Proteomics in Diagnosis of Prostate Cancer/ Протеомика Во Дијагноза На Простатниот Карцином

Abstract Prostate cancer (PCa) is the second most frequently diagnosed malignancy in men worldwide. The introduction of prostate specific antigen (PSA) has greatly increased the number of men diagnosed with PCa but at the same time, as a result of the low specificity, led to overdiagnosis, resulting to unnecessary biopsies and high medical cost treatments. The primary goal in PCa research today is to find a biomarker or biomarker set for clear and effecttive diagnosis of PCa as well as for distinction between aggressive and indolent cancers. Different proteomic technologies such as 2-D PAGE, 2-D DIGE, MALDI MS profiling, shotgun proteomics with label-based (ICAT, iTRAQ) and label-free (SWATH) quantification, MudPIT, CE-MS have been applied to the study of PCa in the past 15 years. Various biological samples, including tumor tissue, serum, plasma, urine, seminal plasma, prostatic secretions and prostatic-derived exosomes were analyzed with the aim of identifying diagnostic and prognostic biomarkers and developing a deeper understanding of the disease at the molecular level. This review is focused on the overall analysis of expression proteomics studies in the PCa field investigating all types of human samples in the search for diagnostics biomarkers. Emphasis is given on proteomics platforms used in biomarker discovery and characterization, explored sources for PCa biomarkers, proposed candidate biomarkers by comparative proteomics studies and the possible future clinical application of those candidate biomarkers in PCa screening and diagnosis. In addition, we review the specificity of the putative markers and existing challenges in the proteomics research of PCa.

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Advances and Perspectives in Prostate Cancer Biomarker Discovery in the Last 5 Years through Tissue and Urine Metabolomics

Metabolites ◽

10.3390/metabo11030181 ◽

2021 ◽

Vol 11 (3) ◽

pp. 181

Author(s):

Ana Rita Lima ◽

Joana Pinto ◽

Filipa Amaro ◽

Maria de Lourdes Bastos ◽

Márcia Carvalho ◽

...

Keyword(s):

Prostate Cancer ◽

Biomarker Discovery ◽

Specific Antigen ◽

Cancer Biomarker ◽

Metabolic Reprogramming ◽

The Past ◽

Promising Strategy ◽

Ideal Approach ◽

Novel Biomarkers ◽

The Impact

Prostate cancer (PCa) is the second most diagnosed cancer in men worldwide. For its screening, serum prostate specific antigen (PSA) test has been largely performed over the past decade, despite its lack of accuracy and inability to distinguish indolent from aggressive disease. Metabolomics has been widely applied in cancer biomarker discovery due to the well-known metabolic reprogramming characteristic of cancer cells. Most of the metabolomic studies have reported alterations in urine of PCa patients due its noninvasive collection, but the analysis of prostate tissue metabolome is an ideal approach to disclose specific modifications in PCa development. This review aims to summarize and discuss the most recent findings from tissue and urine metabolomic studies applied to PCa biomarker discovery. Eighteen metabolites were found consistently altered in PCa tissue among different studies, including alanine, arginine, uracil, glutamate, fumarate, and citrate. Urine metabolomic studies also showed consistency in the dysregulation of 15 metabolites and, interestingly, alterations in the levels of valine, taurine, leucine and citrate were found in common between urine and tissue studies. These findings unveil that the impact of PCa development in human metabolome may offer a promising strategy to find novel biomarkers for PCa diagnosis.

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exRNA Signatures in Extracellular Vesicles and their Tumor-Lineage from Prostate Cancer

10.1101/2020.09.28.20190009 ◽

2020 ◽

Author(s):

Navneet Dogra ◽

Mehmet Eren Ahsen ◽

Edgar Gonzalez Kozlova ◽

Tzu-yi Chen ◽

kimaada allette ◽

...

