentary
Novel Target Opportunities in Non-Metastatic Castrate Resistant Prostate Cancer
by Stephanie Gleicher, Baylee A. Porter, Disharee Nath, Guanqun Li, Rakesh Khanna, Hanan Goldberg, Marcin Kortylewski, Gennady Bratslavsky and Leszek Kotula
Cancers 2021, 13(10), 2426; https://doi.org/10.3390/cancers13102426 - 17 May 2021
Cited by 2 | Viewed by 2879
Abstract
Nearly one third of men will incur biochemical recurrence after treatment for localized prostate cancer. Androgen deprivation therapy (ADT) is the therapeutic mainstay; however, some patients will transition to a castrate resistant state (castrate resistant prostate cancer, CRPC). Subjects with CRPC may develop [...] Read more.
Nearly one third of men will incur biochemical recurrence after treatment for localized prostate cancer. Androgen deprivation therapy (ADT) is the therapeutic mainstay; however, some patients will transition to a castrate resistant state (castrate resistant prostate cancer, CRPC). Subjects with CRPC may develop symptomatic metastatic disease (mCRPC) and incur mortality several years later. Prior to metastatic disease, however, men acquire non-metastatic CRPC (nmCRPC) which lends the unique opportunity for intervention to delay disease progression and symptoms. This review addresses current therapies for nmCRPC, as well as novel therapeutics and pathway strategies targeting men with nmCRPC. Full article
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17 pages, 3835 KiB  
Article
Gene Regulation Network Analysis on Human Prostate Orthografts Highlights a Potential Role for the JMJD6 Regulon in Clinical Prostate Cancer
by Mario Cangiano, Magda Grudniewska, Mark J. Salji, Matti Nykter, Guido Jenster, Alfonso Urbanucci, Zoraide Granchi, Bart Janssen, Graham Hamilton, Hing Y. Leung and Inès J. Beumer
Cancers 2021, 13(9), 2094; https://doi.org/10.3390/cancers13092094 - 26 Apr 2021
Cited by 6 | Viewed by 3031
Abstract
Background: Prostate cancer (PCa) is the second most common tumour diagnosed in men. Tumoral heterogeneity in PCa creates a significant challenge to develop robust prognostic markers and novel targets for therapy. An analysis of gene regulatory networks (GRNs) in PCa may provide insight [...] Read more.
Background: Prostate cancer (PCa) is the second most common tumour diagnosed in men. Tumoral heterogeneity in PCa creates a significant challenge to develop robust prognostic markers and novel targets for therapy. An analysis of gene regulatory networks (GRNs) in PCa may provide insight into progressive PCa. Herein, we exploited a graph-based enrichment score to integrate data from GRNs identified in preclinical prostate orthografts and differentially expressed genes in clinical resected PCa. We identified active regulons (transcriptional regulators and their targeted genes) associated with PCa recurrence following radical prostatectomy. Methods: The expression of known transcription factors and co-factors was analysed in a panel of prostate orthografts (n = 18). We searched for genes (as part of individual GRNs) predicted to be regulated by the highest number of transcriptional factors. Using differentially expressed gene analysis (on a per sample basis) coupled with gene graph enrichment analysis, we identified candidate genes and associated GRNs in PCa within the UTA cohort, with the most enriched regulon being JMJD6, which was further validated in two additional cohorts, namely EMC and ICGC cohorts. Cox regression analysis was performed to evaluate the association of the JMJD6 regulon activity with disease-free survival time in the three clinical cohorts as well as compared to three published prognostic gene signatures (TMCC11, BROMO-10 and HYPOXIA-28). Results: 1308 regulons were correlated to transcriptomic data from the three clinical prostatectomy cohorts. The JMJD6 regulon was identified as the top enriched regulon in the UTA cohort and again validated in the EMC cohort as the top-ranking regulon. In both UTA and EMC cohorts, the JMJD6 regulon was significantly associated with cancer recurrence. Active JMJD6 regulon also correlated with disease recurrence in the ICGC cohort. Furthermore, Kaplan–Meier analysis confirmed shorter time to recurrence in patients with active JMJD6 regulon for all three clinical cohorts (UTA, EMC and ICGC), which was not the case for three published prognostic gene signatures (TMCC11, BROMO-10 and HYPOXIA-28). In multivariate analysis, the JMJD6 regulon status significantly predicted disease recurrence in the UTA and EMC, but not ICGC datasets, while none of the three published signatures significantly prognosticate for cancer recurrence. Conclusions: We have characterised gene regulatory networks from preclinical prostate orthografts and applied transcriptomic data from three clinical cohorts to evaluate the prognostic potential of the JMJD6 regulon. Full article
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10 pages, 1222 KiB  
Article
Increased Pathway Complexity Is a Prognostic Biomarker in Metastatic Castration-Resistant Prostate Cancer
by Bram De Laere, Alessio Crippa, Ashkan Mortezavi, Christophe Ghysel, Prabhakar Rajan, Martin Eklund, Alexander Wyatt, Luc Dirix, Piet Ost, Henrik Grönberg, Johan Lindberg and on behalf of the CORE and ProBio Investigators
Cancers 2021, 13(7), 1588; https://doi.org/10.3390/cancers13071588 - 30 Mar 2021
Cited by 1 | Viewed by 3061
Abstract
Metastatic castration-resistant prostate cancer (mCRPC) is a heterogeneous disease, characterized by common and rare driver gene alterations that provide a selective growth advantage for progressing tumour cells. We hypothesized that the number of distinct gene driver alteration-affected pathways or gene classes was associated [...] Read more.
