Life | Special Issue : Prostate Cancer

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Predictive Value of Circulating Tumor Cells Detected by ISET^® in Patients with Non-Metastatic Prostate Cancer Undergoing Radical Prostatectomy

by Laura Nalleli Garrido Castillo, Arnaud Mejean, Philippe Vielh, Julien Anract, Alessandra Decina, Bertrand Nalpas, Naoual Benali-Furet, Isabelle Desitter and Patrizia Paterlini-Bréchot

Life 2022, 12(2), 165; https://doi.org/10.3390/life12020165 - 22 Jan 2022

Cited by 1 | Viewed by 2575

Abstract

There is an unmet need for reliable biomarkers to predict prostate cancer recurrence after prostatectomy in order to better guide the choice of surgical treatment. We have evaluated the predictive value of the preoperative detection of Circulating Tumor Cells (CTC) for prostate cancer [...] Read more.

There is an unmet need for reliable biomarkers to predict prostate cancer recurrence after prostatectomy in order to better guide the choice of surgical treatment. We have evaluated the predictive value of the preoperative detection of Circulating Tumor Cells (CTC) for prostate cancer recurrence after surgery. A cohort of 108 patients with non-metastatic prostate adenocarcinoma undergoing radical prostatectomy was tested for the presence of CTC before prostatectomy using ISET^®. Disease recurrence was assessed by the increase in serum PSA level after prostatectomy. The following factors were assessed for statistical association with prostate cancer recurrence: the presence of CTC, serum PSA, Gleason score, and pT stage using univariate and multivariate analyses, with a mean follow-up of 34.9 months. Prostate cancer recurrence was significantly associated with the presence of at least 1 CTC at the preoperative time point (p < 0.001; Predictive value = 0.83). Conversely, the absence of prostate cancer recurrence was significantly associated with the lack of CTC detection at diagnosis (Predictive value = 1). Our multivariate analysis shows that only CTC presence is an independent risk factor associated with prostate cancer recurrence after prostatectomy (p < 0.001). Our results suggest that CTC detection by ISET^® before surgery is an interesting candidate predictive marker for cancer recurrence in patients with non-metastatic PCa. Full article

(This article belongs to the Special Issue Prostate Cancer)

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12 pages, 2996 KiB

Open AccessEditor’s ChoiceArticle

Promoter Demethylation Upregulates STEAP1 Gene Expression in Human Prostate Cancer: In Vitro and In Silico Analysis

by Sandra M. Rocha, Inês Sousa, Inês M. Gomes, Patrícia Arinto, Pedro Costa-Pinheiro, Eduarda Coutinho, Cecília R. Santos, Carmen Jerónimo, Manuel C. Lemos, Luís A. Passarinha, Sílvia Socorro and Cláudio J. Maia

Life 2021, 11(11), 1251; https://doi.org/10.3390/life11111251 - 17 Nov 2021

Cited by 5 | Viewed by 2212

Abstract

The Six Transmembrane Epithelial Antigen of the Prostate (STEAP1) is an oncogene overexpressed in several human tumors, particularly in prostate cancer (PCa). However, the mechanisms involved in its overexpression remain unknown. It is well known that epigenetic modifications may result in [...] Read more.

The Six Transmembrane Epithelial Antigen of the Prostate (STEAP1) is an oncogene overexpressed in several human tumors, particularly in prostate cancer (PCa). However, the mechanisms involved in its overexpression remain unknown. It is well known that epigenetic modifications may result in abnormal gene expression patterns, contributing to tumor initiation and progression. Therefore, this study aimed to analyze the methylation pattern of the STEAP1 gene in PCa versus non-neoplastic cells. Bisulfite amplicon sequencing of the CpG island at the STEAP1 gene promoter showed a higher methylation level in non-neoplastic PNT1A prostate cells than in human PCa samples. Bioinformatic analysis of the GEO datasets also showed the STEAP1 gene promoter as being demethylated in human PCa, and a negative association with STEAP1 mRNA expression was observed. These results are supported by the treatment of non-neoplastic PNT1A cells with DNMT and HDAC inhibitors, which induced a significant increase in STEAP1 mRNA expression. In addition, the involvement of HDAC in the regulation of STEAP1 mRNA expression was corroborated by a negative association between STEAP1 mRNA expression and HDAC4,5,7 and 9 in human PCa. In conclusion, our work indicates that STEAP1 overexpression in PCa can be driven by the hypomethylation of STEAP1 gene promoter. Full article