Keyword(s):

Prostate Cancer ◽

Differential Expression ◽

Extracellular Vesicles ◽

Small Rna ◽

Tumor Tissue ◽

Biomarker Discovery ◽

De Novo ◽

Culture Media ◽

Tumor Resection ◽

Small Rna Sequencing

Circulating extracellular vesicles (EVs) present in the bodily fluids of patients with cancer may provide non-invasive access to the tumor tissue. Yet, the transcriptomic lineage of tumor-derived EVs before and after tumor-resection remains poorly understood. Here, we established 60 total small RNA-sequencing profiles from 17 aggressive prostate cancer (PCa) patients tumor and adjacent normal tissue, and EVs isolated from urine, serum, and cancer cell culture media. We interrogated the key satellite alteration in tumor-derived EVs and found that resection of tumor prostate tissue leads to differential expression of reactive oxygen species (ROS), P53 pathways, inflammatory/cytokines, oncogenes, and tumor suppressor genes in the EV nanosatellites. Furthermore, we provide a set of novel EV-specific RNA signature, which are present in cancer but are nonexistent in post-resection patients with undetectable cancer. Finally, using a de novo RNAseq assembly followed by characterization of the small RNA landscape, we found novel small RNA clusters (smRCs) in the EVs, which reside in the unannotated regions. Novel smRCs were orthogonally validated for their differential expression in the biomarker discovery cohort using RT-qPCR. We demonstrate that circulating tumor EVs provide a glimpse of the tumor tissue biology, resolving a major bottleneck in the current liquid biopsy efforts. Secretory vesicles appear to be playing a key role in non-canonical Wnt signaling and miRNA pathways, similar to the circulating tumor cells (CTCs), hence, we propose that such vesicles be called circulating tumor extracellular vesicles (CTEVs).

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Xanthine Oxidase/Dehydrogenase Activity as a Source of Oxidative Stress in Prostate Cancer Tissue

Diagnostics ◽

10.3390/diagnostics10090668 ◽

2020 ◽

Vol 10 (9) ◽

pp. 668

Author(s):

Andrej Veljković ◽

Jovan Hadži-Dokić ◽

Dušan Sokolović ◽

Dragoslav Bašić ◽

Ljubinka Veličković-Janković ◽

...

Keyword(s):

Oxidative Stress ◽

Prostate Cancer ◽

Xanthine Oxidase ◽

Dehydrogenase Activity ◽

Tumor Tissue ◽

Specific Antigen ◽

Cancer Tissue ◽

Prostate Carcinogenesis ◽

Promising Treatment

Prostate cancer (PC) is one of the most frequent malignancies. Better biomarkers are constantly wanted, such as those which can help with the prediction of cancer behavior. What is also needed is a marker which may serve as a possible therapeutic target. Oxidative stress (OS), which is a hallmark of cancer, is included in the pathogenesis and progression of PC. We have conducted the present study to determine whether xanthine oxidase/dehydrogenase activity is the source of OS in prostate tissue. We have also determined the concentration of TBA-reactive substances (TBARS) and advanced oxidation protein products (AOPP), as well as the activity of catalase. Xanthine oxidase (XO) activity is significantly higher (p < 0.001) in tumor tissue when compared to the control healthy tissue. The concentration of TBARS (p < 0.001) and AOPP (p < 0.05) are also higher in tumor tissue. Catalase has raised its activity (p < 0.05) versus the control. There is also a strong correlation between XO activity and prostate-specific antigen (PSA) levels in the serum. These results indicate a significant role of XO activity in OS in prostate carcinogenesis, and it could be a possible theranostic biomarker, which can be important for a better understanding of the disease, its evolution, and prognosis. A promising treatment may be using XO inhibitors such as allopurinol as adjuvant therapy.

