Prostate Health Index (Phi) and Prostate Cancer Antigen 3 (PCA3) Significantly Improve Prostate Cancer Detection at Initial Biopsy in a Total PSA Range of 2–10 ng/ml

Many efforts to reduce prostate specific antigen (PSA) overdiagnosis and overtreatment have been made. To this aim, Prostate Health Index (Phi) and Prostate Cancer Antigen 3 (PCA3) have been proposed as new more specific biomarkers. We evaluated the ability of phi and PCA3 to identify prostate cancer (PCa) at initial prostate biopsy in men with total PSA range of 2–10 ng/ml. The performance of phi and PCA3 were evaluated in 300 patients undergoing first prostate biopsy. ROC curve analyses tested the accuracy (AUC) of phi and PCA3 in predicting PCa. Decision curve analyses (DCA) were used to compare the clinical benefit of the two biomarkers. We found that the AUC value of phi (0.77) was comparable to those of %p2PSA (0.76) and PCA3 (0.73) with no significant differences in pairwise comparison (%p2PSA vs phi p = 0.673, %p2PSA vs. PCA3 p = 0.417 and phi vs. PCA3 p = 0.247). These three biomarkers significantly outperformed fPSA (AUC = 0.60), % fPSA (AUC = 0.62) and p2PSA (AUC = 0.63). At DCA, phi and PCA3 exhibited a very close net benefit profile until the threshold probability of 25%, then phi index showed higher net benefit than PCA3. Multivariable analysis showed that the addition of phi and PCA3 to the base multivariable model (age, PSA, %fPSA, DRE, prostate volume) increased predictive accuracy, whereas no model improved single biomarker performance. Finally we showed that subjects with active surveillance (AS) compatible cancer had significantly lower phi and PCA3 values (p<0.001 and p = 0.01, respectively). In conclusion, both phi and PCA3 comparably increase the accuracy in predicting the presence of PCa in total PSA range 2–10 ng/ml at initial biopsy, outperforming currently used %fPSA.     

Biomarker Discovery in Human Prostate Cancer: an Update in Metabolomics Studies

Prostate cancer (PCa) is the most frequently diagnosed cancer and the second leading cause of cancer death among men in Western countries. Current screening techniques are based on the measurement of serum prostate specific antigen (PSA) levels and digital rectal examination. A decisive diagnosis of PCa is based on prostate biopsies; however, this approach can lead to false-positive and false-negative results. Therefore, it is important to discover new biomarkers for the diagnosis of PCa, preferably noninvasive ones. Metabolomics is an approach that allows the analysis of the entire metabolic profile of a biological system. As neoplastic cells have a unique metabolic phenotype related to cancer development and progression, the identification of dysfunctional metabolic pathways using metabolomics can be used to discover cancer biomarkers and therapeutic targets. In this study, we review several metabolomics studies performed in prostatic fluid, blood plasma/serum, urine, tissues and immortalized cultured cell lines with the objective of discovering alterations in the metabolic phenotype of PCa and thus discovering new biomarkers for the diagnosis of PCa. Encouraging results using metabolomics have been reported for PCa, with sarcosine being one of the most promising biomarkers identified to date. However, the use of sarcosine as a PCa biomarker in the clinic remains a controversial issue within the scientific community. Beyond sarcosine, other metabolites are considered to be biomarkers for PCa, but they still need clinical validation. Despite the lack of metabolomics biomarkers reaching clinical practice, metabolomics proved to be a powerful tool in the discovery of new biomarkers for PCa detection.     

