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Diagnostic, Prognostic and Predictive Biomarkers in Prostate Cancer 2019
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Diagnostic, Prognostic and Predictive Biomarkers in Prostate Cancer 2019

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 August 2019) | Viewed by 95171

Special Issue Editors

Prof. Dr. Carsten Stephan

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Guest Editor
Department of Urology, Charité-Universitätsmedizin Berlin, Germany
Interests: biomarkers of prostate cancer; artificial neural networks; prostate health index
Special Issues, Collections and Topics in MDPI journals
Prof. Klaus Jung

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Guest Editor
Department of Urology, Charité University Hospital, 10117 Berlin, Germany
Interests: clinical biochemistry; molecular and biochemical urooncology; RNA and DNA biology; general laboratory medicine

Special Issue Information

Dear Colleagues,

Prostate cancer is the most common cancer in men in the Western world. Therefore, its early diagnosis, which is mainly based on serum prostate-specific antigen (PSA), has especially gained attention in several fields of research. New biomarkers in serum and urine have been described; for example, the prostate health index (PHI) or urinary Prostate cancer gene 3 (PCA3), or others, including several biomarker-based multivariate models. However, not only the diagnosis, but also, more so, the prognosis or further prediction of this very common disease is important to know. Here, several new nucleic acid or protein-based tissue biomarkers have been described. As already described for other types of cancer, individualized medicine, such as theranostics, a combination of diagnostics and therapeutics, has been a new attraction for late stage prostate cancer, including castration resistant prostate cancer. This Special Issue focuses on “Diagnostic, Prognostic and Predictive Biomarkers in Prostate Cancer”.

We warmly welcome submissions, including original papers and reviews, on this widely-discussed topic.

Prof. Carsten Stephan
Prof. Klaus Jung
Guest Editors

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Urinary biomarkers on prostate cancer
  • Serum/plasma biomarkers
  • Tissue biomarkers (nuleic acid/protein-based)
  • Prognostic factors
  • Multivariate models

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Published Papers (19 papers)