(This article belongs to the Special Issue Prostate Cancer)

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11 pages, 8941 KiB

Open AccessArticle

The Urine Biomarker PUR-4 Is Positively Associated with the Amount of Gleason 4 in Human Prostate Cancers

by Richard Y. Ball, Ryan Cardenas, Mark S. Winterbone, Marcelino Y. Hanna, Chris Parker, Rachel Hurst, Daniel S. Brewer, Lauren D’Sa, Rob Mills, Colin S. Cooper and Jeremy Clark

Life 2021, 11(11), 1172; https://doi.org/10.3390/life11111172 - 03 Nov 2021

Cited by 1 | Viewed by 4385

Abstract

The Prostate Urine Risk (PUR) biomarker is a four-group classifier for predicting outcome in patients prior to biopsy and for men on active surveillance. The four categories correspond to the probabilities of the presence of normal tissue (PUR-1), D’Amico low-risk (PUR-2), intermediate-risk (PUR-3), [...] Read more.

The Prostate Urine Risk (PUR) biomarker is a four-group classifier for predicting outcome in patients prior to biopsy and for men on active surveillance. The four categories correspond to the probabilities of the presence of normal tissue (PUR-1), D’Amico low-risk (PUR-2), intermediate-risk (PUR-3), and high-risk (PUR-4) prostate cancer. In the current study we investigate how the PUR-4 status is linked to Gleason grade, prostate volume, and tumor volume as assessed from biopsy (n = 215) and prostatectomy (n = 9) samples. For biopsy data PUR-4 status alone was linked to Gleason Grade group (GG) (Spearman’s, ρ = 0.58, p < 0.001 trend). To assess the impact of tumor volume each GG was dichotomized into Small and Large volume cancers relative to median volume. For GG1 (Gleason Pattern 3 + 3) cancers volume had no impact on PUR-4 status. In contrast for GG2 (3 + 4) and GG3 (4 + 3) cancers PUR-4 levels increased in large volume cancers with statistical significance observed for GG2 (p = 0.005; Games-Howell). These data indicated that PUR-4 status is linked to the presence of Gleason Pattern 4. To test this observation tumor burden and Gleason Pattern were assessed in nine surgically removed and sectioned prostates allowing reconstruction of 3D maps. PUR-4 was not correlated with Gleason Pattern 3 amount, total tumor volume or prostate size. A strong correlation was observed between amount of Gleason Pattern 4 tumor and PUR-4 signature (r = 0.71, p = 0.034, Pearson’s). These observations shed light on the biological significance of the PUR biomarker and support its use as a non-invasive means of assessing the presence of clinically significant prostate cancer. Full article

(This article belongs to the Special Issue Prostate Cancer)

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16 pages, 2888 KiB

Open AccessArticle

Prostate Cancer Aggressiveness Prediction Using CT Images

by Bruno Mendes, Inês Domingues, Augusto Silva and João Santos

Life 2021, 11(11), 1164; https://doi.org/10.3390/life11111164 - 31 Oct 2021

Cited by 5 | Viewed by 2437

Abstract

Prostate Cancer (PCa) is mostly asymptomatic at an early stage and often painless requiring active surveillance screening. Transrectal Ultrasound Guided Biopsy (TRUS) is the principal method to diagnose PCa following a histological examination by observing cell pattern irregularities and assigning the Gleason Score [...] Read more.