Explication of the roles of prostate health index (PHI) and urokinase plasminogen activator (uPA) as diagnostic and predictor tools for prostate cancer in equivocal PSA range of 4–10 ng/mL

BackgroundProstate cancer (PCa) is one of the most commonly encountered cancers and the leading cause of death worldwide. Currently used biomarkers accounts difficulties in discriminating benign from malignant cases or predicting outcome, so investigating new biomarkers performance is needed.ObjectivesAssessment of diagnostic and predictor roles of prostate health index (PHI) and urokinase plasminogen activator (uPA) in PCa.Methods194 males with initial tPSA of 4–10 ng/mL were categorized into three groups: PCa, benign prostatic hyperplasia (BPH) and healthy control. Serum levels of tPSA, fPSA, p2PSA, and uPA were performed by ELISA with calculation of PHI as (p2PSA/fPSA) × √PSA.ResultsPHI and uPA were significantly higher in PCa patients relevant to BPH and healthy control (p ≤ 0.001). Both markers outperformed all assessed biomarkers and showed the highest area under the curve (AUC) in ROC curve analysis. Both were significantly higher in PCa patients with {Gleason score ≥ 7, late stages (cT2b,c; T3), LN extension and distant metastasis}relative to their counterparts. Additionally, PHI and uPA and were independent predictors of distant metastasis and Gleason score ≥ 7, while PHI was predictor of LN invasion (β = 0.25, p = 0.004).ConclusionPHI and uPA would be of potential value in discriminating between PCa, BPH and healthy men in addition, both are promising as independent predictors of adverse pathological features.     

An overview of prostate cancer (PCa) diagnosis: Potential role of miRNAs

Prostate cancer is the second most frequently diagnosed cancer among men worldwide, with the estimated sixth leading cause of cancer death. Despite major advancements in clinical biology and imaging, digital rectal examination (DRE), prostate-specific antigen (PSA), and biopsies indication remain the keystone for screening. Several kits are used to detect genomic changes and non-coding RNAs in the sample. However, its indication remains controversial for screening purposes. There is an urged need for non-invasive biomarkers to implement precision medicine. Recent research shows that miRNAs have an important role in the diagnostic, prognostic, and therapeutic agents as non-invasive biomarkers. Though prostate cancer data remains controversial in other cancer types, such as breast cancer, miR-21 expression is upregulated. Here, we reported a prolonged revision of miRNAs as prostate cancer prognostic, diagnostic, and predictive tools, including data on androgen receptor (AR) signaling, epithelial-mesenchymal transition (EMT) process, and cancer stem cells (CSCs) regulation. The combined utilization of miRNAs with other tests will help patients and clinicians to select the most appropriate personalized treatment and to avoid overdiagnosis and unnecessary biopsies. Future clinical applications of our reported novel miRNAs have a substantial role in the primary diagnosis of prostate cancer to help treatment decisions.     

Identification of PSA peptide mimotopes using phage display peptide library

Prostate cancer (PCa) is one of the most common types of cancer in men in the United States and is the second leading cause of cancer related death in men. Clinically, secreted prostate specific antigen (PSA) has gained recognition because of its proteolytic activity being directly linked to PCa cell proliferation leading to disease initiation and progression. Using phage display technology, we identified four distinct cyclical peptides. These peptides apart from differences in their amino acid sequence, elicited minimal cross reactive antibody responses against each other. One of the four peptides analyzed produced an antibody response that recognizes the PSA protein. We demonstrate that the synthetic PSA peptide mimics identified in our study are immunologically active and produce neutralizing activity and this has relevance and utility for prostate cancer disease progression.     

Screening for Prostate Cancer: A Review of the ERSPC and PLCO Trials

The advent of prostate-specific antigen (PSA) testing in the early 1980s revolutionized the diagnosis of prostate cancer. As a result of PSA testing, there has been a surge in the number of prostate cancer diagnoses. This review examines the results of 2 recent landmark trials that studied the effect of screening on prostate cancer mortality: the European Randomized Study of Screening for Prostate Cancer (ERSPC) and the US-based Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial.Key words: PSA screening, European Randomized Study of Screening for Prostate Cancer (ERSPC), Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening TrialProstate cancer poses a significant problem for men’s health; it has become the most common malignancy and the second most common cause of cancer death in American men. It is estimated that 1 in 6 men will be diagnosed with prostate cancer at some time in their lives, and more than 30,000 men died of the disease in 2002.¹ The advent of prostate-specific antigen (PSA) testing in the early 1980s revolutionized the diagnosis of prostate cancer, and, as a result, there has been a surge in the number of prostate cancer diagnoses.Similar to other common malignancies, such as breast and cervical cancer, population screening with this effective tumor marker appears enticing, and the American health care model has advocated PSA screening since the early 1990s. This review examines the results of 2 recent landmark trials: the European Randomized Study of Screening for Prostate Cancer (ERSPC)¹ and the US-based Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial.² The results of these trials have contributed significantly to our understanding of the effects and efficacy of prostate cancer screening, and its difficulties. Both trials examined mortality as the endpoint, and both found little effect on mortality from screening.     

