Abstract
Rapid and reliable diagnosis of prostate cancer (PCa) is highly desirable as current used methods lack specificity. In addition, identification of PCa biomarkers that can classify patients into high- and low-risk groups for disease progression at early stage will improve treatment decision-making. Here, we describe a set of protein-combination panels in urinary extracellular vesicles (EVs), defined by targeted proteomics and immunoblotting techniques that improve early non-invasive detection and stratification of PCa patients.We report a two-protein combination in urinary EVs that classifies benign and PCa patients (ADSV-TGM4), and a combination of five proteins able to significantly distinguish between high- and low-grade PCa patients (CD63-GLPK5-SPHM-PSA-PAPP). Proteins composing the panels were validated by immunohistochemistry assays in tissue microarrays (TMAs) confirming a strong link between the urinary EVs proteome and alterations in PCa tissues. Moreover, ADSV and TGM4 abundance yielded a high diagnostic potential in tissue and promising TGM4 prognostic power. These results suggest that the proteins identified in urinary EVs distinguishing high- and low grade PCa are a reflection of histological changes that may be a consequence of their functional involvement in PCa development. In conclusion, our study resulted in the identification of protein-combination panels present in urinary EVs that exhibit high sensitivity and specificity for PCa detection and patient stratification. Moreover, our study highlights the potential of targeted proteomic approaches–such as selected reaction monitoring (SRM)–as diagnostic assay for liquid biopsies via urinary EVs to improve diagnosis and prognosis of suspected PCa patients.
Highlights
Prostate cancer (PCa) is the most frequently diagnosed cancer and the second leading cause of cancer related death among men in developed countries [1]
In this work we used a targeted proteomics approach to quantify a set of 64 proteins in urinary extracellular vesicles (EVs) in the context of prostate cancer (PCa) biomarker validation in a cohort of 107 individual urine-derived human samples
We measured protein abundance changes in urinary EVs by selected reaction monitoring (SRM), and we built proteinbased panels for PCa diagnosis and prognosis in urinary EVs, which we checked in tissue microarrays analysis
Summary
Prostate cancer (PCa) is the most frequently diagnosed cancer and the second leading cause of cancer related death among men in developed countries [1]. The currently used diagnostic methods for PCa detection are far from ideal. A significant rate of unnecessary prostate biopsies (PB) is practiced [2]. There is still a clear need for new biomarkers for a fast and reliable diagnosis of PCa. Because of the prostate location in the body, in direct contact with the urethra, prostate (cancer) secrete products can be detected in urine. Urine has been intensively studied as a liquid biopsy source of biomarkers for PCa [3,4,5,6]. The low protein concentration, the presence of salts and the vast dynamic range of protein expression in urine turn it into a complicated fluid for the discovery of proteinbased biomarkers [7]
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