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Research

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15 pages, 2736 KiB  
Article
Proteomics-Metabolomics Combined Approach Identifies Peroxidasin as a Protector against Metabolic and Oxidative Stress in Prostate Cancer
by Jodi Dougan, Ohuod Hawsawi, Liza J. Burton, Gabrielle Edwards, Kia Jones, Jin Zou, Peri Nagappan, Guangdi Wang, Qiang Zhang, Alira Danaher, Nathan Bowen, Cimona Hinton and Valerie A. Odero-Marah
Int. J. Mol. Sci. 2019, 20(12), 3046; https://doi.org/10.3390/ijms20123046 - 21 Jun 2019
Cited by 29 | Viewed by 4818
Abstract
Peroxidasin (PXDN), a human homolog of Drosophila PXDN, belongs to the family of heme peroxidases and has been found to promote oxidative stress in cardiovascular tissue, however, its role in prostate cancer has not been previously elucidated. We hypothesized that PXDN promotes prostate [...] Read more.
Peroxidasin (PXDN), a human homolog of Drosophila PXDN, belongs to the family of heme peroxidases and has been found to promote oxidative stress in cardiovascular tissue, however, its role in prostate cancer has not been previously elucidated. We hypothesized that PXDN promotes prostate cancer progression via regulation of metabolic and oxidative stress pathways. We analyzed PXDN expression in prostate tissue by immunohistochemistry and found increased PXDN expression with prostate cancer progression as compared to normal tissue or cells. PXDN knockdown followed by proteomic analysis revealed an increase in oxidative stress, mitochondrial dysfunction and gluconeogenesis pathways. Additionally, Liquid Chromatography with tandem mass spectrometry (LC-MS/MS)-based metabolomics confirmed that PXDN knockdown induced global reprogramming associated with increased oxidative stress and decreased nucleotide biosynthesis. We further demonstrated that PXDN knockdown led to an increase in reactive oxygen species (ROS) associated with decreased cell viability and increased apoptosis. Finally, PXDN knockdown decreased colony formation on soft agar. Overall, the data suggest that PXDN promotes progression of prostate cancer by regulating the metabolome, more specifically, by inhibiting oxidative stress leading to decreased apoptosis. Therefore, PXDN may be a biomarker associated with prostate cancer and a potential therapeutic target. Full article
(This article belongs to the Special Issue Diagnostic, Prognostic and Predictive Biomarkers in Prostate Cancer 2019)
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13 pages, 3605 KiB  
Article
Glycidamide Promotes the Growth and Migratory Ability of Prostate Cancer Cells by Changing the Protein Expression of Cell Cycle Regulators and Epithelial-to-Mesenchymal Transition (EMT)-Associated Proteins with Prognostic Relevance
by Titus Ime Ekanem, Chi-Chen Huang, Ming-Heng Wu, Ding-Yen Lin, Wen-Fu T. Lai and Kuen-Haur Lee
Int. J. Mol. Sci. 2019, 20(9), 2199; https://doi.org/10.3390/ijms20092199 - 04 May 2019
Cited by 8 | Viewed by 3225
Abstract
Acrylamide (AA) and glycidamide (GA) can be produced in carbohydrate-rich food when heated at a high temperature, which can induce a malignant transformation. It has been demonstrated that GA is more mutagenic than AA. It has been shown that the proliferation rate of [...] Read more.
Acrylamide (AA) and glycidamide (GA) can be produced in carbohydrate-rich food when heated at a high temperature, which can induce a malignant transformation. It has been demonstrated that GA is more mutagenic than AA. It has been shown that the proliferation rate of some cancer cells are increased by treatment with GA; however, the exact genes that are induced by GA in most cancer cells are not clear. In the present study, we demonstrated that GA promotes the growth of prostate cancer cells through induced protein expression of the cell cycle regulator. In addition, we also found that GA promoted the migratory ability of prostate cancer cells through induced epithelial-to-mesenchymal transition (EMT)-associated protein expression. In order to understand the potential prognostic relevance of GA-mediated regulators of the cell cycle and EMT, we present a three-gene signature to evaluate the prognosis of prostate cancer patients. Further investigations suggested that the three-gene signature (CDK4, TWIST1 and SNAI2) predicted the chances of survival better than any of the three genes alone for the first time. In conclusion, we suggested that the three-gene signature model can act as marker of GA exposure. Hence, this multi-gene panel may serve as a promising outcome predictor and potential therapeutic target in prostate cancer patients. Full article
(This article belongs to the Special Issue Diagnostic, Prognostic and Predictive Biomarkers in Prostate Cancer 2019)
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10 pages, 1233 KiB  
Article
rs4143815-PDL1, a New Potential Immunogenetic Biomarker of Biochemical Recurrence in Locally Advanced Prostate Cancer after Radiotherapy
by Chiara Zanusso, Eva Dreussi, Roberto Bortolus, Chiara Romualdi, Sara Gagno, Elena De Mattia, Loredana Romanato, Franca Sartor, Luca Quartuccio, Erika Cecchin and Giuseppe Toffoli
Int. J. Mol. Sci. 2019, 20(9), 2082; https://doi.org/10.3390/ijms20092082 - 27 Apr 2019
Cited by 7 | Viewed by 2552
Abstract
Up to 30–50% of patients with locally advanced prostate cancer (PCa) undergoing radiotherapy (RT) experience biochemical recurrence (BCR). The immune system affects the RT response. Immunogenetics could define new biomarkers for personalization of PCa patients’ treatment. The aim of this study is to [...] Read more.