PSA及其相关检测指标在早期前列腺癌诊断中的临床价值

前列腺癌(PCa)是影响老年男性的恶性肿瘤之一,具有较高的发病率和死亡率,我国PCa患者人数逐年升高,因此进行早期的诊断和治疗具有重要意义。前列腺特异性抗原(PSA)对于早期PCa的诊断、治疗和预后具有重要作用,本文分别对PSA相关指标(F/TPSA、CPSA、PSAV、PSAD、PSATZ)应用于早期PCa诊断中的价值进行综述,旨在为临床诊断PCa提供理论依据。     

Circulating microRNAs as potential diagnostic biomarkers and therapeutic targets in prostate cancer: Current status and future perspectives

Prostate cancer (PCa) is one of the most common malignancies among men. Despite advancement in technology and medicine over past decades, late diagnosis remains a critical milestone in effective treatment. Therefore, it is necessary to identify novel and reliable biomarkers which are specifically sensitive and specific for prognosis and prediction of clinical outcomes. MicroRNAs (miRNAs) play important roles in posttranslational regulations of genes. Circulating and exosomal miRNAs can be applied as useful diagnostic markers for a different type of malignancies, including PCa. Herein, we summarized various roles of miRNAs (diagnostic, therapeutic, and prognostic) in PCa. Moreover, we highlighted exosomal miRNAs as a new candidate in diagnosis and monitoring response to therapy in patients with PCa.     

NMR-based metabolomics studies of human prostate cancer tissue

Introduction

Prostate cancer (PCa) is one of the most prevalent cancers in men worldwide. Serum prostate-specific antigen (PSA) remains the most used biomarker in the detection and management of patients with PCa, in spite of the problems related with its low specificity, false positive rate and overdiagnosis. Furthermore, PSA is unable to discriminate indolent from aggressive PCa, which can lead to overtreatment. Early diagnosed and treated PCa can have a good prognosis and is potentially curable. Therefore, the discovery of new biomarkers able to detect clinically significant aggressive PCa is urgently needed.

Methods

This revision was based on an electronic literature search, using Pubmed, with Nuclear Magnetic Resonance (NMR), tissue and prostate cancer as keywords. All metabolomic studies performed in PCa tissues by NMR spectroscopy, from 2007 until March 2018, were included in this review.

Results

In the context of cancer, metabolomics allows the analysis of the entire metabolic profile of cancer cells. Several metabolic alterations occur in cancer cells to sustain their abnormal rates of proliferation. NMR proved to be a suitable methodology for the evaluation of these metabolic alterations in PCa tissues, allowing to unveil alterations in citrate, spermine, choline, choline-related compounds, lactate, alanine and glutamate.

Conclusion

The study of the metabolic alterations associated with PCa progression, accomplished by the analysis of PCa tissue by NMR, offers a promising approach for elucidating biochemical pathways affected by PCa and also for discovering new clinical biomarkers. The main metabolomic alterations associated with PCa development and promising biomarker metabolites for diagnosis of PCa were outlined.

     

The C-Terminal Fragment of Prostate-Specific Antigen,a 2331 Da Peptide,as a New Urinary Pathognomonic Biomarker Candidate for Diagnosing Prostate Cancer

Background and Objectives

Prostate cancer (PCa) is one of the most common cancers and leading cause of cancer-related deaths in men. Mass screening has been carried out since the 1990s using prostate-specific antigen (PSA) levels in the serum as a PCa biomarker. However, although PSA is an excellent organ-specific marker, it is not a cancer-specific marker. Therefore, the aim of this study was to discover new biomarkers for the diagnosis of PCa.

