Urinary biomarkers for prostate cancer: a review

Although the routine use of serum prostate-specific antigen (PSA) testing has undoubtedly increased prostate cancer (PCa) detection, one of its main drawbacks is its lack of specificity. As a consequence, many men undergo unnecessary biopsies or treatments for indolent tumours. PCa-specific markers are needed for the early detection of the disease and the prediction of aggressiveness of a prostate tumour. Since PCa is a heterogeneous disease, a panel of tumour markers is fundamental for a more precise diagnosis. Several biomarkers are promising due to their specificity for the disease in tissue. However, tissue is unsuitable as a possible screening tool. Since urine can be easily obtained in a non-invasive manner, it is a promising substrate for biomarker testing. This article reviews the biomarkers for the non-invasive testing of PCa in urine.     

Extracellular vesicles in prostate cancer: a narrative review

Over the past decade, there has been remarkable progress in prostate cancer biomarker discovery using urine- and blood-based assays. A liquid biopsy is a minimally invasive procedure to investigate the cancer-related molecules in circulating tumor cells (CTCs), cell-free DNA, and extracellular vesicles (EVs). Liquid biopsies have the advantage of detecting heterogeneity as well as acquired resistance in cancer. EVs are cell-derived vesicles enclosed by a lipid bilayer and contain various molecules, such as nucleic acids, proteins, and lipids. In patients with cancer, EVs derived from tumors can be isolated from urine, plasma, and serum. The advances in isolation techniques provide the opportunity to use EVs as biomarkers in the clinic. Emerging evidence suggests that EVs can be useful biomarkers for the diagnosis of prostate cancer, especially high-grade cancer. EVs can also be potent biomarkers for the prediction of disease progression in patients with castration-resistant prostate cancer (CRPC). EVs shed from cancer and stromal cells are involved in the development of tumor microenvironments, enhancing cancer progression, metastasis, and drug resistance. Here, we provide an overview of the use of EVs for the diagnosis of clinically significant prostate cancer as well as for predicting disease progression. We also discuss the biological function of EVs, which regulate cancer progression.     

Urinary extracellular vesicles: a rising star in bladder cancer management

Clinically, the detection of bladder cancer (BCa) typically requires cystoscopy, which is potentially harmful and sometimes accompanied by adverse effects. Thus, new biomarkers are desirable for improving the management of BCa. Recently, “liquid biopsy” has received enormous attentions and has been extensively studied due to its promising clinical implication for precise medicine. Especially, extracellular vesicles (EVs) have attracted strong interest as a potential source of biomarkers. EVs have been reported to be found in almost all types of body fluids and are easy to collect. In addition, EVs tightly reflect the current state of the disease by inheriting specific biomolecules from their parental cells. Urinary EVs have gained great scientific interest in the field of BCa biomarker research since urine is in direct contact with BCa and can contain large amounts of EVs from the tumour microenvironment. To date, various kinds of biomolecules, including noncoding RNAs, mRNAs, and proteins, have been investigated as biomarkers in urinary EVs. In this narrative review, we summarize the recent advances regarding urinary EVs as non-invasive biomarkers in patients with BCa. The current hurdles in the clinical implications of EV-based liquid biopsy and the potential applications of EV research are also discussed.     

Identification of novel biomarkers of prostate cancer through integrated analysis

BackgroundThe current methods adopted to screen for prostate cancer (PCa) can sometimes be misleading and inaccurate. Moreover, for advanced stages of PCa, the current effect of treatment is not satisfactory for some patients. Accordingly, we aimed to identify new biomarkers for the diagnosis and prognosis of PCa.MethodsA series of bioinformatic tools were utilized to search for potential new biomarkers of PCa and analyze their functions, expression, clinical relevance, prognostic value, and underlying mechanisms.ResultsAlthough ASPN was overexpressed in PCa, EDN3, PENK, MEIS2, IGF1, and CXCL12 were downregulated. The univariate Cox regression analysis showed that abnormally high expression of ASPN and low expression of other genes predicted worse prognosis. Moreover, the multivariate Cox regression analysis showed that ASPN, PENK, and MEIS2 were independently associated with the overall survival (OS) of patients, whereas other markers were not. The outcomes of gene ontology and gene set enrichment analysis showed that the expression levels of these genes might be associated with cell proliferation and infiltration of immune cells in PCa.ConclusionsWe demonstrated that ASPN, EDN3, PENK, MEIS2, IGF1, and CXCL12 are possibly novel diagnostic indicators for PCa, whereas ASPN, PENK, and MEIS2 show appealing potential to predict the prognosis of this disease.     