Metastatic castration-resistant prostate cancer (mCRPC) is a heterogeneous disease, characterized by common and rare driver gene alterations that provide a selective growth advantage for progressing tumour cells. We hypothesized that the number of distinct gene driver alteration-affected pathways or gene classes was associated with poor prognosis in patients initiating androgen receptor signalling inhibitors (ARSi). We performed a post hoc analysis of an amalgamated baseline circulating tumour DNA (ctDNA) mutational landscape dataset of ARSi-treated men with mCRPC (n = 342). We associated the detected hotspot, pathogenic, and/or high impact protein function-affecting perturbations in 39 genes into 13 pathways. Progression-free (PFS) and overall survival (OS) were analysed using Kaplan–Meier curves and multivariate Cox regression models. Driver gene alterations were detected in 192/342 (56.1%) evaluable patients. An increased number of affected pathways, coined pathway complexity index (PCI), resulted in a decremental PFS and OS, and was independently associated with prognosis once ≥3 pathway or gene classes were affected (PFS HR (95%CI): 1.7 (1.02–2.84), p = 0.04, and OS HR (95%CI): 2.5 (1.06–5.71), p = 0.04). Additionally, visceral disease and baseline PSA and plasma ctDNA levels were independently associated with poor prognosis. Elevated PCI is associated with poor ARSi outcome and supports comprehensive genomic profiling to better infer mCRPC prognosis. Full article
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17 pages, 3789 KiB  
Article
STAMP2 Expression Mediated by Cytokines Attenuates Their Growth-Limiting Effects in Prostate Cancer Cells
by Nicklas Pihlstrøm, Yang Jin, Zeynep Nenseth, Omer F. Kuzu and Fahri Saatcioglu
Cancers 2021, 13(7), 1579; https://doi.org/10.3390/cancers13071579 - 30 Mar 2021
Cited by 10 | Viewed by 2656
Abstract
Inflammatory events and dysregulated cytokine expression are implicated in prostate cancer (PCa), but the underlying molecular mechanisms are poorly understood at present. We have previously identified six transmembrane protein of the prostate 2 (STAMP2, also known as STEAP4) as an androgen-regulated gene, as [...] Read more.
Inflammatory events and dysregulated cytokine expression are implicated in prostate cancer (PCa), but the underlying molecular mechanisms are poorly understood at present. We have previously identified six transmembrane protein of the prostate 2 (STAMP2, also known as STEAP4) as an androgen-regulated gene, as well as a key regulator of PCa growth and survival. STAMP2 is also regulated by, and participates in, inflammatory signaling in other tissues and pathologies. Here, we show that the proinflammatory cytokines interleukin 6 (IL-6) and Interleukin 1 beta (IL-1β) significantly increase and strongly synergize in promoting STAMP2 expression in PCa cells. The two cytokines increase androgen-induced STAMP2 expression, but not expression of other known androgen target genes, suggesting a unique interplay of androgens and cytokines in regulating STAMP2 expression. Interestingly, STAMP2 knockdown significantly increased the ability of IL-6 and IL-1β to inhibit PCa cell growth in vitro. These results suggest that STAMP2 may represent a unique node through which inflammatory events mediate their effects on PCa growth and survival. Full article
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16 pages, 730 KiB  
Review
Preclinical Models in Prostate Cancer: Resistance to AR Targeting Therapies in Prostate Cancer
by Wout Devlies, Florian Handle, Gaëtan Devos, Steven Joniau and Frank Claessens
Cancers 2021, 13(4), 915; https://doi.org/10.3390/cancers13040915 - 22 Feb 2021
Cited by 14 | Viewed by 4049
Abstract
Prostate cancer is an androgen-driven tumor. Different prostate cancer therapies consequently focus on blocking the androgen receptor pathway. Clinical studies reported tumor resistance mechanisms by reactivating and bypassing the androgen pathway. Preclinical models allowed the identification, confirmation, and thorough study of these pathways. [...] Read more.
Prostate cancer is an androgen-driven tumor. Different prostate cancer therapies consequently focus on blocking the androgen receptor pathway. Clinical studies reported tumor resistance mechanisms by reactivating and bypassing the androgen pathway. Preclinical models allowed the identification, confirmation, and thorough study of these pathways. This review looks into the current and future role of preclinical models to understand resistance to androgen receptor-targeted therapies. Increasing knowledge on this resistance will greatly improve insights into tumor pathophysiology and future treatment strategies in prostate cancer. Full article
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19 pages, 1730 KiB  
Review
The Value of Real-World Data in Understanding Prostate Cancer Risk and Improving Clinical Care: Examples from Swedish Registries
by Kerri Beckmann, Hans Garmo, Ingela Franck Lissbrant and Pär Stattin
Cancers 2021, 13(4), 875; https://doi.org/10.3390/cancers13040875 - 19 Feb 2021
Cited by 9 | Viewed by 4543
Abstract
Real-world data (RWD), that is, data from sources other than controlled clinical trials, play an increasingly important role in medical research. The development of quality clinical registers, increasing access to administrative data sources, growing computing power and data linkage capacities have contributed to [...] Read more.