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A Rich Array of Prostate Cancer Molecular Biomarkers: Opportunities and Challenges

International Journal of Molecular Sciences ◽

10.3390/ijms20081813 ◽

2019 ◽

Vol 20 (8) ◽

pp. 1813 ◽

Cited By ~ 22

Author(s):

Indu Kohaar ◽

Gyorgy Petrovics ◽

Shiv Srivastava

Keyword(s):

Prostate Cancer ◽

Early Detection ◽

Biomarker Discovery ◽

Early Stage ◽

Specific Antigen ◽

Cancer Type ◽

Genomic Technologies ◽

Individualized Approach ◽

Prognostic Tests ◽

Disease Stratification

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.

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An Innovative Immunoanalysis Strategy towards Sensitive Recognition of PSA Biomarker in Human Plasma Samples Using Flexible and Portable Paper Based Biosensor: A New Platform towards POC Detection of Cancer Biomarkers Using Integration of Pen-on Paper Technology with Immunoassays Methods

ImmunoAnalysis ◽

10.34172/ia.2021.06 ◽

2021 ◽

Vol 1 (1) ◽

pp. 6-6

Author(s):

Fatemeh Farshchi ◽

Arezoo Saadati ◽

Houman Kholafazad kordasht ◽

Mohammad Hasanzadeh

Keyword(s):

Prostate Cancer ◽

Human Plasma ◽

Specific Antigen ◽

Cost Effective ◽

Plasma Samples ◽

Label Free ◽

Free Paper ◽

Detection Range ◽

Efficient Treatment ◽

Human Plasma Samples

Background: The prostate-specific antigen (PSA) is one of the best markers for detecting prostate cancer. Rapid and real time recognition of PSA biomarker could be helpful in the early diagnosis and efficient treatment of prostate cancer. One of the usual methods to identify this biomarker is ELISA, which has a picomolar detection range but requires specialized personnel and also this technique is time-consuming and expensive. Methods: Cost-effective POC devices are great solutions because they are very cost-effective, sensitive and simple, do not require expert operators and have a high response time in a short time. With that in mind, in this work, a novel and simple label-free paper-based electrochemical immunosensor were designed by using conductive Ag-ink and designed directly by pen on paper technique on the surface of photographic paper, which is a suitable substrate for antibody immobilization, for rapid detection of PSA. Results: Based on the obtained results, under the optimum conditions, the synthesized Ag ink has a great substrate for antibody (Ab) and antigen (Ag) immobilization. The linear range was from 0.001 to 30 μg/L and the obtained low limite of quantification (LLOQ) was 0.001μg/L. This immunosensor also tested in human plasma samples, which had good analytical power. Conclusion: The proposed paper-based immunoassay could be a hopefully new and cheap tool for the diagnosis of other biomarkers.

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Accelerating protein biomarker discovery and translation from proteomics research for clinical utility

Bioanalysis ◽

10.4155/bio-2020-0198 ◽

2020 ◽

Vol 12 (20) ◽

pp. 1469-1481

Author(s):

Jiwen Chen ◽

Naiyu Zheng

Keyword(s):

Clinical Utility ◽

Biomarker Discovery ◽

Clinical Applications ◽

Clinical Perspective ◽

Significant Progress ◽

Clinical Implementation ◽

Protein Biomarkers ◽

Protein Biomarker ◽

The Past ◽

Proteomics Research

Discovery proteomics research has made significant progress in the past several years; however, the number of protein biomarkers deployed in clinical practice remains rather limited. There are several scientific and procedural gaps between discovery proteomics research and clinical implementation, which have contributed to poor biomarker validity and few clinical applications. The complexity and low throughput of proteomics approaches have added additional barriers for biomarker assay translation to clinical applications. Recently, targeted proteomics have become a powerful tool to bridge the biomarker discovery to clinical validation. In this perspective, we discuss the challenges and strategies in proteomics research from a clinical perspective, and propose several recommendations for discovery proteomics research to accelerate protein biomarker discovery and translation for future clinical applications.