Up to 30–50% of patients with locally advanced prostate cancer (PCa) undergoing radiotherapy (RT) experience biochemical recurrence (BCR). The immune system affects the RT response. Immunogenetics could define new biomarkers for personalization of PCa patients’ treatment. The aim of this study is to define the immunogenetic biomarkers of 10 year BCR (primary aim), 10 year overall survival (OS) and 5 year BCR (secondary aims). In this mono-institutional retrospective study, 549 Caucasian patients (a discovery set n = 418; a replication set n = 131) were affected by locally advanced PCa and homogeneously treated with RT. In the training set, associations were made between 447 SNPs in 77 genes of the immune system; and 10 year BCR and 10 year OS were tested through a multivariate Cox proportional hazard model. Significant SNPs (p-value < 0.05, q-value < 0.15) were analyzed in the replication set. Replicated SNPs were tested for 5 year BCR in both sets of patients. A polymorphism in the PDL1 gene (rs4143815) was the unique potential genetic variant of 10 year BCR (training set: p = 0.003, HR (95% CI) = 0.58 (0.41–0.83); replication set: p = 0.063, HR (95% CI) = 0.52 (0.26–1.04)) that was significantly associated with 5 year BCR (training set: p = 0.009, HR (95% CI) = 0.59 (0.40–0.88); replication set: p = 0.036, HR (95% CI) = 0.39 (0.16–0.94)). No biomarkers of OS were replicated. rs4143815-PDL1 arose as a new immunogenetic biomarker of BCR in PCa, giving new insights into the RT/immune system interaction, which could be potentially useful in new approaches using anti-PDL1 therapies for PCa. Full article
(This article belongs to the Special Issue Diagnostic, Prognostic and Predictive Biomarkers in Prostate Cancer 2019)
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12 pages, 1580 KiB  
Article
Reduced T-cell Numbers and Elevated Levels of Immunomodulatory Cytokines in Metastatic Prostate Cancer Patients De Novo Resistant to Abiraterone and/or Enzalutamide Therapy
by Sumanta K. Pal, Dayson Moreira, Haejung Won, Seok Woon White, Pryanka Duttagupta, Marc Lucia, Jeremy Jones, JoAnn Hsu and Marcin Kortylewski
Int. J. Mol. Sci. 2019, 20(8), 1831; https://doi.org/10.3390/ijms20081831 - 13 Apr 2019
Cited by 37 | Viewed by 4390
Abstract
Currently, there are two Food and Drug Administration (FDA)-approved drugs for androgen deprivation therapy (ADT) of metastatic castration-resistant prostate cancer (mCRPC) patients: abiraterone and enzalutamide. However, our understanding of the effect of these therapies on the immune system in mCRPC patients remains limited. [...] Read more.
Currently, there are two Food and Drug Administration (FDA)-approved drugs for androgen deprivation therapy (ADT) of metastatic castration-resistant prostate cancer (mCRPC) patients: abiraterone and enzalutamide. However, our understanding of the effect of these therapies on the immune system in mCRPC patients remains limited. Here, we examined how abiraterone and enzalutamide treatment affects levels of soluble immune mediators in plasma and in circulating immune cells of 44 mCRPC patients. We found that the baseline levels of cytokines fibroblast growth factor (FGF), granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin 10 (IL-10), and IL-6 were significantly lower in ADT-sensitive compared to de novo resistant patients. In addition, resistant patients showed significantly lower T cell frequencies. When comparing the levels of cytokines over the course of treatment, we observed that the levels of proinflammatory mediators, such as interferon-γ (IFN-γ), IL-5, macrophage inflammatory protein 1 alpha (MIP-1α), and tumor necrosis factor alpha (TNFα), were significantly increased in the ADT-sensitive patients. At the same time, the abiraterone/enzalutamide therapy did not reduce the percentage of tolerogenic myeloid cell populations, such as polymorphonuclear myeloid-derived suppressor cells, which retained unaltered expression of programmed death-ligand 1 (PD-L1) and B7-H3. Overall, our results suggest that certain immune markers, such as IL-6 and the frequency of effector T cells, could be predictive of therapeutic response to ADT therapies in mCRPC patients. Full article
(This article belongs to the Special Issue Diagnostic, Prognostic and Predictive Biomarkers in Prostate Cancer 2019)
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13 pages, 1908 KiB  
Article
N-Linked Glycosylation and Near-Infrared Spectroscopy in the Diagnosis of Prostate Cancer
by Tijl Vermassen, Sander De Bruyne, Jonas Himpe, Nicolaas Lumen, Nico Callewaert, Sylvie Rottey and Joris Delanghe
Int. J. Mol. Sci. 2019, 20(7), 1592; https://doi.org/10.3390/ijms20071592 - 29 Mar 2019
Cited by 6 | Viewed by 2705
Abstract
Background: Performing a prostate biopsy is the most robust and reliable way to diagnose prostate cancer (PCa), and to determine the disease grading. As little to no biochemical markers for prostate tissue exist, we explored the possibilities of tissue N-glycosylation and near-infrared spectroscopy [...] Read more.