Real-world data (RWD), that is, data from sources other than controlled clinical trials, play an increasingly important role in medical research. The development of quality clinical registers, increasing access to administrative data sources, growing computing power and data linkage capacities have contributed to greater availability of RWD. Evidence derived from RWD increases our understanding of prostate cancer (PCa) aetiology, natural history and effective management. While randomised controlled trials offer the best level of evidence for establishing the efficacy of medical interventions and making causal inferences, studies using RWD offer complementary evidence about the effectiveness, long-term outcomes and safety of interventions in real-world settings. RWD provide the only means of addressing questions about risk factors and exposures that cannot be “controlled”, or when assessing rare outcomes. This review provides examples of the value of RWD for generating evidence about PCa, focusing on studies using data from a quality clinical register, namely the National Prostate Cancer Register (NPCR) Sweden, with longitudinal data on advanced PCa in Patient-overview Prostate Cancer (PPC) and data linkages to other sources in Prostate Cancer data Base Sweden (PCBaSe). Full article
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25 pages, 1236 KiB  
Review
Preclinical and Clinical Status of PSMA-Targeted Alpha Therapy for Metastatic Castration-Resistant Prostate Cancer
by Asta Juzeniene, Vilde Yuli Stenberg, Øyvind Sverre Bruland and Roy Hartvig Larsen
Cancers 2021, 13(4), 779; https://doi.org/10.3390/cancers13040779 - 13 Feb 2021
Cited by 52 | Viewed by 6809
Abstract
Bone, lymph node, and visceral metastases are frequent in castrate-resistant prostate cancer patients. Since such patients have only a few months’ survival benefit from standard therapies, there is an urgent need for new personalized therapies. The prostate-specific membrane antigen (PSMA) is overexpressed in [...] Read more.
Bone, lymph node, and visceral metastases are frequent in castrate-resistant prostate cancer patients. Since such patients have only a few months’ survival benefit from standard therapies, there is an urgent need for new personalized therapies. The prostate-specific membrane antigen (PSMA) is overexpressed in prostate cancer and is a molecular target for imaging diagnostics and targeted radionuclide therapy (theragnostics). PSMA-targeted α therapies (PSMA-TAT) may deliver potent and local radiation more selectively to cancer cells than PSMA-targeted β therapies. In this review, we summarize both the recent preclinical and clinical advances made in the development of PSMA-TAT, as well as the availability of therapeutic α-emitting radionuclides, the development of small molecules and antibodies targeting PSMA. Lastly, we discuss the potentials, limitations, and future perspectives of PSMA-TAT. Full article
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26 pages, 1842 KiB  
Review
Identification of Germline Genetic Variants that Increase Prostate Cancer Risk and Influence Development of Aggressive Disease
by Edward J. Saunders, Zsofia Kote-Jarai and Rosalind A. Eeles
Cancers 2021, 13(4), 760; https://doi.org/10.3390/cancers13040760 - 12 Feb 2021
Cited by 25 | Viewed by 4210
Abstract
Prostate cancer (PrCa) is a heterogeneous disease, which presents in individual patients across a diverse phenotypic spectrum ranging from indolent to fatal forms. No robust biomarkers are currently available to enable routine screening for PrCa or to distinguish clinically significant forms, therefore late [...] Read more.
Prostate cancer (PrCa) is a heterogeneous disease, which presents in individual patients across a diverse phenotypic spectrum ranging from indolent to fatal forms. No robust biomarkers are currently available to enable routine screening for PrCa or to distinguish clinically significant forms, therefore late stage identification of advanced disease and overdiagnosis plus overtreatment of insignificant disease both remain areas of concern in healthcare provision. PrCa has a substantial heritable component, and technological advances since the completion of the Human Genome Project have facilitated improved identification of inherited genetic factors influencing susceptibility to development of the disease within families and populations. These genetic markers hold promise to enable improved understanding of the biological mechanisms underpinning PrCa development, facilitate genetically informed PrCa screening programmes and guide appropriate treatment provision. However, insight remains largely lacking regarding many aspects of their manifestation; especially in relation to genes associated with aggressive phenotypes, risk factors in non-European populations and appropriate approaches to enable accurate stratification of higher and lower risk individuals. This review discusses the methodology used in the elucidation of genetic loci, genes and individual causal variants responsible for modulating PrCa susceptibility; the current state of understanding of the allelic spectrum contributing to PrCa risk; and prospective future translational applications of these discoveries in the developing eras of genomics and personalised medicine. Full article
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15 pages, 958 KiB  
Review
Pharmacoepidemiological Evaluation in Prostate Cancer—Common Pitfalls and How to Avoid Them
by Aino Siltari, Anssi Auvinen and Teemu J. Murtola
Cancers 2021, 13(4), 696; https://doi.org/10.3390/cancers13040696 - 9 Feb 2021
Cited by 6 | Viewed by 2944
Abstract
Pharmacoepidemiologic research provides opportunities to evaluate how commonly used drug groups, such as cholesterol-lowering or antidiabetic drugs, may affect the prostate cancer risk or mortality. This type of research is valuable in estimating real-life drug effects. Nonetheless, pharmacoepidemiological studies are prone to multiple [...] Read more.
