Metabolic alterations in urine extracellular vesicles are associated to prostate cancer pathogenesis and progression

Marc Clos-Garcia,Ana Loizaga-Iriarte,Patricia Zuñiga-Garcia,Pilar Sánchez-Mosquera,Ana Rosa Cortazar,Esperanza González,Verónica Torrano,Cristina Alonso,Miriam Pérez-Cormenzana,Aitziber Ugalde-Olano,Isabel Lacasa-Viscasillas,Azucena Castro,Felix Royo,Miguel Unda,Arkaitz Carracedo,Juan M Falcón-Pérez

doi:10.1080/20013078.2018.1470442

Abstract

ABSTRACTUrine contains extracellular vesicles (EVs) that concentrate molecules and protect them from degradation. Thus, isolation and characterisation of urinary EVs could increase the efficiency of biomarker discovery. We have previously identified proteins and RNAs with differential abundance in urinary EVs from prostate cancer (PCa) patients compared to benign prostate hyperplasia (BPH). Here, we focused on the analysis of the metabolites contained in urinary EVs collected from patients with PCa and BPH. Targeted metabolomics analysis of EVs was performed by ultra-high-performance liquid chromatography–mass spectrometry. The correlation between metabolites and clinical parameters was studied, and metabolites with differential abundance in PCa urinary EVs were detected and mapped into cellular pathways. We detected 248 metabolites belonging to different chemical families including amino acids and various lipid species. Among these metabolites, 76 exhibited significant differential abundance between PCa and BPH. Interestingly, urine EVs recapitulated many of the metabolic alterations reported in PCa, including phosphathidylcholines, acyl carnitines, citrate and kynurenine. Importantly, we found elevated levels of the steroid hormone, 3beta-hydroxyandros-5-en-17-one-3-sulphate (dehydroepiandrosterone sulphate) in PCa urinary EVs, in line with the potential elevation of androgen synthesis in this type of cancer. This work supports urinary EVs as a non-invasive source to infer metabolic changes in PCa.

Highlights

Prostate cancer (PCa) is among the most frequently diagnosed and deadly types of cancer in men in Western countries
The size of the particles increased with the stage of the PCa, the major difference was observed between benign prostate hyperplasia (BPH) and PCa stage 3 (Figure 1)
Our data show that urine from advanced PCa patients contains a higher proportion of large extracellular vesicles (EVs) than BPH patients

Summary

Introduction

Prostate cancer (PCa) is among the most frequently diagnosed and deadly types of cancer in men in Western countries (http://globocan.iarc.fr). Prostate-specific antigen (PSA) blood screening tests, together with clinical T-stage and Gleason score are the standard tests to discriminate patients with low, intermediate or high risk to suffer PCa [1]. Metabolomics is recognised as the ultimate “omics” discipline with high potential to identify sensitive and specific markers, and to understand the mechanisms involved in the development of pathological processes [2]. Metabolomics comprises the qualitative and quantitative measurement of the metabolic response to physiological or pathological stimuli. It involves the extraction and measurement of low molecular weight molecules (e.g. amino acids, sugars, bile acids, fatty acids, vitamins, etc.) belonging to different metabolic pathways to generate metabolic profiles of cells, tissues or biofluids [5,6].

Methods

Results

Conclusion