Background: Performing a prostate biopsy is the most robust and reliable way to diagnose prostate cancer (PCa), and to determine the disease grading. As little to no biochemical markers for prostate tissue exist, we explored the possibilities of tissue N-glycosylation and near-infrared spectroscopy (NIR) in PCa diagnosis. Methods: Tissue specimens from 100 patients (benign prostate hyperplasia (BPH), n = 50; and PCa, n = 50) were obtained. The fresh-frozen tissue was dispersed and a tissue N-glycosylation profile was determined. Consequently, the formalin-fixed paraffin-embedded slides were analyzed using NIR spectroscopy. A comparison was made between the benign and malignant tissue, and between the various Gleason scores. Results: A difference was observed for the tissue of N-glycosylation between the benign and malignant tissue. These differences were located in the fycosylation ratios and the total amount of bi- and tetra-antennary structures (all p < 0.0001). These differences were also present between various Gleason scores. In addition, the NIR spectra revealed changes between the benign and malignant tissue in several regions. Moreover, spectral ranges of 1055–1065 nm and 1450–1460 nm were significantly different between the Gleason scores (p = 0.0042 and p = 0.0195). Conclusions: We have demonstrated biochemical changes in the N-glycan profile of prostate tissue, which allows for the distinction between malignant and benign tissue, as well as between various Gleason scores. These changes can be correlated to the changes observed in the NIR spectra. This could possibly further improve the histological assessment of PCa diagnosis, although further method validation is needed. Full article
(This article belongs to the Special Issue Diagnostic, Prognostic and Predictive Biomarkers in Prostate Cancer 2019)
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12 pages, 4185 KiB  
Article
Gamma-Tocotrienol Induces Apoptosis in Prostate Cancer Cells by Targeting the Ang-1/Tie-2 Signalling Pathway
by Kai Dun Tang, Ji Liu, Pamela J. Russell, Judith A. Clements and Ming-Tat Ling
Int. J. Mol. Sci. 2019, 20(5), 1164; https://doi.org/10.3390/ijms20051164 - 07 Mar 2019
Cited by 29 | Viewed by 3796
Abstract
Emerging evidence suggests that gamma-tocotrienol (γ-T3), a vitamin E isomer, has potent anti-cancer properties against a wide-range of cancers. γ-T3 not only inhibited the growth and survival of cancer cells in vitro, but also suppressed angiogenesis and tumour metastasis under in vivo conditions. [...] Read more.
Emerging evidence suggests that gamma-tocotrienol (γ-T3), a vitamin E isomer, has potent anti-cancer properties against a wide-range of cancers. γ-T3 not only inhibited the growth and survival of cancer cells in vitro, but also suppressed angiogenesis and tumour metastasis under in vivo conditions. Recently, γ-T3 was found to target cancer stem cells (CSCs), leading to suppression of tumour formation and chemosensitisation. Despite its promising anti-cancer potential, the exact mechanisms responsible for the effects of γ-T3 are still largely unknown. Here, we report the identification of Ang-1 (Angiopoietin-1)/Tie-2 as a novel γ-T3 downstream target. In prostate cancer cells, γ-T3 treatment leads to the suppression of Ang-1 at both the mRNA transcript and protein levels. Supplementing the cells with Ang-1 was found to protect them against the anti-CSC effect of γ-T3. Intriguingly, inactivation of Tie-2, a member receptor that mediates the effect of Ang-1, was found to significantly enhance the cytotoxic effect of γ-T3 through activation of AMP-activated protein kinase (AMPK) and subsequent interruption of autophagy. Our results highlighted the therapeutic potential of using γ-T3 in combination with a Tie-2 inhibitor to treat advanced prostate cancer. Full article
(This article belongs to the Special Issue Diagnostic, Prognostic and Predictive Biomarkers in Prostate Cancer 2019)
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13 pages, 2679 KiB  
Article
Development of a Transcriptional Amplification System Based on the PEG3 Promoter to Target Androgen Receptor-Positive and -Negative Prostate Cancer Cells
by Pallavi Jain, Pier-Luc Clermont, Francis Desmeules, Amina Zoubeidi, Bertrand Neveu and Frédéric Pouliot
Int. J. Mol. Sci. 2019, 20(1), 216; https://doi.org/10.3390/ijms20010216 - 08 Jan 2019
Cited by 3 | Viewed by 3977
Abstract
Localized prostate cancer (PCa) is often curable, whereas metastatic disease treated by castration inevitably progresses toward castration-resistant PCa (CRPC). Most CRPC treatments target androgen receptor (AR) signaling. However, not all CRPC cells rely on AR activity for survival and proliferation. With advances in [...] Read more.
Localized prostate cancer (PCa) is often curable, whereas metastatic disease treated by castration inevitably progresses toward castration-resistant PCa (CRPC). Most CRPC treatments target androgen receptor (AR) signaling. However, not all CRPC cells rely on AR activity for survival and proliferation. With advances in immunotherapy and fluid biopsies for cancer management, expression systems specific for both AR-positive and -negative PCa are required for virus-based vaccines and cell imaging. To target both AR-responsive and non-responsive cells, we developed a three-step transcriptional amplification (3STA) system based on the progression elevated gene-3 (PEG3) promoter named PEG3AP1-3STA. Notably, we report on different genetic modifications that significantly improved PEG3 promoter’s strength in PCa cells. Adenoviruses incorporating PEG3 promoter with and without transcriptional amplification systems were generated. The potential of PEG3AP1-3STA to target PCa cells was then evaluated in vitro and in vivo in androgen-responsive and non-responsive PCa cell lines. PEG3AP1-3STA was shown to be active in all PCa cell lines and not regulated by androgens, and its activity was amplified 97-fold compared to that of a non-amplified promoter. The PEG3AP1-3STA system can thus be used to target advanced AR+ and AR− cells for imaging or immunovirotherapy in advanced PCa. Full article
(This article belongs to the Special Issue Diagnostic, Prognostic and Predictive Biomarkers in Prostate Cancer 2019)
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Review