Pharmacoepidemiologic research provides opportunities to evaluate how commonly used drug groups, such as cholesterol-lowering or antidiabetic drugs, may affect the prostate cancer risk or mortality. This type of research is valuable in estimating real-life drug effects. Nonetheless, pharmacoepidemiological studies are prone to multiple sources of bias that mainly arise from systematic differences between medication users and non-users. If these are not appreciated and properly controlled for, there is a risk of obtaining biased results and reaching erroneous conclusions. Therefore, in order to improve the quality of future research, we describe common biases in pharmacoepidemiological studies, particularly in the context of prostate cancer research. We also list common ways to mitigate these biases and to estimate causality between medication use and cancer outcomes. Full article
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25 pages, 1280 KiB  
Review
Molecular and Functional Links between Neurodevelopmental Processes and Treatment-Induced Neuroendocrine Plasticity in Prostate Cancer Progression
by Roosa Kaarijärvi, Heidi Kaljunen and Kirsi Ketola
Cancers 2021, 13(4), 692; https://doi.org/10.3390/cancers13040692 - 9 Feb 2021
Cited by 18 | Viewed by 4647
Abstract
Neuroendocrine plasticity and treatment-induced neuroendocrine phenotypes have recently been proposed as important resistance mechanisms underlying prostate cancer progression. Treatment-induced neuroendocrine prostate cancer (t-NEPC) is highly aggressive subtype of castration-resistant prostate cancer which develops for one fifth of patients under prolonged androgen deprivation. In [...] Read more.
Neuroendocrine plasticity and treatment-induced neuroendocrine phenotypes have recently been proposed as important resistance mechanisms underlying prostate cancer progression. Treatment-induced neuroendocrine prostate cancer (t-NEPC) is highly aggressive subtype of castration-resistant prostate cancer which develops for one fifth of patients under prolonged androgen deprivation. In recent years, understanding of molecular features and phenotypic changes in neuroendocrine plasticity has been grown. However, there are still fundamental questions to be answered in this emerging research field, for example, why and how do the prostate cancer treatment-resistant cells acquire neuron-like phenotype. The advantages of the phenotypic change and the role of tumor microenvironment in controlling cellular plasticity and in the emergence of treatment-resistant aggressive forms of prostate cancer is mostly unknown. Here, we discuss the molecular and functional links between neurodevelopmental processes and treatment-induced neuroendocrine plasticity in prostate cancer progression and treatment resistance. We provide an overview of the emergence of neurite-like cells in neuroendocrine prostate cancer cells and whether the reported t-NEPC pathways and proteins relate to neurodevelopmental processes like neurogenesis and axonogenesis during the development of treatment resistance. We also discuss emerging novel therapeutic targets modulating neuroendocrine plasticity. Full article
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21 pages, 948 KiB  
Review
Grading Evolution and Contemporary Prognostic Biomarkers of Clinically Significant Prostate Cancer
by Konrad Sopyllo, Andrew M. Erickson and Tuomas Mirtti
Cancers 2021, 13(4), 628; https://doi.org/10.3390/cancers13040628 - 5 Feb 2021
Cited by 8 | Viewed by 2931
Abstract
Gleason grading remains the strongest prognostic parameter in localized prostate adenocarcinoma. We have here outlined the evolution and contemporary practices in pathological evaluation of prostate tissue samples for Gleason score and Grade group. The state of more observer-independent grading methods with the aid [...] Read more.
Gleason grading remains the strongest prognostic parameter in localized prostate adenocarcinoma. We have here outlined the evolution and contemporary practices in pathological evaluation of prostate tissue samples for Gleason score and Grade group. The state of more observer-independent grading methods with the aid of artificial intelligence is also reviewed. Additionally, we conducted a systematic review of biomarkers that hold promise in adding independent prognostic or predictive value on top of clinical parameters, Grade group and PSA. We especially focused on hard end points during the follow-up, i.e., occurrence of metastasis, disease-specific mortality and overall mortality. In peripheral blood, biopsy-detected prostate cancer or in surgical specimens, we can conclude that there are more than sixty biomarkers that have been shown to have independent prognostic significance when adjusted to conventional risk assessment or grouping. Our search brought up some known putative markers and panels, as expected. Also, the synthesis in the systematic review indicated markers that ought to be further studied as part of prospective trials and in well characterized patient cohorts in order to increase the resolution of the current clinico-pathological prognostic factors. Full article
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17 pages, 1037 KiB  
Review
Targeting the Hippo Pathway in Prostate Cancer: What’s New?
by Kelly Coffey
Cancers 2021, 13(4), 611; https://doi.org/10.3390/cancers13040611 - 4 Feb 2021
Cited by 14 | Viewed by 4471
Abstract
Identifying novel therapeutic targets for the treatment of prostate cancer (PC) remains a key area of research. With the emergence of resistance to androgen receptor (AR)-targeting therapies, other signalling pathways which crosstalk with AR signalling are important. Over recent years, evidence has accumulated [...] Read more.