Prostate Cancer (PCa) is mostly asymptomatic at an early stage and often painless requiring active surveillance screening. Transrectal Ultrasound Guided Biopsy (TRUS) is the principal method to diagnose PCa following a histological examination by observing cell pattern irregularities and assigning the Gleason Score (GS) according to the recommended guidelines. This procedure presents sampling errors and, being invasive may cause complications to the patients. External Beam Radiotherapy Treatment (EBRT) is presented as curative option for localised and locally advanced disease, as a palliative option for metastatic low-volume disease or after prostatectomy for prostate bed and pelvic nodes salvage. In the EBRT worflow a Computed Tomography (CT) scan is performed as the basis for dose calculations and volume delineations. In this work, we evaluated the use of data-characterization algorithms (radiomics) from CT images for PCa aggressiveness assessment. The fundamental motivation relies on the wide availability of CT images and the need to provide tools to assess EBRT effectiveness. We used Pyradiomics and Local Image Features Extraction (LIFEx) to extract features and search for a radiomic signature within CT images. Finnaly, when applying Principal Component Analysis (PCA) to the features, we were able to show promising results. Full article

(This article belongs to the Special Issue Prostate Cancer)

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15 pages, 1204 KiB

Open AccessEditor’s ChoiceArticle

Association of Circulating Tumor Cells with Inflammatory and Biomarkers in the Blood of Patients with Metastatic Castration-Resistant Prostate Cancer

by Gerit Theil, Carlotta Lindner, Joanna Bialek and Paolo Fornara

Life 2021, 11(7), 664; https://doi.org/10.3390/life11070664 - 06 Jul 2021

Cited by 4 | Viewed by 2159

Abstract

The identification of specific biomarkers that recognize the functional drivers of heterogeneity in prostate cancer (PCa) and personalized treatment remain challenging in systemic medicine. Liquid biopsy allows for the detection and analysis of personalized predictive biomarkers in single blood samples and specifies the [...] Read more.

The identification of specific biomarkers that recognize the functional drivers of heterogeneity in prostate cancer (PCa) and personalized treatment remain challenging in systemic medicine. Liquid biopsy allows for the detection and analysis of personalized predictive biomarkers in single blood samples and specifies the current stage of cancer. The aim of our preliminary study was to investigate the association between an elevated circulating tumor cell (CTC) count and the levels of inflammatory factors (IL-6 and IL-8) and biomarkers (DKK-1, PSA, sHER2, and CD44) in patients with metastasized castration-resistant PCa (mCPRC) under chemotherapy and those with localized PCa. Such an association could be used as a component of cancer progression monitoring. We compared the sensitivity and specificity of two CTC isolation platforms. Twenty-eight patients (12 mCRPC and 16 localized PCa patients) were enrolled. Over the study period, the CTC detection rates were 84% with CellCollector^® and 73.5% with CellSearch^® System in mCPRC patients. The CTC counts determined by the CellSearch^® System (CTC_CS) were correlated significantly with the DKK-1, sHER-2, and PSA concentrations in mCRPC patients. The CTC counts captured by CellCollector^® demonstrated no significant association with the concentrations of the tested blood-based biomarkers. The CTC_CS count (AUC = 0.9 (95% CI: 0.72–1.0)) and the PSA level (AUC = 0.95 (95% CI: 0.83–1.0)) presented approximately the same sensitivity and specificity for the overall survival of mCRPC patients. For better personalized characterization, further research on CTC phenotyping and their interactions with tumor-associated blood-released factors is needed. Full article

(This article belongs to the Special Issue Prostate Cancer)

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16 pages, 4271 KiB

Open AccessArticle

Site-Specific and Common Prostate Cancer Metastasis Genes as Suggested by Meta-Analysis of Gene Expression Data

by Ivana Samaržija

Life 2021, 11(7), 636; https://doi.org/10.3390/life11070636 - 30 Jun 2021

Cited by 7 | Viewed by 2605

Abstract

Anticancer therapies mainly target primary tumor growth and little attention is given to the events driving metastasis formation. Metastatic prostate cancer, in comparison to localized disease, has a much worse prognosis. In the work presented here, groups of genes that are common to [...] Read more.