Materials and Methods

We focused on urine samples voided following prostate massage (digital rectal examination [DRE]) and conducted a peptidomic analysis of these samples using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF/MSⁿ). Urinary biomaterials were concentrated and desalted using CM-Sepharose prior to the following analyses being performed by MALDI-TOF/MSⁿ: 1) differential analyses of mass spectra; 2) determination of amino acid sequences; and 3) quantitative analyses using a stable isotope-labeled internal standard.

Results

Multivariate analysis of the MALDI-TOF/MS mass spectra of urinary extracts revealed a 2331 Da peptide in urine samples following DRE. This peptide was identified as a C-terminal PSA fragment composed of 19 amino acid residues. Moreover, quantitative analysis of the relationship between isotope-labeled synthetic and intact peptides using MALDI-TOF/MS revealed that this peptide may be a new pathognomonic biomarker candidate that can differentiate PCa patients from non-cancer subjects.

Conclusion

The results of the present study indicate that the 2331 Da peptide fragment of PSA may become a new pathognomonic biomarker for the diagnosis of PCa. A further large-scale investigation is currently underway to assess the possibility of using this peptide in the early detection of PCa.     

Hospital parking garage

Prostate cancer is a serious health care problem in the United States. Whether or not to screen for it has become a timely issue. Although a large number of men have clinically important, asymptomatic, undetected prostate cancer, an even larger number have clinically unimportant cancer. To justify screening programs, not only must we avoid detecting biologically unimportant cancers, we must also detect and effectively treat that subset of tumors that, if undiagnosed, would progress, produce symptoms, and reduce life expectancy. Serum prostate-specific antigen (PSA) assay, or its variations such as PSA density, PSA velocity, and age-specific reference ranges, and the digital rectal examination are the best tests for detecting clinically important, asymptomatic, curable tumors. Recent data suggest that using serum PSA levels does not result in an overdetection of unimportant tumors. Highly effective, curative treatment of localized prostate cancer is available. These factors promote optimism that screening for prostate cancer will ultimately prove beneficial. Nonetheless, men should be informed regarding the benefits and possible risks before being screened for prostate cancer.     

Insensitivity to the growth inhibitory effects of activin A: an acquired capability in prostate cancer progression

Prostate cancer (PCa), the most common non-skin cancer in men, is a worldwide health concern. Treatment options for aggressive PCa are limited to androgen deprivation therapies (ADT), which are ineffective, with robust diagnostic options also being limited. The prostate specific antigen (PSA) test, for instance, is subject to high levels of false positive results and cannot distinguish between cancer confined to the prostate and aggressive metastatic cancer. As such, additional therapeutic and diagnostic options are urgently required. In recent years, a clear association between activins and prostate cancer has become evident. Activins are members of the TGF-β superfamily and are responsible for a plethora of physiological processes, including cell proliferation, apoptosis, immune surveillance, embryonic development, and follicle stimulating hormone (FSH) regulation. Activin A normally inhibits cancer development and progression, however, cancer cell growth in high-grade PCa is not inhibited by this protein. The mechanism for this apparent acquired capability to resist activin A-mediated growth inhibition is currently not well understood. Thus, the aim of this review is to analyse the role of activin A in PCa progression and to present mechanisms by which transformed cells may escape its effects. The overarching hypothesis is that insensitivity to the growth inhibitory effects of activin A is an acquired capability in PCa progression. Therefore, local and genetic elements that may be responsible for this change in cellular sensitivity to activin A during cancer progression will be highlighted with a view to identifying potential diagnostic or therapeutic targets.     

