Lange Sigrun, Bernstein Darryl Ethan, Dimov Nikolay, Puttaswamy Srinivasu, Johnston Ian, Kraev Igor, Needham Sarah R, Vasdev Nikhil, Inal Jameel M
Pathobiology and Extracellular Vesicles Research Group, School of Life Sciences, University of Westminster, London W1W 6UW, UK.
Hertfordshire and Bedfordshire Urological Cancer Centre, Department of Urology, Lister Hospital, East and North Hertfordshire Teaching NHS Trust, Stevenage, Hertfordshire SG1 4AB, UK.
Int J Mol Sci. 2025 Jul 18;26(14):6895. doi: 10.3390/ijms26146895.
Urinary extracellular vesicles (U-EVs) are gaining increasing interest as non-invasive liquid biopsy tools for clinical use. Prostate cancer (PCa) is amongst the highest cancer-related cause of death in men, and therefore, the identification of non-invasive robust biomarkers is of high importance. This study assessed U-EV profiles from individuals affected by PCa at Gleason scores 6-9, compared with healthy controls. U-EVs were characterised and assessed for proteomic cargo content by LC-MS/MS analysis. The U-EV proteomes were compared for enrichment of gene ontology (GO), KEGG, and Reactome pathways, as well as disease-gene associations. U-EVs ranged in size from 50 to 350 nm, with the majority falling within the 100-200 nm size range for all groups. U-EV protein cargoes from the PCa groups differed significantly from healthy controls, with 16 protein hits unique to the GS 6-7 and 88 hits to the GS 8-9 U-EVs. Pathway analysis showed increased enrichment in the PCa U-EVs of biological process GO (5 and 37 unique to GS 6-7 and GS 8-9, respectively), molecular function GO (3 and 6 unique to GS 6-7 and GS 8-9, respectively), and cellular component GO (10 and 22 unique to GS 6-7 and GS 8-9, respectively) pathways. A similar increase was seen for KEGG pathways (11 unique to GS 8-9) and Reactome pathways (102 unique to GS 8-9). Enrichment of disease-gene associations was also increased in the PCa U-EVs, with highest differences for the GS 8-9 U-EVs (26 unique terms). The pathway enrichment in the PCa U-EVs was related to several key inflammatory, cell differentiation, cell adhesion, oestrogen signalling, and infection pathways. Unique GO and KEGG pathways enriched for the GS 8-9 U-EVs were associated with cell-cell communication, immune and stress responses, apoptosis, peptidase activity, antioxidant activity, platelet aggregation, mitosis, proteasome, mRNA stability oxytocin signalling, cardiomyopathy, and several neurodegenerative diseases. Our findings highlight U-EVs as biomarkers to inform disease pathways in prostate cancer patients and offer a non-invasive biomarker tool for clinical use.
尿细胞外囊泡（U-EVs）作为用于临床的非侵入性液体活检工具正越来越受到关注。前列腺癌（PCa）是男性癌症相关死亡的主要原因之一，因此，识别非侵入性的可靠生物标志物至关重要。本研究评估了Gleason评分6-9的前列腺癌患者与健康对照者的U-EV谱。通过液相色谱-串联质谱（LC-MS/MS）分析对U-EVs进行表征并评估其蛋白质组含量。比较了U-EV蛋白质组在基因本体论（GO）、京都基因与基因组百科全书（KEGG）和Reactome通路以及疾病-基因关联方面的富集情况。U-EVs的大小在50至350纳米之间，所有组中的大多数都在100-200纳米大小范围内。前列腺癌组的U-EV蛋白质含量与健康对照者有显著差异，GS 6-7组有16种独特的蛋白质，GS 8-9组有88种独特的蛋白质。通路分析显示，前列腺癌U-EVs在生物过程GO（GS 6-7组和GS 8-9组分别有5种和37种独特的）、分子功能GO（GS 并6-7组和GS 8-9组分别有3种和6种独特的）和细胞成分GO（GS 6-7组和GS 8-9组分别有10种和22种独特的）通路中的富集增加。KEGG通路（GS 8-9组有11种独特的）和Reactome通路（GS 8-9组有102种独特的）也有类似的增加。前列腺癌U-EVs中疾病-基因关联的富集也增加了，GS 8-9组的差异最大（有26个独特的术语）。前列腺癌U-EVs中的通路富集与几个关键的炎症、细胞分化、细胞粘附、雌激素信号传导和感染通路有关。GS 8-9组U-EVs中富集的独特GO和KEGG通路与细胞间通讯、免疫和应激反应、细胞凋亡、肽酶活性、抗氧化活性、血小板聚集、有丝分裂、蛋白酶体、mRNA稳定性、催产素信号传导、心肌病和几种神经退行性疾病有关。我们的研究结果突出了U-EVs作为前列腺癌患者疾病通路信息生物标志物的作用，并为临床应用提供了一种非侵入性生物标志物工具。