Anticancer therapies mainly target primary tumor growth and little attention is given to the events driving metastasis formation. Metastatic prostate cancer, in comparison to localized disease, has a much worse prognosis. In the work presented here, groups of genes that are common to prostate cancer metastatic cells from bones, lymph nodes, and liver and those that are site-specific were delineated. The purpose of the study was to dissect potential markers and targets of anticancer therapies considering the common characteristics and differences in transcriptional programs of metastatic cells from different secondary sites. To that end, a meta-analysis of gene expression data of prostate cancer datasets from the GEO database was conducted. Genes with differential expression in all metastatic sites analyzed belong to the class of filaments, focal adhesion, and androgen receptor signaling. Bone metastases undergo the largest transcriptional changes that are highly enriched for the term of the chemokine signaling pathway, while lymph node metastasis show perturbation in signaling cascades. Liver metastases change the expression of genes in a way that is reminiscent of processes that take place in the target organ. Survival analysis for the common hub genes revealed involvements in prostate cancer prognosis and suggested potential biomarkers. Full article

(This article belongs to the Special Issue Prostate Cancer)

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10 pages, 409 KiB

Open AccessArticle

External Validation of the Briganti Nomogram to Predict Lymph Node Invasion in Prostate Cancer—Setting a New Threshold Value

by Bartosz Małkiewicz, Kuba Ptaszkowski, Klaudia Knecht, Adam Gurwin, Karol Wilk, Paweł Kiełb, Krzysztof Dudek and Romuald Zdrojowy

Life 2021, 11(6), 479; https://doi.org/10.3390/life11060479 - 25 May 2021

Cited by 5 | Viewed by 2377

Abstract

(1) Introduction: The study aimed to test and validate the performance of the 2012 Briganti nomogram as a predictor for pelvic lymph node invasion (LNI) in men who underwent radical prostatectomy (RP) with extended pelvic lymph node dissection (PLND) to examine their performance [...] Read more.

(1) Introduction: The study aimed to test and validate the performance of the 2012 Briganti nomogram as a predictor for pelvic lymph node invasion (LNI) in men who underwent radical prostatectomy (RP) with extended pelvic lymph node dissection (PLND) to examine their performance and to analyse the therapeutic impact of using a different nomogram cut-off. (2) Material and Methods: The study group consisted of 222 men with clinically localized prostate cancer (PCa) who underwent RP with ePLND between 01/2012 and 10/2018. Measurements included: preoperative PSA, clinical stage (CS), primary and secondary biopsy Gleason pattern, and the percentage of positive cores. The area under the curve (AUC) of the receiver operator characteristic analysis was appointed to quantify the accuracy of the primary nomogram model to predict LNI. The extent of estimation associated with the use of this model was graphically depicted using calibration plots. (3) Results: The median number of removed lymph nodes was 16 (IQR 12–21). A total of 53 of 222 patients (23.9%) had LNI. Preoperative clinical and biopsy characteristics differed significantly (all p < 0.005) between men with and without LNI. A nomogram-derived cut-off of 7% could lead to a reduction of 43% (95/222) of lymph node dissection while omitting 19% (10/53) of patients with LNI. The sensitivity, specificity, and negative predictive value associated with the 7% cut-off were 81.1%, 50.3%, and 96.3%, respectively. (4) Conclusions: The analysed nomogram demonstrated high accuracy for LNI prediction. A nomogram-derived cut-off of 7% confirmed good performance characteristics within the first external validation cohort from Poland. Full article

(This article belongs to the Special Issue Prostate Cancer)

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9 pages, 2161 KiB

Open AccessArticle

Prostate Cancer Diagnostic Algorithm as a “Road Map” from the First Stratification of the Patient to the Final Treatment Decision

by Hana Sedláčková, Olga Dolejšová, Milan Hora, Jiří Ferda, Ondřej Hes, Ondřej Topolčan, Radka Fuchsová and Radek Kučera

Life 2021, 11(4), 324; https://doi.org/10.3390/life11040324 - 07 Apr 2021

Cited by 6 | Viewed by 3930

Abstract

The diagnostics of prostate cancer are currently based on three pillars: prostate biomarker panel, imaging techniques, and histological verification. This paper presents a diagnostic algorithm that can serve as a “road map”: from initial patient stratification to the final decision regarding treatment. The [...] Read more.