Identifying novel therapeutic targets for the treatment of prostate cancer (PC) remains a key area of research. With the emergence of resistance to androgen receptor (AR)-targeting therapies, other signalling pathways which crosstalk with AR signalling are important. Over recent years, evidence has accumulated for targeting the Hippo signalling pathway. Discovered in Drosophila melanogasta, the Hippo pathway plays a role in the regulation of organ size, proliferation, migration and invasion. In response to a variety of stimuli, including cell–cell contact, nutrients and stress, a kinase cascade is activated, which includes STK4/3 and LATS1/2 to inhibit the effector proteins YAP and its paralogue TAZ. Transcription by their partner transcription factors is inhibited by modulation of YAP/TAZ cellular localisation and protein turnover. Trnascriptional enhanced associate domain (TEAD) transcription factors are their classical transcriptional partner but other transcription factors, including the AR, have been shown to be modulated by YAP/TAZ. In PC, this pathway can be dysregulated by a number of mechanisms, making it attractive for therapeutic intervention. This review looks at each component of the pathway with a focus on findings from the last year and discusses what knowledge can be applied to the field of PC. Full article
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19 pages, 1526 KiB  
Review
Eighty Years of Targeting Androgen Receptor Activity in Prostate Cancer: The Fight Goes on
by Eva Estébanez-Perpiñá, Charlotte L. Bevan and Iain J. McEwan
Cancers 2021, 13(3), 509; https://doi.org/10.3390/cancers13030509 - 29 Jan 2021
Cited by 32 | Viewed by 6300
Abstract
Prostate cancer (PCa) is the most common cancer in men in the West, other than skin cancer, accounting for over a quarter of cancer diagnoses in US men. In a seminal paper from 1941, Huggins and Hodges demonstrated that prostate tumours and metastatic [...] Read more.
Prostate cancer (PCa) is the most common cancer in men in the West, other than skin cancer, accounting for over a quarter of cancer diagnoses in US men. In a seminal paper from 1941, Huggins and Hodges demonstrated that prostate tumours and metastatic disease were sensitive to the presence or absence of androgenic hormones. The first hormonal therapy for PCa was thus castration. In the subsequent eighty years, targeting the androgen signalling axis, where possible using drugs rather than surgery, has been a mainstay in the treatment of advanced and metastatic disease. Androgens signal via the androgen receptor, a ligand-activated transcription factor, which is the direct target of many such drugs. In this review we discuss the role of the androgen receptor in PCa and how the combination of structural information and functional screenings is continuing to be used for the discovery of new drug to switch off the receptor or modify its function in cancer cells. Full article
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25 pages, 4651 KiB  
Review
Derivation and Application of Molecular Signatures to Prostate Cancer: Opportunities and Challenges
by Dimitrios Doultsinos and Ian G. Mills
Cancers 2021, 13(3), 495; https://doi.org/10.3390/cancers13030495 - 28 Jan 2021
Cited by 16 | Viewed by 4076
Abstract
Prostate cancer is a high-incidence cancer that requires improved patient stratification to ensure accurate predictions of risk and treatment response. Due to the significant contributions of transcription factors and epigenetic regulators to prostate cancer progression, there has been considerable progress made in developing [...] Read more.
Prostate cancer is a high-incidence cancer that requires improved patient stratification to ensure accurate predictions of risk and treatment response. Due to the significant contributions of transcription factors and epigenetic regulators to prostate cancer progression, there has been considerable progress made in developing gene signatures that may achieve this. Some of these are aligned to activities of key drivers such as the androgen receptor, whilst others are more agnostic. In this review, we present an overview of these signatures, the strategies for their derivation, and future perspectives on their continued development and evolution. Full article
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32 pages, 18029 KiB  
Review
Resistance to Antiandrogens in Prostate Cancer: Is It Inevitable, Intrinsic or Induced?
by Norman J. Maitland
Cancers 2021, 13(2), 327; https://doi.org/10.3390/cancers13020327 - 17 Jan 2021
Cited by 26 | Viewed by 4782
Abstract
Increasingly sophisticated therapies for chemical castration dominate first-line treatments for locally advanced prostate cancer. However, androgen deprivation therapy (ADT) offers little prospect of a cure, as resistant tumors emerge rather rapidly, normally within 30 months. Cells have multiple mechanisms of resistance to even [...] Read more.