Circ_0061140 stimulates the malignant development of prostate cancer by targeting miR-1193

BackgroundThis study sought to explore the expression pattern in prostate cancer (PCa) tissues, as well as the regulatory effects of circ_0061140 on the proliferative potential of PCa cells.MethodsA quantitative real-time polymerase chain reaction (qRT-PCR) analysis was undertaken to detect circ_0061140 levels in 43 paired PCa tissues and adjacent normal tissues. After the knockdown of circ_0061140, changes in the proliferative potential of PCa cells and tumor growth in nude mice with PCa were detected. Finally, the relationship of circ_0061140 and miR-1193 in the development of PCa was assessed.ResultsThe results showed that circ_0061140 was upregulated in PCa tissues. PCa patients with higher Gleason score or larger sized tumors expressed higher levels of circ_0061140. Additionally, the knockdown of circ_0061140 inhibited the proliferative potential of PCa cells. MiR-1193 was the target gene binding circ_0061140, and its level was negatively regulated by circ_0061140. Finally, rescue experiments showed that miR-1193 was regulated by circ_0061140 in the development of PCa.ConclusionsCirc_0061140 is upregulated in PCa tissues, and is closely linked to Gleason score and tumor size in PCa. Additionally, it causes PCa cells to proliferate by negatively regulating miR-1193.     

The role of circulating extracellular vesicles in breast cancer classification and molecular subtyping

Currently, tumor biopsies are used for breast cancer molecular subtyping. Biopsies are associated with various pathological changes and are thought to contribute to the dissemination of tumor cells. Extracellular vesicles shed by tumor cells into circulation exhibit the molecular signature of the parent cells. Herein, we show that proteomic analysis of circulating EV can discriminate BC patients from healthy subjects and indicate stage of the disease. Also, we performed a correlation between the BC molecular subtype using plasma EV and immunohistochemistry of tumor biopsies. Circulating EV may represent a useful, non‐invasive tool to study the molecular makeup of BC tumors.     

Concentration of enzymatically active prostate-specific antigen (PSA) in the extracellular fluid of primary human prostate cancers and human prostate cancer xenograft models

BACKGROUND: Prostate-specific antigen (PSA) targeted prodrugs are under development in our laboratory. Concentrations of total PSA and enzymatically active PSA produced by various human prostate cancer xenograft models have not been well characterized. METHODS: The concentration of PSA secreted into the extracellular fluid (ECF) in normal human prostate tissue, primary prostate cancers obtained directly from patients, and serially passageable human prostate cancer xenografts (PC-82, LNCaP, LAPC-4) were determined using Tandem assays. Percent enzymatically active PSA in the ECF and in conditioned media was also determined using a previously validated assay employing a monoclonal antibody to the PSA catalytic site. In addition, the concentration and activity of PSA within sera from men with and without prostate cancer, as well as from tumor-bearing animals, was likewise assayed. RESULTS: Normal human prostate tissue and primary human prostate cancers have high concentrations of PSA in the ECF (i.e., 1600-2100 nM). The majority of this PSA is enzymatically active (i.e., 80-90%). Human PC-82 prostate cancer xenografts also have high concentrations of PSA in the ECF (624 +/- 360 nM), and the majority of this PSA is also enzymatically active (i.e., 66 +/- 4%). In contrast, much lower concentrations of PSA are found in the ECF from LNCaP (45 +/- 9 nM) and LAPC-4 (7.3 +/- 0.6 nM). Only a small portion of the total PSA isolated from DHT-containing, serum-free, conditioned media from these cell lines is enzymatically active (i.e., approximately 18%). While PSA was detected in all serum samples regardless of the type of host, no enzymatically active PSA was detected in any of these serum samples. CONCLUSIONS: Prostate cancers obtained directly from patients produce and secrete large amounts of PSA, the majority of which is highly enzymatically active. In contrast, while PSA was detected in the sera, none of this PSA was enzymatically active. This is also the case for the human PC-82 prostate cancer xenografts. In contrast, LNCaP and LAPC-4 human prostate cancer xenograft models secrete approximately 70-300-fold less PSA in the ECF than prostate cancers from patients and the majority of this PSA is enzymatically inactive. Also, the serum from these animals had detectable PSA, but none of this PSA was enzymatically active. Thus, these latter two prostate cancer models define the least and the PC-82, the most, optimized xenograft model for screening PSA targeted prodrugs.     