The diagnostics of prostate cancer are currently based on three pillars: prostate biomarker panel, imaging techniques, and histological verification. This paper presents a diagnostic algorithm that can serve as a “road map”: from initial patient stratification to the final decision regarding treatment. The algorithm is based on a review of the current literature combined with our own experience. Diagnostic algorithms are a feature of an advanced healthcare system in which all steps are consciously coordinated and optimized to ensure the proper individualization of the treatment process. The prostate cancer diagnostic algorithm was created using the prostate specific antigen and in particular the Prostate Health Index in the first line of patient stratification. It then continued on the diagnostic pathway via imaging techniques, biopsy, or active surveillance, and then on to the treatment decision itself. In conclusion, the prostate cancer diagnostic algorithm presented here is a functional tool for initial patient stratification, comprehensive staging, and aggressiveness assessment. Above all, emphasis is placed on the use of the Prostate Health Index (PHI) in the first stratification of the patients as a predictor of aggressiveness and clinical stage of prostrate cancer (PCa). The inclusion of PHI in the algorithm significantly increases the accuracy and speed of the diagnostic procedure and allows to choose the optimal pathway just from the beginning. The use of advanced diagnostic techniques allows us to move towards to a more advanced level of cancer care. This diagnostics algorithm has become a standard of care in our hospital. The algorithm is continuously validated and modified based on our results. Full article

(This article belongs to the Special Issue Prostate Cancer)

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9 pages, 1134 KiB

Open AccessEditor’s ChoiceArticle

Long Noncoding RNA NEAT1 as a Potential Candidate Biomarker for Prostate Cancer

by Diana Nitusca, Anca Marcu, Alis Dema, Loredana Balacescu, Ovidiu Balacescu, Razvan Bardan, Alin Adrian Cumpanas, Ioan Ovidiu Sirbu, Bogdan Petrut, Edward Seclaman and Catalin Marian

Life 2021, 11(4), 320; https://doi.org/10.3390/life11040320 - 06 Apr 2021

Cited by 9 | Viewed by 2444

Abstract

Background: Prostate cancer (PCa) remains one of the leading causes of cancer-related mortality in men worldwide, mainly due to unsatisfactory diagnostic methods used at present, which lead to overdiagnosis, unnecessary biopsies and treatment, or misdiagnosis in early asymptomatic stages. New diagnostic biomarkers are [...] Read more.

Background: Prostate cancer (PCa) remains one of the leading causes of cancer-related mortality in men worldwide, mainly due to unsatisfactory diagnostic methods used at present, which lead to overdiagnosis, unnecessary biopsies and treatment, or misdiagnosis in early asymptomatic stages. New diagnostic biomarkers are needed for a correct and early diagnosis. Long noncoding RNAs (lncRNAs) have been broadly studied for their involvement in PCa biology, as well as for their potential role as diagnostic biomarkers. Methods: We conducted lncRNA profiling in plasma and microdissected formalin-fixed paraffin-embedded (FFPE) tissues of PCa patients and attempted validation for commonly dysregulated individual lncRNAs. Results: Plasma profiling revealed eight dysregulated lncRNAs, while microarray analysis revealed 717 significantly dysregulated lncRNAs, out of which only nuclear-enriched abundant transcript 1 (NEAT1) was commonly upregulated in plasma samples and FFPE tissues. NEAT1’s individual validation revealed statistically significant upregulation (FC = 2.101, p = 0.009). Receiver operating characteristic (ROC) analysis showed an area under the curve (AUC) value of 0.7298 for NEAT1 (95% CI = 0.5812–0.8785), suggesting a relatively high diagnostic value, thus having a potential biomarker role for this malignancy. Conclusions: We present herein data suggesting that NEAT1 could serve as a diagnostic biomarker for PCa. Additional studies of larger cohorts are needed to confirm our findings, as well as the oncogenic mechanism of NEAT1 in the development of PCa. Full article

(This article belongs to the Special Issue Prostate Cancer)

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15 pages, 1028 KiB

Open AccessArticle

Analysis of Brain Functions in Men with Prostate Cancer under Androgen Deprivation Therapy: A One-Year Longitudinal Study

by Vanessa Sánchez-Martínez, Cristina Buigues, Rut Navarro-Martínez, Laura García-Villodre, Noura Jeghalef, María Serrano-Carrascosa, José Rubio-Briones and Omar Cauli

Life 2021, 11(3), 227; https://doi.org/10.3390/life11030227 - 10 Mar 2021

Cited by 11 | Viewed by 2767

Abstract

The relationship between cognitive decline and androgen deprivation therapy (ADT) under luteinizing hormone-releasing hormone (LHRH) analogues is unclear, and there is a scarcity of longitudinal studies considering the interaction between cognition, depressive symptoms and sleep quality in men with prostate cancer (PCa) treated [...] Read more.