Increasingly sophisticated therapies for chemical castration dominate first-line treatments for locally advanced prostate cancer. However, androgen deprivation therapy (ADT) offers little prospect of a cure, as resistant tumors emerge rather rapidly, normally within 30 months. Cells have multiple mechanisms of resistance to even the most sophisticated drug regimes, and both tumor cell heterogeneity in prostate cancer and the multiple salvage pathways result in castration-resistant disease related genetically to the original hormone-naive cancer. The timing and mechanisms of cell death after ADT for prostate cancer are not well understood, and off-target effects after long-term ADT due to functional extra-prostatic expression of the androgen receptor protein are now increasingly being recorded. Our knowledge of how these widely used treatments fail at a biological level in patients is deficient. In this review, I will discuss whether there are pre-existing drug-resistant cells in a tumor mass, or whether resistance is induced/selected by the ADT. Equally, what is the cell of origin of this resistance, and does it differ from the treatment-naïve tumor cells by differentiation or dedifferentiation? Conflicting evidence also emerges from studies in the range of biological systems and species employed to answer this key question. It is only by improving our understanding of this aspect of treatment and not simply devising another new means of androgen inhibition that we can improve patient outcomes. Full article
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2020

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17 pages, 2379 KiB  
Article
ATM Kinase Inhibition Preferentially Sensitises PTEN-Deficient Prostate Tumour Cells to Ionising Radiation
by Conor Hanna, Victoria L. Dunne, Steven M. Walker, Karl T. Butterworth, Nuala McCabe, David J. J. Waugh, Richard D. Kennedy and Kevin M. Prise
Cancers 2021, 13(1), 79; https://doi.org/10.3390/cancers13010079 - 30 Dec 2020
Cited by 5 | Viewed by 2698
Abstract
Radical radiotherapy, often in combination with hormone ablation, is a safe and effective treatment option for localised or locally-advanced prostate cancer. However, up to 30% of patients with locally advanced PCa will go on to develop biochemical failure, within 5 years, following initial [...] Read more.
Radical radiotherapy, often in combination with hormone ablation, is a safe and effective treatment option for localised or locally-advanced prostate cancer. However, up to 30% of patients with locally advanced PCa will go on to develop biochemical failure, within 5 years, following initial radiotherapy. Improving radiotherapy response is clinically important since patients exhibiting biochemical failure develop castrate-resistant metastatic disease for which there is no curative therapy and median survival is 8–18 months. The aim of this research was to determine if loss of PTEN (highly prevalent in advanced prostate cancer) is a novel therapeutic target in the treatment of advanced prostate cancer. Previous work has demonstrated PTEN-deficient cells are sensitised to inhibitors of ATM, a key regulator in the response to DSBs. Here, we have shown the role of PTEN in cellular response to IR was both complex and context-dependent. Secondly, we have confirmed ATM inhibition in PTEN-depleted cell models, enhances ionising radiation-induced cell killing with minimal toxicity to normal prostate RWPE-1 cells. Furthermore, combined treatment significantly inhibited PTEN-deficient tumour growth compared to PTEN-expressing counterparts, with minimal toxicity observed. We have further shown PTEN loss is accompanied by increased endogenous levels of ROS and DNA damage. Taken together, these findings provide pre-clinical data for future clinical evaluation of ATM inhibitors as a neoadjuvant/adjuvant in combination with radiation therapy in prostate cancer patients harbouring PTEN mutations. Full article
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20 pages, 632 KiB  
Review
Commercialized Blood-, Urinary- and Tissue-Based Biomarker Tests for Prostate Cancer Diagnosis and Prognosis
by Wieke C. H. Visser, Hans de Jong, Willem J. G. Melchers, Peter F. A. Mulders and Jack A. Schalken
Cancers 2020, 12(12), 3790; https://doi.org/10.3390/cancers12123790 - 16 Dec 2020
Cited by 18 | Viewed by 4327
Abstract
In the diagnosis and prognosis of prostate cancer (PCa), the serum prostate-specific antigen test is widely used but is associated with low specificity. Therefore, blood-, urinary- and tissue-based biomarker tests have been developed, intended to be used in the diagnostic and prognostic setting [...] Read more.
In the diagnosis and prognosis of prostate cancer (PCa), the serum prostate-specific antigen test is widely used but is associated with low specificity. Therefore, blood-, urinary- and tissue-based biomarker tests have been developed, intended to be used in the diagnostic and prognostic setting of PCa. This review provides an overview of commercially available biomarker tests developed to be used in several clinical stages of PCa management. In the diagnostic setting, the following tests can help selecting the right patients for initial and/or repeat biopsy: PHI, 4K, MiPS, SelectMDx, ExoDx, Proclarix, ConfirmMDx, PCA3 and PCMT. In the prognostic setting, the Prolaris, OncotypeDx and Decipher test can help in risk-stratification of patients regarding treatment decisions. Following, an overview is provided of the studies available comparing the performance of biomarker tests. However, only a small number of recently published head-to-head comparison studies are available. In contrast, recent research has focused on the use of biomarker tests in relation to the (complementary) use of multiparametric magnetic resonance imaging in PCa diagnosis. Full article
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20 pages, 270 KiB  
Review
Ablative Radiotherapy in Prostate Cancer: Stereotactic Body Radiotherapy and High Dose Rate Brachytherapy
by Ting Martin Ma, Oscar Lilleby, Wolfgang A. Lilleby and Amar U. Kishan
Cancers 2020, 12(12), 3606; https://doi.org/10.3390/cancers12123606 - 2 Dec 2020
Cited by 6 | Viewed by 2565
Abstract
Prostate cancer (PCa) is the most common noncutaneous solid organ malignancy among men worldwide. Radiation therapy is a standard of care treatment option that has historically been delivered in the form of small daily doses of radiation over the span of multiple weeks. [...] Read more.