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Prostate-specific antigen testing among primary care physicians and urologists: Patterns of care and impact of professional society guidelines.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.5_suppl.40 ◽

2012 ◽

Vol 30 (5_suppl) ◽

pp. 40-40

Author(s):

Sandip M. Prasad ◽

G. Caleb Alexander ◽

Scott E. Eggener

Keyword(s):

Prostate Cancer ◽

United States ◽

Prostate Specific Antigen ◽

Primary Care Physicians ◽

Medical Condition ◽

Specific Antigen ◽

The United States ◽

Chronic Medical Condition ◽

The Past ◽

Psa Testing

40 Background: During the past decade, the incidence of prostate cancer in the United States has declined. We hypothesized this was related to lower rates of prostate-specific antigen (PSA) testing and sought to evaluate PSA testing rates nationally. Methods: Using the National Ambulatory Medical Care Survey, a nationally representative sample of outpatient visits in the United States, we analyzed rates of PSA testing in men age 40 years or older who visited PCPs or urologists from 1997 to 2008. Results: An estimated 26.6 million (95% CI: 24.8-28.4 million) PSA tests were ordered during 94.5 million (95% CI: 90.9-98.1 million) office visits to urologists and 95 million (95% CI: 87.5-102.8 million) tests were ordered during 1.17 billion (95% CI: 1.15-1.18 billion) visits to PCPs, with an annual increase of 3.4% and 6.0%, respectively (P=0.055 and P<0.001 for trend). After adjusting for year, race, ethnicity, region, insurance and provider type, testing by PCPs was more likely among older men and highest among men aged 60 to 69 years (reference: 40-49 years; OR 2.32, 95% CI: 1.88-2.85). Compared to men without a chronic medical condition, those with one chronic condition had greater odds of receiving a PSA test (OR 1.28, 95% CI: 1.08-1.52). Conclusions: Prostate cancer incidence has declined over the past decade despite increasing rates of office-based PSA testing by PCPs and urologists during the period. Increasing rates of PSA testing merit scrutiny, especially in men with limited life expectancies who are unlikely to benefit from screening.

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A Non-Enzymatic and Label-Free Fluorescence Bioassay for Ultrasensitive Detection of PSA

Molecules ◽

10.3390/molecules24050831 ◽

2019 ◽

Vol 24 (5) ◽

pp. 831 ◽

Cited By ~ 4

Author(s):

Yujie Sun ◽

Chenyun Wang ◽

Hong Zhang ◽

Yulin Zhang ◽

Guojun Zhang

Keyword(s):

Prostate Cancer ◽

Early Diagnosis ◽

Patient Survival ◽

Double Helix ◽

Specific Antigen ◽

Hybridization Chain Reaction ◽

Label Free ◽

Chain Reaction ◽

Dsdna Molecule ◽

The Status

The early diagnosis of prostate cancer is very vital for the improvement of patient survival chances. The content of prostate specific antigen (PSA) in serum is closely related to the status of the prostate cancer. We report a fluorescence bioassay, capable of detecting PSA in a non-enzymatic and label-free manner. PSA gives rise to the structural change of a hairpin, consequently triggering the hybridization chain reaction and forming a long-nicked double-helix, which is not adsorbed by graphene oxide. GelRed, as the signal indicator, then binds with dsDNA molecule, thereby producing the fluorescence. The established bioassay has the merits of simple operation, favorable cost-to-benefit ratios, good stability, and specificity. Moreover, the detection limit of this assay is as low as 10 pg/mL, and the linearity range is wide—from 100 pg/mL to 200 ng/mL. At the same time, this bioassay can realize the detection of PSA in biological samples (human serum, saliva, and urine). Therefore, the bioassay provides a potential means for the early diagnosis of prostate cancer.

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Multi-omics biomarker pipeline reveals elevated levels of protein-glutamine gamma-glutamyltransferase 4 in seminal plasma of prostate cancer patients

10.1101/120873 ◽

2017 ◽

Author(s):

Andrei P. Drabovich ◽

Punit Saraon ◽

Mikalai Drabovich ◽

Theano D. Karakosta ◽

Apostolos Dimitromanolakis ◽

...