The relationship between cognitive decline and androgen deprivation therapy (ADT) under luteinizing hormone-releasing hormone (LHRH) analogues is unclear, and there is a scarcity of longitudinal studies considering the interaction between cognition, depressive symptoms and sleep quality in men with prostate cancer (PCa) treated with ADT. This study aimed to determine if there were differences in the scores obtained in cognitive assessment, depressive symptoms, and sleep quality after one year of ADT and determine the interrelations between sleep, mood, and cognitive status. A prospective longitudinal observational study was designed, in which a cohort of men (mean age was 70.8 years) newly treated with androgen-deprivation therapy was assessed in the first six months of treatment and 12 months later. Analysis of cognitive function by the Mini-Mental State Examination (MMSE) scores indicated a significant (p < 0.05) increase after one year of treatment and by the Brief Scale for Cognitive Evaluation (BCog) scores indicated no changes in the scores before and after one year of treatment. Analysis of depressive symptoms with the Geriatric Depression Scale and sleep quality with the Athens Insomnia Scale (AIS) scores showed significant (p < 0.05) changes after one year of treatment with ADT, with men describing more depressive symptoms and more sleep disturbances. No statistically significant differences were found in the cognitive performance between men with impaired sleep or depression results and those without them. Our study showed no clinical evidence of the relationship between ADT under luteinizing hormone-releasing hormone (LHRH) analogues and cognitive deterioration in 1-year follow-up, but there are impairments in the sleep quality in men with PCa undergoing ADT and an increase in depressive symptoms which has important implications for clinicians as they would impair quality of life and adherence to treatment. Full article

(This article belongs to the Special Issue Prostate Cancer)

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Review

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10 pages, 1202 KiB

Open AccessReview

Wnt and β-Catenin Signaling in the Bone Metastasis of Prostate Cancer

by Zachary Kaplan, Steven P. Zielske, Kristina G. Ibrahim and Frank C. Cackowski

Life 2021, 11(10), 1099; https://doi.org/10.3390/life11101099 - 16 Oct 2021

Cited by 19 | Viewed by 3242

Abstract

Wnt family proteins and β-catenin are critical for the regulation of many developmental and oncogenic processes. Wnts are secreted protein ligands which signal using a canonical pathway, and involve the transcriptional co-activator β-catenin or non-canonical pathways that are independent of β-catenin. Bone metastasis [...] Read more.

Wnt family proteins and β-catenin are critical for the regulation of many developmental and oncogenic processes. Wnts are secreted protein ligands which signal using a canonical pathway, and involve the transcriptional co-activator β-catenin or non-canonical pathways that are independent of β-catenin. Bone metastasis is unfortunately a common occurrence in prostate cancer and can be conceptualized as a series of related steps or processes, most of which are regulated by Wnt ligands and/or β-catenin. At the primary tumor site, cancer cells often take on mesenchymal properties, termed epithelial mesenchymal transition (EMT), which are regulated in part by the Wnt receptor FZD4. Then, Wnt signaling, especially Wnt5A, is of importance as the cells circulate in the blood stream. Upon arriving in the bones, cancer cells migrate and take on stem-like or tumorigenic properties, as aided through Wnt or β-catenin signaling involving CHD11, CD24, and Wnt5A. Additionally, cancer cells can become dormant and evade therapy, in part due to regulation by Wnt5A. In the bones, E-selectin can aid in the reversal of EMT, a process termed mesenchymal epithelial transition (MET), as a part of metastatic tumorigenesis. Once bone tumors are established, Wnt/β-catenin signaling is involved in the suppression of osteoblast function largely through DKK1. Full article

(This article belongs to the Special Issue Prostate Cancer)

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