Prostate cancer (PCa) is the most common noncutaneous solid organ malignancy among men worldwide. Radiation therapy is a standard of care treatment option that has historically been delivered in the form of small daily doses of radiation over the span of multiple weeks. PCa appears to have a unique sensitivity to higher doses of radiation per fraction, rendering it susceptible to abbreviated forms of treatment. Stereotactic body radiation therapy (SBRT) and high-dose-rate brachytherapy (HDRBT) are both modern radiation modalities that allow the precise delivery of ablative doses of radiation to the prostate while maximally sparing sensitive surrounding normal structures. In this review, we highlight the evidence regarding the radiobiology, oncological outcomes, toxicity and dose/fractionation schemes of SBRT and HDRBT monotherapy in men with low-and intermediate-risk PCa. Full article
24 pages, 760 KiB  
Review
Inflammation as a Driver of Prostate Cancer Metastasis and Therapeutic Resistance
by Maddison Archer, Navneet Dogra and Natasha Kyprianou
Cancers 2020, 12(10), 2984; https://doi.org/10.3390/cancers12102984 - 15 Oct 2020
Cited by 81 | Viewed by 7920
Abstract
Prostate cancer is the most common malignancy among men, and progression to metastasis and the emergence of therapeutically resistant disease confers a high mortality rate. Growing evidence implicates inflammation as a driver of prostate cancer development and progression, resulting in increased cancer risk [...] Read more.
Prostate cancer is the most common malignancy among men, and progression to metastasis and the emergence of therapeutically resistant disease confers a high mortality rate. Growing evidence implicates inflammation as a driver of prostate cancer development and progression, resulting in increased cancer risk for prostate cancer. Population-based studies revealed that the use of antinflammatory drugs led to a 23% risk reduction prostate cancer occurrence, a negative association that was stronger in men who specifically used COX-2 inhibitors. Furthermore, patients that were taking aspirin had a 21% reduction in prostate cancer risk, and further, long-term users of daily low dose aspirin had a 29% prostate cancer risk reduction as compared to the controls. Environmental exposure to bacterial and viral infections, exposure to mutagenic agents, and genetic variations predispose the prostate gland to inflammation, with a coordinated elevated expression of inflammatory cytokines (IL-6, TGF-β). It is the dynamics within the tumor microenvironment that empower these cytokines to promote survival and growth of the primary tumor and facilitate disease progression by navigating the immunoregulatory network, phenotypic epithelial-mesenchymal transition (EMT), angiogenesis, anoikis resistance, and metastasis. In this review, we discuss the sources of inflammation in the prostate, the functional contribution of the critical inflammatory effectors to prostate cancer initiation and metastatic progression, and the therapeutic challenges that they impose on treatment of advanced disease and overcoming therapeutic resistance. Growing mechanistic evidence supports the significance of inflammation in localized prostate cancer, and the systemic impact of the process within the tumor microenvironment on disease progression to advanced therapeutically-resistant prostate cancer. Rigorous exploitation of the role of inflammation in prostate cancer progression to metastasis and therapeutic resistance will empower the development of precise biomarker signatures and effective targeted therapeutics to reduce the clinical burden and lethal disease in the future. Full article
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15 pages, 3037 KiB  
Article
Impact of Vasectomy on the Development and Progression of Prostate Cancer: Preclinical Evidence
by Takashi Kawahara, Yuki Teramoto, Yi Li, Hitoshi Ishiguro, Jennifer Gordetsky, Zhiming Yang and Hiroshi Miyamoto
Cancers 2020, 12(8), 2295; https://doi.org/10.3390/cancers12082295 - 15 Aug 2020
Cited by 6 | Viewed by 3401
Abstract
Some observational studies have implied a link between vasectomy and an elevated risk of prostate cancer. We investigated the impact of vasectomy on prostate cancer outgrowth, mainly using preclinical models. Neoplastic changes in the prostate were compared in transgenic TRAMP mice that underwent [...] Read more.