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17 pages, 1567 KiB  
Review
Future Aspects of CDK5 in Prostate Cancer: From Pathogenesis to Therapeutic Implications
by Muhammet Oner, Eugene Lin, Mei-Chih Chen, Fu-Ning Hsu, G M Shazzad Hossain Prince, Kun-Yuan Chiu, Chieh-Lin Jerry Teng, Tsung-Ying Yang, Hsin-Yi Wang, Chia-Herng Yue, Ching-Han Yu, Chih-Ho Lai, Jer-Tsong Hsieh and Ho Lin
Int. J. Mol. Sci. 2019, 20(16), 3881; https://doi.org/10.3390/ijms20163881 - 09 Aug 2019
Cited by 20 | Viewed by 6809
Abstract
Cyclin-dependent kinase 5 (CDK5) is a unique member of the cyclin-dependent kinase family. CDK5 is activated by binding with its regulatory proteins, mainly p35, and its activation is essential in the development of the central nervous system (CNS) and neurodegeneration. Recently, it has [...] Read more.
Cyclin-dependent kinase 5 (CDK5) is a unique member of the cyclin-dependent kinase family. CDK5 is activated by binding with its regulatory proteins, mainly p35, and its activation is essential in the development of the central nervous system (CNS) and neurodegeneration. Recently, it has been reported that CDK5 plays important roles in regulating various biological and pathological processes, including cancer progression. Concerning prostate cancer, the androgen receptor (AR) is majorly involved in tumorigenesis, while CDK5 can phosphorylate AR and promotes the proliferation of prostate cancer cells. Clinical evidence has also shown that the level of CDK5 is associated with the progression of prostate cancer. Interestingly, inhibition of CDK5 prevents prostate cancer cell growth, while drug-triggered CDK5 hyperactivation leads to apoptosis. The blocking of CDK5 activity by its small interfering RNAs (siRNA) or Roscovitine, a pan-CDK inhibitor, reduces the cellular AR protein level and triggers the death of prostate cancer cells. Thus, CDK5 plays a crucial role in the growth of prostate cancer cells, and AR regulation is one of the important pathways. In this review paper, we summarize the significant studies on CDK5-mediated regulation of prostate cancer cells. We propose that the CDK5–p35 complex might be an outstanding candidate as a diagnostic marker and potential target for prostate cancer treatment in the near future. Full article
(This article belongs to the Special Issue Diagnostic, Prognostic and Predictive Biomarkers in Prostate Cancer 2019)
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15 pages, 425 KiB  
Review
Identification of Novel Biomarkers of Homologous Recombination Defect in DNA Repair to Predict Sensitivity of Prostate Cancer Cells to PARP-Inhibitors
by Daniela Criscuolo, Francesco Morra, Riccardo Giannella, Aniello Cerrato and Angela Celetti
Int. J. Mol. Sci. 2019, 20(12), 3100; https://doi.org/10.3390/ijms20123100 - 25 Jun 2019
Cited by 30 | Viewed by 5993
Abstract
One of the most common malignancies in men is prostate cancer, for which androgen deprivation is the standard therapy. However, prostate cancer cells become insensitive to anti-androgen treatment and proceed to a castration-resistant state with limited therapeutic options. Therefore, besides the androgen deprivation [...] Read more.
One of the most common malignancies in men is prostate cancer, for which androgen deprivation is the standard therapy. However, prostate cancer cells become insensitive to anti-androgen treatment and proceed to a castration-resistant state with limited therapeutic options. Therefore, besides the androgen deprivation approach, novel biomarkers are urgently required for specific targeting in this deadly disease. Recently, germline or somatic mutations in the homologous recombination (HR) DNA repair genes have been identified in at least 20–25% of metastatic castration-resistant prostate cancers (mCRPC). Defects in genes involved in HR DNA repair can sensitize cancer cells to poly(ADP-ribose) polymerase (PARP) inhibitors, a class of drugs already approved by the Food and Drug Administration (FDA) for breast and ovarian cancer carrying germline mutations in BRCA1/2 genes. For advanced prostate cancer carrying Breast cancer1/2 (BRCA1/2) or ataxia telengiectasia mutated (ATM) mutations, preclinical studies and clinical trials support the use of PARP-inhibitors, which received breakthrough therapy designation by the FDA. Based on these assumptions, several trials including DNA damage response and repair (DDR) targeting have been launched and are ongoing for prostate cancer. Here, we review the state-of-the-art potential biomarkers that could be predictive of cancer cell synthetic lethality with PARP inhibitors. The identification of key molecules that are affected in prostate cancer could be assayed in future clinical studies to better stratify prostate cancer patients who might benefit from target therapy. Full article
(This article belongs to the Special Issue Diagnostic, Prognostic and Predictive Biomarkers in Prostate Cancer 2019)
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22 pages, 1064 KiB  
Review
Dysregulated Transcriptional Control in Prostate Cancer
by Simon J. Baumgart, Ekaterina Nevedomskaya and Bernard Haendler
Int. J. Mol. Sci. 2019, 20(12), 2883; https://doi.org/10.3390/ijms20122883 - 13 Jun 2019
Cited by 19 | Viewed by 4790
Abstract
Recent advances in whole-genome and transcriptome sequencing of prostate cancer at different stages indicate that a large number of mutations found in tumors are present in non-protein coding regions of the genome and lead to dysregulated gene expression. Single nucleotide variations and small [...] Read more.
Recent advances in whole-genome and transcriptome sequencing of prostate cancer at different stages indicate that a large number of mutations found in tumors are present in non-protein coding regions of the genome and lead to dysregulated gene expression. Single nucleotide variations and small mutations affecting the recruitment of transcription factor complexes to DNA regulatory elements are observed in an increasing number of cases. Genomic rearrangements may position coding regions under the novel control of regulatory elements, as exemplified by the TMPRSS2-ERG fusion and the amplified enhancer identified upstream of the androgen receptor (AR) gene. Super-enhancers are increasingly found to play important roles in aberrant oncogenic transcription. Several players involved in these processes are currently being evaluated as drug targets and may represent new vulnerabilities that can be exploited for prostate cancer treatment. They include factors involved in enhancer and super-enhancer function such as bromodomain proteins and cyclin-dependent kinases. In addition, non-coding RNAs with an important gene regulatory role are being explored. The rapid progress made in understanding the influence of the non-coding part of the genome and of transcription dysregulation in prostate cancer could pave the way for the identification of novel treatment paradigms for the benefit of patients. Full article