Keyword(s):

Prostate Cancer ◽

Blood Serum ◽

Cancer Patients ◽

Seminal Plasma ◽

Biomarker Discovery ◽

Prognostic Significance ◽

Specific Antigen ◽

Low Grade ◽

Gamma Glutamyltransferase ◽

Negative Biopsy

AbstractPurposeProstate-specific antigen, a blood serum biomarker of prostate cancer, lacks specificity and prognostic significance, so considerable efforts are devoted to developing novel biomarkers. Seminal plasma, due to its proximity to prostate, is a promising fluid for biomarker discovery and non-invasive diagnostics. In this study, we investigated if seminal plasma proteins could increase specificity of detecting primary prostate cancer and discriminate between high- and low-grade cancers.Experimental DesignTo select 148 most promising biomarker candidates, we combined proteins identified through five independent data mining or experimental approaches: tissue transcriptomics, seminal plasma proteomics, cell secretomics, tissue specificity and androgen regulation. A rigorous biomarker development pipeline based on targeted proteomics assays was designed to evaluate the most promising candidates.ResultsWe qualified 77 and verified 19 proteins in seminal plasma of 67 negative biopsy and 155 prostate cancer patients. Verification revealed a prostate-specific, secreted and androgen-regulated protein-glutamine gamma-glutamyltransferase 4 (TGM4), which could predict prostate cancer on biopsy and outperformed age and serum PSA. Machine-learning approaches also revealed improved multi-marker combinations for diagnosis and prognosis. In the independent verification set measured by an inhouse ELISA, TGM4 was up-regulated 3.7-fold (P=0.006) and revealed AUC 0.66 for detecting prostate cancer on biopsy for patients with serum PSA≥4 ng/mL and age≥50. Low levels of TGM4 (median 120 pg/mL) were detected in blood serum, but could not differentiate between negative biopsy, prostate cancer or prostate inflammation.ConclusionsPerformance of TGM4 warrants its further investigation within the distinct genomic subtypes and evaluation for the inclusion into emerging multi-biomarker panels.

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A Quest to Identify Prostate Cancer Circulating Biomarkers with a Bench-to-Bedside Potential

Journal of Biomarkers ◽

10.1155/2014/321680 ◽

2014 ◽

Vol 2014 ◽

pp. 1-12 ◽

Cited By ~ 3

Author(s):

Jaspreet Singh Batra ◽

Swati Girdhani ◽

Lynn Hlatky

Keyword(s):

Prostate Cancer ◽

Large Scale ◽

Specific Antigen ◽

Health Concern ◽

Treatment Modalities ◽

Potential Candidate ◽

Circulating Biomarkers ◽

Major Health ◽

The Past

Prostate cancer (PCA) is a major health concern in current times. Ever since prostate specific antigen (PSA) was introduced in clinical practice almost three decades ago, the diagnosis and management of PCA have been revolutionized. With time, concerns arose as to the inherent shortcomings of this biomarker and alternatives were actively sought. Over the past decade new PCA biomarkers have been identified in tissue, blood, urine, and other body fluids that offer improved specificity and supplement our knowledge of disease progression. This review focuses on superiority of circulating biomarkers over tissue biomarkers due to the advantages of being more readily accessible, minimally invasive (blood) or noninvasive (urine), accessible for sampling on regular intervals, and easily utilized for follow-up after surgery or other treatment modalities. Some of the circulating biomarkers like PCA3, IL-6, and TMPRSS2-ERG are now detectable by commercially available kits while others like microRNAs (miR-21, -221, -141) and exosomes hold potential to become available as multiplexed assays. In this paper, we will review some of these potential candidate circulating biomarkers that either individually or in combination, once validated with large-scale trials, may eventually get utilized clinically for improved diagnosis, risk stratification, and treatment.

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