Some observational studies have implied a link between vasectomy and an elevated risk of prostate cancer. We investigated the impact of vasectomy on prostate cancer outgrowth, mainly using preclinical models. Neoplastic changes in the prostate were compared in transgenic TRAMP mice that underwent vasectomy vs. sham surgery performed at 4 weeks of age. One of the molecules identified by DNA microarray (i.e., ZKSCAN3) was then assessed in radical prostatectomy specimens and human prostate cancer lines. At 24 weeks, gross tumor (p = 0.089) and poorly differentiated adenocarcinoma (p = 0.036) occurred more often in vasectomized mice. Vasectomy significantly induced ZKSCAN3 expression in prostate tissues from C57BL/6 mice and prostate cancers from TRAMP mice. Immunohistochemistry showed increased ZKSCAN3 expression in adenocarcinoma vs. prostatic intraepithelial neoplasia (PIN), PIN vs. non-neoplastic prostate, Grade Group ≥3 vs. ≤2 tumors, pT3 vs. pT2 tumors, pN1 vs. pN0 tumors, and prostate cancer from patients with a history of vasectomy. Additionally, strong (2+/3+) ZKSCAN3 expression (p = 0.002), as an independent prognosticator, or vasectomy (p = 0.072) was associated with the risk of tumor recurrence. In prostate cancer lines, ZKSCAN3 silencing resulted in significant decreases in cell proliferation/migration/invasion. These findings suggest that there might be an association between vasectomy and the development and progression of prostate cancer, with up-regulation of ZKSCAN3 expression as a potential underlying mechanism. Full article
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15 pages, 1296 KiB  
Article
Characteristics of PSA Bounce after Radiotherapy for Prostate Cancer: A Meta-Analysis
by Narisa Dewi Maulany Darwis, Takahiro Oike, Nobuteru Kubo, Soehartati A Gondhowiardjo and Tatsuya Ohno
Cancers 2020, 12(8), 2180; https://doi.org/10.3390/cancers12082180 - 5 Aug 2020
Cited by 10 | Viewed by 5818
Abstract
The rate and characteristics of prostate-specific antigen (PSA) bounce post-radiotherapy remain unclear. To address this issue, we performed a meta-analysis. Reports of PSA bounce post-radiotherapy with a cutoff of 0.2 ng/mL were searched by using Medline and Web of Science. The primary endpoint [...] Read more.
The rate and characteristics of prostate-specific antigen (PSA) bounce post-radiotherapy remain unclear. To address this issue, we performed a meta-analysis. Reports of PSA bounce post-radiotherapy with a cutoff of 0.2 ng/mL were searched by using Medline and Web of Science. The primary endpoint was the occurrence rate, and the secondary endpoints were bounce characteristics such as amplitude, time to occurrence, nadir value, and time to nadir. Radiotherapy modality, age, risk classification, androgen deprivation therapy, and the follow-up period were extracted as clinical variables. Meta-analysis and univariate meta-regression were performed with random-effect modeling. Among 290 search-positive studies, 50 reports including 26,258 patients were identified. The rate of bounce was 31%; amplitude was 1.3 ng/mL; time to occurrence was 18 months; nadir value was 0.5 ng/mL; time to nadir was 33 months. Univariate meta-regression analysis showed that radiotherapy modality (29.7%), age (20.2%), and risk classification (12.2%) were the major causes of heterogeneity in the rate of bounce. This is the first meta-analysis of PSA bounce post-radiotherapy. The results are useful for post-radiotherapy surveillance of prostate cancer patients. Full article
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18 pages, 1131 KiB  
Review
Mechanisms of Androgen Receptor Agonist- and Antagonist-Mediated Cellular Senescence in Prostate Cancer
by Miriam Kokal, Kimia Mirzakhani, Thanakorn Pungsrinont and Aria Baniahmad
Cancers 2020, 12(7), 1833; https://doi.org/10.3390/cancers12071833 - 8 Jul 2020
Cited by 27 | Viewed by 6881
Abstract
The androgen receptor (AR) plays a leading role in the control of prostate cancer (PCa) growth. Interestingly, structurally different AR antagonists with distinct mechanisms of antagonism induce cell senescence, a mechanism that inhibits cell cycle progression, and thus seems to be a key [...] Read more.
The androgen receptor (AR) plays a leading role in the control of prostate cancer (PCa) growth. Interestingly, structurally different AR antagonists with distinct mechanisms of antagonism induce cell senescence, a mechanism that inhibits cell cycle progression, and thus seems to be a key cellular response for the treatment of PCa. Surprisingly, while physiological levels of androgens promote growth, supraphysiological androgen levels (SAL) inhibit PCa growth in an AR-dependent manner by inducing cell senescence in cancer cells. Thus, oppositional acting ligands, AR antagonists, and agonists are able to induce cellular senescence in PCa cells, as shown in cell culture model as well as ex vivo in patient tumor samples. This suggests a dual AR-signaling dependent on androgen levels that leads to the paradox of the rational to keep the AR constantly inactivated in order to treat PCa. These observations however opened the option to treat PCa patients with AR antagonists and/or with androgens at supraphysiological levels. The latter is currently used in clinical trials in so-called bipolar androgen therapy (BAT). Notably, cellular senescence is induced by AR antagonists or agonist in both androgen-dependent and castration-resistant PCa (CRPC). Pathway analysis suggests a crosstalk between AR and the non-receptor tyrosine kinase Src-Akt/PKB and the PI3K-mTOR-autophagy signaling in mediating AR-induced cellular senescence in PCa. In this review, we summarize the current knowledge of therapeutic induction and intracellular pathways of AR-mediated cellular senescence. Full article
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