(This article belongs to the Special Issue Diagnostic, Prognostic and Predictive Biomarkers in Prostate Cancer 2019)
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18 pages, 1046 KiB  
Review
ZBTB46, SPDEF, and ETV6: Novel Potential Biomarkers and Therapeutic Targets in Castration-Resistant Prostate Cancer
by AbdulFattah Salah Fararjeh and Yen-Nien Liu
Int. J. Mol. Sci. 2019, 20(11), 2802; https://doi.org/10.3390/ijms20112802 - 08 Jun 2019
Cited by 14 | Viewed by 4652 | Correction
Abstract
Prostate cancer (PCa) is the second most common killer among men in Western countries. Targeting androgen receptor (AR) signaling by androgen deprivation therapy (ADT) is the current therapeutic regime for patients newly diagnosed with metastatic PCa. However, most patients relapse and become resistant [...] Read more.
Prostate cancer (PCa) is the second most common killer among men in Western countries. Targeting androgen receptor (AR) signaling by androgen deprivation therapy (ADT) is the current therapeutic regime for patients newly diagnosed with metastatic PCa. However, most patients relapse and become resistant to ADT, leading to metastatic castration-resistant PCa (CRPC) and eventually death. Several proposed mechanisms have been proposed for CRPC; however, the exact mechanism through which CRPC develops is still unclear. One possible pathway is that the AR remains active in CRPC cases. Therefore, understanding AR signaling networks as primary PCa changes into metastatic CRPC is key to developing future biomarkers and therapeutic strategies for PCa and CRPC. In the current review, we focused on three novel biomarkers (ZBTB46, SPDEF, and ETV6) that were demonstrated to play critical roles in CRPC progression, epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI) drug resistance, and the epithelial-to-mesenchymal transition (EMT) for patients treated with ADT or AR inhibition. In addition, we summarize how these potential biomarkers can be used in the clinic for diagnosis and as therapeutic targets of PCa. Full article
(This article belongs to the Special Issue Diagnostic, Prognostic and Predictive Biomarkers in Prostate Cancer 2019)
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16 pages, 1253 KiB  
Review
Targeting Angiogenesis in Prostate Cancer
by Zsombor Melegh and Sebastian Oltean
Int. J. Mol. Sci. 2019, 20(11), 2676; https://doi.org/10.3390/ijms20112676 - 31 May 2019
Cited by 88 | Viewed by 6515
Abstract
Prostate cancer is the most commonly diagnosed cancer among men in the Western world. Although localized disease can be effectively treated with established surgical and radiopharmaceutical treatments options, the prognosis of castration-resistant advanced prostate cancer is still disappointing. The objective of this study [...] Read more.
Prostate cancer is the most commonly diagnosed cancer among men in the Western world. Although localized disease can be effectively treated with established surgical and radiopharmaceutical treatments options, the prognosis of castration-resistant advanced prostate cancer is still disappointing. The objective of this study was to review the role of angiogenesis in prostate cancer and to investigate the effectiveness of anti-angiogenic therapies. A literature search of clinical trials testing the efficacy of anti-angiogenic therapy in prostate cancer was performed using Pubmed. Surrogate markers of angiogenic activity (microvessel density and vascular endothelial growth factor A (VEGF-A) expression) were found to be associated with tumor grade, metastasis, and prognosis. Six randomizedstudies were included in this review: two phase II trials on localized and hormone-sensitive disease (n = 60 and 99 patients) and four phase III trials on castration-resistant refractory disease (n = 873 to 1224 patients). Although the phase II trials showed improved relapse-free survival and stabilisation of the disease, the phase III trials found increased toxicity and no significant improvement in overall survival. Although angiogenesis appears to have an important role in prostate cancer, the results of anti-angiogenic therapy in castration-resistant refractory disease have hitherto been disappointing. There are various possible explanations for this lack of efficacy in castration-resistant refractory disease: redundancy of angiogenic pathways, molecular heterogeneity of the disease, loss of tumor suppressor protein phosphatase and tensin homolog (PTEN) expression as well as various VEGF-A splicing isoforms with pro- and anti-angiogenic activity. A better understanding of the molecular mechanisms of angiogenesis may help to develop effective anti-angiogenic therapy in prostate cancer. Full article
(This article belongs to the Special Issue Diagnostic, Prognostic and Predictive Biomarkers in Prostate Cancer 2019)
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19 pages, 627 KiB  
Review
A Rich Array of Prostate Cancer Molecular Biomarkers: Opportunities and Challenges
by Indu Kohaar, Gyorgy Petrovics and Shiv Srivastava
Int. J. Mol. Sci. 2019, 20(8), 1813; https://doi.org/10.3390/ijms20081813 - 12 Apr 2019
Cited by 103 | Viewed by 11109
Abstract
Prostate cancer is the most prevalent non-skin cancer in men and is the leading cause of cancer-related death. Early detection of prostate cancer is largely determined by a widely used prostate specific antigen (PSA) blood test and biopsy is performed for definitive diagnosis. [...] Read more.
Prostate cancer is the most prevalent non-skin cancer in men and is the leading cause of cancer-related death. Early detection of prostate cancer is largely determined by a widely used prostate specific antigen (PSA) blood test and biopsy is performed for definitive diagnosis. Prostate cancer is asymptomatic in the early stage of the disease, comprises of diverse clinico-pathologic and progression features, and is characterized by a large subset of the indolent cancer type. Therefore, it is critical to develop an individualized approach for early detection, disease stratification (indolent vs. aggressive), and prediction of treatment response for prostate cancer. There has been remarkable progress in prostate cancer biomarker discovery, largely through advancements in genomic technologies. A rich array of prostate cancer diagnostic and prognostic tests has emerged for serum (4K, phi), urine (Progensa, T2-ERG, ExoDx, SelectMDx), and tumor tissue (ConfirmMDx, Prolaris, Oncoytype DX, Decipher). The development of these assays has created new opportunities for improving prostate cancer diagnosis, prognosis, and treatment decisions. While opening exciting opportunities, these developments also pose unique challenges in terms of selecting and incorporating these assays into the continuum of prostate cancer patient care. Full article