A mechanistic insight into the anti-metastatic role of the prostate specific antigen

AimSince its discovery Prostate Specific Antigen (PSA), also referred to as kallikrein-3 (KLK3), has been used as standard circulating biomarker for prostate cancer (PCa). However, its specificity remains not adequate and its mechanism of action still elusive. Therefore, deciphering PSA role throughout PCa-pathobiology would be relevant in improving both cancer diagnosis and outcome prediction. We investigated the possible role played by PSA on/in the tumor microenvironment and over the first steps of cancer invasion.MethodsFresh PCa-specimens and cell lines were used for ex-vivo/in-vitro invasion assays and assessment of prostate tissue-PSA (tPSA), type 1 collagen (COL1A1) and ß1-integrin expression. Tissue Cancer Genome Atlas (TCGA) and Decipher® datasets were considered to estimate tPSA clinical relevance.ResultsA more precise, inverse, correspondence between tPSA and clinical/pathological parameters was found than for circulating PSA. KLK3 combined with Gleason grade and pathologic stage, better predicted cancer-related mortality. Consistently, we demonstrated that PSA inhibits prostate extracellular-matrix (ECM) invasion by PCa cells. As for the mechanism of action, we provided novel information that PSA is able to cleave COL1A1, a main component of the ECM. Finally, ß1-integrin, a crucial COL1A1 transducing-receptor involved in tumor adhesion/invasion, resulted to be downregulated in PCa specimens with higher levels of tPSA.ConclusionsBy interfering with type 1 collagen and its downstream targets, PSA may hamper adhesion and path of the cancer cells through ECM and their migration ability, thus explaining the inverse correlation highlighted between prostate tPSA levels and clinically significant disease.     

Cholesterol accumulation in prostate cancer: A classic observation from a modern perspective

Prostate cancer (PCa) is the most common cancer in men in developed countries. Epidemiological studies have associated high blood-cholesterol levels with an increased risk of PCa, whilst cholesterol-lowering drugs (statins) reduce the risk of advanced PCa. Furthermore, normal prostate epithelial cells have an abnormally high cholesterol content, with cholesterol levels increasing further during progression to PCa. In this review, we explore why and how this occurs.     

Semen as a rich source of diagnostic biomarkers for prostate cancer: latest evidence and implications

Molecular and Cellular Biochemistry - Prostate cancer (PCa) is one of the most common cancers in men and the cause of numerous cancer deaths in the world. Nowadays, based on diagnostic criteria,...     

Détection des différentes formes du prostate-specific antigen et autres kallicréines dans le cancer de la prostate

Prostate cancer is the most common cancer in men over 50 years old and the second leading cause of cancer death. Prostate-specific antigen (PSA) is widely used for the diagnosis and follow-up of prostate cancer. PSA, also called kallikrein 3, is a member of the human kallikrein-type serine protease family and circulates in the blood stream in the form of complexes with serum protease inhibitors and in free form. However, free PSA is also a heterogeneous mixture of different molecular PSA forms: proPSA, intact and clived mature forms. The clinical significance of these different forms is still unclear but their specific measurement in serum could improve the specificity of PSA for detecting cancer or predicting treatment outcome. Others kallikreins including kallikrein 2, 4, 11, 14 and 15 are also emerging as complementary markers to PSA for prostate cancer. Multiple detection of the different molecular forms of PSA, as well as of these kallikreins, in addition to total PSA, could significantly increase the diagnostic utility of PSA and may add prognostic value by bringing clinical information on the cancer progression.     

Advances in proteomic prostate cancer biomarker discovery

Prostate cancer is the most common non-cutaneous cancer in men in the United States. For reasons largely unknown, the incidence of prostate cancer has increased in the last two decades, in spite or perhaps because of a concomitant increase in serum prostate-specific antigen (PSA) screening. While PSA is acknowledged not to be an ideal biomarker for prostate cancer detection, it is however widely used by physicians due to lack of an alternative. Thus, the identification of a biomarker(s) that can complement or replace PSA represents a major goal for prostate cancer research. Screening complex biological specimens such as blood, urine, and tissue to identify protein biomarkers has become increasingly popular over the last decade thanks to advances in proteomic discovery methods. The completion of human genome sequence together with new development in mass spectrometry instrumentation and bioinformatics has been a major driving force in biomarker discovery research. Here we review the current state of proteomic applications as applied to various sample sources including blood, urine, tissue, and “secretome” for the purpose of prostate cancer biomarker discovery. Additionally, we review recent developments in validation of putative markers, efforts at systems biology approach, and current challenges of proteomics in biomarker discovery.