Perioperative complications of radical retropubic prostatectomy in patients with locally advanced prostate cancer: a comparison with clinically localized prostate cancer

Radical prostatectomy (RP) continues to be an effective surgical therapy for prostate carcinoma, particularly for organ-confined prostate cancer (PCa). Recently, RP has also been used in the treatment of locally advanced prostate cancer. However, little research has been performed to elucidate the perioperative complications associated with RP in patients with clinically localized or locally advanced PCa. We sought to analyse the incidence of complications in these two groups after radical retropubic prostatectomy (RRP). From June 2002 to July 2010, we reviewed 379 PCa patients who underwent RRP in our hospital. Among these cases, 196 had clinically localized PCa (T_1a–T_2c: group 1), and 183 had locally advanced PCa (≥T_3a: group 2). The overall complication incidence was 21.9%, which was lower than other studies have reported. Perioperative complications in patients with locally advanced PCa mirror those in patients with clinically localized PCa (26.2% vs. 17.8%, P=0.91). Our results showed that perioperative complications could not be regarded as a factor to consider in regarding RP in patients with cT₃ or greater.     

Prostate volume as an independent predictor of prostate cancer in men with PSA of 10–50?ng ml?1

Prostate volume (PV) has been shown to be associated with prostate cancer (PCa) detection rates in men with a prostate-specific antigen (PSA) in the ‘grey zone'' (2.0–10.0 ng ml⁻¹). However, the PSA ‘grey zone'' in Asian men should be higher because the incidence of PCa in Asian men is relatively low. Therefore, we evaluated the association between PV and PCa detection rates in men with PSAs measuring 10–50 ng ml⁻¹. Men who underwent a 13-core prostatic biopsy with PV documentation participated in the study. A multivariate stepwise regression was used to evaluate whether the PV at time of prostate biopsy could predict the risk of PCa. The rates of PCa among men in different PSA ranges, stratified by PV medians (<60 and ≥60 ml), were calculated. There were 261 men included in the final analysis. PV was the strongest predictor of PCa risk (odds ratio, 0.02; P<0.001) compared to other variables. The PCa rates in men with PVs measuring <60 and ≥60 ml in the 10–19.9 ng ml⁻¹ PSA group were 40.6% and 15.1%, respectively, while the rates for men with PSAs measuring 20–50 ng ml⁻¹ were 65.1% and 26.8%. PV is an independent predictor of PCa in men with PSA measuring 10–50 ng ml⁻¹. In clinical practice, particularly for those countries with lower incidences of PCa, PV should be considered when counselling patients with PSAs measuring 10–50 ng ml⁻¹ regarding their PCa risks.     

Effect of obesity on the prognosis and recurrence of prostate cancer after radical prostatectomy: a meta-analysis

BackgroundObesity has been found to be closely related to the increased risk of fatal prostate cancer (PCa), however there remains no evidence that further clarifies the relationship between obesity and the postoperative recurrence and poor prognosis of PCa. In this study, a systematic review and meta-analysis were performed to systematically evaluate the effect of obesity on the prognosis and recurrence of PCa after radical prostatectomy (RP).MethodsA literature search of the PubMed, Web of Science, and Embase databases was performed covering articles published between January 2013 and January 2020. Articles regarding the correlation between body mass index (BMI) and the prognosis and recurrence of PCa following RP were included in the meta-analysis. Two investigators independently screened the literature and extracted relevant data including publication information, key results, number of cancer cases, and multivariable-adjusted odds ratios (ORs) with 95% confidence intervals (CIs). Meta-analysis was performed using RevMan 5.3 and Stata 16.0 software, and forest plots, funnel plots, and sensitivity analysis were also conducted.ResultsA total of 14 articles were included, all of which were analyzed for clinicopathological characteristics. Eight articles reported the biochemical recurrence (BCR) with prostate-specific antigen (PSA) as the predictor, and six articles reported the positive surgical margins (PSM). The meta-analysis showed that obese PCa patients had more postoperative recurrence and poor prognosis compared with the normal weight PCa patients, and the difference was statistically significant (OR =1.25, 95% CI: 1.10, 1.43). BCR exhibited no significant difference between obese and non-obese PCa patients after surgery (OR =1.2, 95% CI: 0.96, 1.46), and there were also no notable differences in PSM between the groups (OR =1.16, 95% CI: 0.99, 1.36). Subgroup analysis showed that obese PCa patients in the Americas (95% CI: 1.11, 1.37) and Europe (95% CI: 1.11, 1.78) were more likely to have surgical recurrence and poor prognosis (OR =1.40). Obese patients in the Americas were also more likely to have BCR after surgery (95% CI: 1.07, 1.36).ConclusionsObesity easily leads to poor prognosis and recurrence of PCa after RP.