(This article belongs to the Special Issue Diagnostic, Prognostic and Predictive Biomarkers in Prostate Cancer 2019)
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19 pages, 561 KiB  
Review
Prediction Medicine: Biomarkers, Risk Calculators and Magnetic Resonance Imaging as Risk Stratification Tools in Prostate Cancer Diagnosis
by Daniël F. Osses, Monique J. Roobol and Ivo G. Schoots
Int. J. Mol. Sci. 2019, 20(7), 1637; https://doi.org/10.3390/ijms20071637 - 02 Apr 2019
Cited by 70 | Viewed by 6565
Abstract
This review discusses the most recent evidence for currently available risk stratification tools in the detection of clinically significant prostate cancer (csPCa), and evaluates diagnostic strategies that combine these tools. Novel blood biomarkers, such as the Prostate Health Index (PHI) and 4Kscore, show [...] Read more.
This review discusses the most recent evidence for currently available risk stratification tools in the detection of clinically significant prostate cancer (csPCa), and evaluates diagnostic strategies that combine these tools. Novel blood biomarkers, such as the Prostate Health Index (PHI) and 4Kscore, show similar ability to predict csPCa. Prostate cancer antigen 3 (PCA3) is a urinary biomarker that has inferior prediction of csPCa compared to PHI, but may be combined with other markers like TMPRSS2-ERG to improve its performance. Original risk calculators (RCs) have the advantage of incorporating easy to retrieve clinical variables and being freely accessible as a web tool/mobile application. RCs perform similarly well as most novel biomarkers. New promising risk models including novel (genetic) markers are the SelectMDx and Stockholm-3 model (S3M). Prostate magnetic resonance imaging (MRI) has evolved as an appealing tool in the diagnostic arsenal with even stratifying abilities, including in the initial biopsy setting. Merging biomarkers, RCs and MRI results in higher performances than their use as standalone tests. In the current era of prostate MRI, the way forward seems to be multivariable risk assessment based on blood and clinical parameters, potentially extended with information from urine samples, as a triaging test for the selection of candidates for MRI and biopsy. Full article
(This article belongs to the Special Issue Diagnostic, Prognostic and Predictive Biomarkers in Prostate Cancer 2019)
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20 pages, 2354 KiB  
Review
Glycans as Biomarkers in Prostate Cancer
by Emma Scott and Jennifer Munkley
Int. J. Mol. Sci. 2019, 20(6), 1389; https://doi.org/10.3390/ijms20061389 - 19 Mar 2019
Cited by 81 | Viewed by 8634
Abstract
Prostate cancer is the most commonly diagnosed malignancy in men, claiming over 350,000 lives worldwide annually. Current diagnosis relies on prostate-specific antigen (PSA) testing, but this misses some aggressive tumours, and leads to the overtreatment of non-harmful disease. Hence, there is an urgent [...] Read more.
Prostate cancer is the most commonly diagnosed malignancy in men, claiming over 350,000 lives worldwide annually. Current diagnosis relies on prostate-specific antigen (PSA) testing, but this misses some aggressive tumours, and leads to the overtreatment of non-harmful disease. Hence, there is an urgent unmet clinical need to identify new diagnostic and prognostic biomarkers. As prostate cancer is a heterogeneous and multifocal disease, it is likely that multiple biomarkers will be needed to guide clinical decisions. Fluid-based biomarkers would be ideal, and attention is now turning to minimally invasive liquid biopsies, which enable the analysis of tumour components in patient blood or urine. Effective diagnostics using liquid biopsies will require a multifaceted approach, and a recent high-profile review discussed combining multiple analytes, including changes to the tumour transcriptome, epigenome, proteome, and metabolome. However, the concentration on genomics-based paramaters for analysing liquid biopsies is potentially missing a goldmine. Glycans have shown huge promise as disease biomarkers, and data suggests that integrating biomarkers across multi-omic platforms (including changes to the glycome) can improve the stratification of patients with prostate cancer. A wide range of alterations to glycans have been observed in prostate cancer, including changes to PSA glycosylation, increased sialylation and core fucosylation, increased O-GlcNacylation, the emergence of cryptic and branched N-glyans, and changes to galectins and proteoglycans. In this review, we discuss the huge potential to exploit glycans as diagnostic and prognostic biomarkers for prostate cancer, and argue that the inclusion of glycans in a multi-analyte liquid biopsy test for prostate cancer will help maximise clinical utility. Full article
(This article belongs to the Special Issue Diagnostic, Prognostic and Predictive Biomarkers in Prostate Cancer 2019)
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12 pages, 1194 KiB  
Review
Focal Neuroendocrine Differentiation of Conventional Prostate Adenocarcinoma as a Prognostic Factor after Radical Prostatectomy: A Systematic Review and Meta-Analysis
by Mehdi Kardoust Parizi, Takehiro Iwata, Shoji Kimura, Florian Janisch, Mohammad Abufaraj, Pierre I. Karakiewicz, Dmitry Enikeev, Leonid M. Rapoport, Georg Hutterer and Shahrokh F. Shariat
Int. J. Mol. Sci. 2019, 20(6), 1374; https://doi.org/10.3390/ijms20061374 - 19 Mar 2019
Cited by 7 | Viewed by 3720
Abstract
The biologic and prognostic value of focal neuroendocrine differentiation (NED) in conventional prostate adenocarcinoma (PC) patients who undergo radical prostatectomy (RP) remains controversial. In this systematic review and meta-analysis, we assessed the association of focal NED in conventional PC with oncological outcomes after [...] Read more.
