Urinary Exosomes from Bladder Cancer Patients Show a Residual Cancer Phenotype despite Complete Pathological Downstaging

Abstract

Invasive urinary bladder cancer shows high recurrence rates after cystectomy even with apparent complete downstaging at cystectomy. Exosomes are nano-sized vesicles important in cell-cell communication, which have been hypothesized to contribute to cancer dissemination and recurrence. The aim of this study was to investigate if pro-carcinogenic exosomes could be detected in urine from histologically downstaged bladder cancer patients. 13 Patients were included in this study. Paired ureter and urine samples from nine patients underwent mass spectrometry, while samples from the remaining patients were used for exosome characterization. At cystectomy, exosomes were isolated from bladder and ureter urine, whereafter quantitative proteome profiling was performed. Urinary exosomes clustered based on whether they came from the bladder, with tumour contact, or the ureters, without tumour contact, even though all came from completely downstaged patients. Proteins overexpressed in exosomes derived from bladder urine contained several oncogenes and were mainly associated with tumour metabolism pathways. Although patients were histologically tumour-free at cystectomy, the bladder urine contained exosomes with a carcinogenic metabolic profile. This suggests a continuous release of exosomes from the bladder, which may promote recurrence at distant sites through metabolic rewiring, even after apparent complete downstaging. These exosomes, coming from either undetected cancer cells or partly transformed cells, are likely to increase the risk of metastasis and encourages cystectomy even in completely downstaged patients.

Creation of a Continent Urinary Bladder Reservoir Vascularized by Omentum as a Possible Surgical Option for Canine Trigonal/Urethral Urothelial Carcinoma

“…The previously described "field effect" has been suggested as a potential cause for local recurrence [4,9]. In addition, exosomes released from histologically unaffected bladder urothelium may also contribute to metastasis or recurrence [47]. As such, tumor could recur within the neoreservoir or at the stoma despite complete surgical excision.…”

The Emerging Role of Extracellular Vesicles in Endocrine Resistant Breast Cancer

“…Extracellular vesicles (EVs) are multi-signal messengers naturally released by all cell types into the extracellular space that can be recovered from common biological fluids, such as blood, urine, breast milk, seminal fluids, saliva and malignant effusion [ 19 , 20 , 21 , 22 , 23 , 24 ]. Initially observed in plasma by Chargaff and West in 1946 as platelet-derived particles and then described by Wolf in 1967 as “platelet dust”, the EVs are now well recognized as key players in intercellular communication in both physiological and pathological conditions.…”

Proteomic Analysis of Exosomes for Discovery of Protein Biomarkers for Prostate and Bladder Cancer

“…Potential exosomal protein biomarkers from urine and cell lines were recently identified using MS-based proteomics ( Table 3 ). They are promising for both BCa diagnosis and prediction of BCa progression [ 14 , 31 , 95 , 96 , 97 , 98 ].…”

“…For BCa urine exosome analysis, Hiltbrunner et al used paired exosomes from bladder and ureter urine of the same BCa patients to discover BCa-specific exosomal biomarkers (with or without bladder contact) [ 95 ]. They discovered several oncoproteins overexpressed in exosomes derived from bladder urine.…”