The biologic and prognostic value of focal neuroendocrine differentiation (NED) in conventional prostate adenocarcinoma (PC) patients who undergo radical prostatectomy (RP) remains controversial. In this systematic review and meta-analysis, we assessed the association of focal NED in conventional PC with oncological outcomes after RP. A literature search using PubMed, Scopus, Web of Science, and Cochrane Library was conducted on December 2018 to find relevant studies according to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines. We used a fixed-effect model to analyze the impact of focal NED in RP specimen on progression-free survival defined by biochemical recurrence (BCR). A total of 16 studies with the outcomes of disease progression and survival were eligible. No patient in these studies received androgen deprivation therapy prior to RP. Eleven studies found no significant correlation between focal NED and outcomes of interest, while five studies reported a significant association of focal NED assessed by immunohistochemical chromogranin A or serotonin staining with BCR or survival. Focal NED was associated with higher BCR rates after RP with a pooled HR of 1.39 (95% CI 1.07‒1.81) in five studies. No heterogeneity was reported in this analysis (I2 = 21.7%, p = 0.276). In conclusion, focal NED in conventional PC is associated with worse prognosis after RP. Its presence should be reported in pathologic reports and its true clinical impact should be assessed in well-designed prospective controlled studies. Full article
(This article belongs to the Special Issue Diagnostic, Prognostic and Predictive Biomarkers in Prostate Cancer 2019)
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20 pages, 986 KiB  
Review
Assessment of miR-98-5p, miR-152-3p, miR-326 and miR-4289 Expression as Biomarker for Prostate Cancer Diagnosis
by Leire Moya, Jonelle Meijer, Sarah Schubert, Farhana Matin and Jyotsna Batra
Int. J. Mol. Sci. 2019, 20(5), 1154; https://doi.org/10.3390/ijms20051154 - 06 Mar 2019
Cited by 53 | Viewed by 4222
Abstract
Prostate cancer (PCa) is one of the most commonly diagnosed cancers worldwide, accounting for almost 1 in 5 new cancer diagnoses in the US alone. The current non-invasive biomarker prostate specific antigen (PSA) has lately been presented with many limitations, such as low [...] Read more.
Prostate cancer (PCa) is one of the most commonly diagnosed cancers worldwide, accounting for almost 1 in 5 new cancer diagnoses in the US alone. The current non-invasive biomarker prostate specific antigen (PSA) has lately been presented with many limitations, such as low specificity and often associated with over-diagnosis. The dysregulation of miRNAs in cancer has been widely reported and it has often been shown to be specific, sensitive and stable, suggesting miRNAs could be a potential specific biomarker for the disease. Previously, we identified four miRNAs that are significantly upregulated in plasma from PCa patients when compared to healthy controls: miR-98-5p, miR-152-3p, miR-326 and miR-4289. This panel showed high specificity and sensitivity in detecting PCa (area under the curve (AUC) = 0.88). To investigate the specificity of these miRNAs as biomarkers for PCa, we undertook an in depth analysis on these miRNAs in cancer from the existing literature and data. Additionally, we explored their prognostic value found in the literature when available. Most studies showed these miRNAs are downregulated in cancer and this is often associated with cancer progression and poorer overall survival rate. These results suggest our four miRNA signatures could potentially become a specific PCa diagnostic tool of which prognostic potential should also be explored. Full article
(This article belongs to the Special Issue Diagnostic, Prognostic and Predictive Biomarkers in Prostate Cancer 2019)
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19 pages, 1566 KiB  
Review
Jumping on the Bandwagon: A Review on the Versatile Applications of Gold Nanostructures in Prostate Cancer
by Monira Sarkis, Esther Ghanem and Kamil Rahme
Int. J. Mol. Sci. 2019, 20(4), 970; https://doi.org/10.3390/ijms20040970 - 23 Feb 2019
Cited by 4 | Viewed by 4691
Abstract
Prostate cancer (PCa) has remarkably emerged as a prominent disease in the face of the male population. Conventional treatments like prostatectomy or radiation can be curative only if PCa is diagnosed at an early stage. In the field of targeted therapy, a bevy [...] Read more.
Prostate cancer (PCa) has remarkably emerged as a prominent disease in the face of the male population. Conventional treatments like prostatectomy or radiation can be curative only if PCa is diagnosed at an early stage. In the field of targeted therapy, a bevy of novel therapeutic approaches have left a landmark in PCa treatment and have proven to extend survival via distinct modes of actions. Nanotherapy has started to take root and has become the hype of the century by virtue of its abundant advantages. Scientists have invested a great deal of interest in the development of nanostructures such as gold nanoparticles (AuNPs), which hold particularly great hope for PCa theranostics. In this article, we present an overview of the studies published after 1998 that involve the use of different functionalized AuNPs to treat and diagnose PCa. Special reference is given to various in vitro and in vivo methods employed to shuttle AuNPs to PCa cells. Major studies show an enhancement of either detection or treatment of PCa when compared to their non-targeted counterparts, especially when AuNPs are tagged with specific ligands, such as antibodies, tea natural extracts, folate, anisamide, receptor inhibitors, and chitosan. Future approaches of treatment are dependent on those worthy multifunctional molecules, and are dictated by their ability to achieve a more versatile cancer therapeutic approach. Full article
(This article belongs to the Special Issue Diagnostic, Prognostic and Predictive Biomarkers in Prostate Cancer 2019)
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1 pages, 149 KiB  
Correction
Correction: Fararjeh, A-F S., et al. ZBTB46, SPDEF, ETV6 Novel Potential Biomarkers and Therapeutic Targets in Castration Resistance Prostate Cancer. Int. J. Mol. Sci. 2019, 20, 2802
by Abdul-Fattah Salah Fararjeh and Yen-Nien Liu
Int. J. Mol. Sci. 2020, 21(12), 4243; https://doi.org/10.3390/ijms21124243 - 14 Jun 2020
Viewed by 1278
Abstract
The authors wish to make the following correction to this paper [...] Full article
(This article belongs to the Special Issue Diagnostic, Prognostic and Predictive Biomarkers in Prostate Cancer 2019)
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