Targeted proteomics in urinary extracellular vesicles identifies biomarkers for diagnosis and prognosis of prostate cancer
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Tamara Sequeiros1, Marina Rigau1, Cristina Chiva2,3, Melania Montes1, Iolanda Garcia-Grau1, Marta Garcia1, Sherley Diaz4, Ana Celma5, Irene Bijnsdorp6, Alex Campos8, Primiano Di Mauro9, Salvador Borrós9, Jaume Reventós10,11, Andreas Doll1, Rosanna Paciucci1, Michiel Pegtel7, Inés de Torres1,4, Eduard Sabidó2,3, Juan Morote1,5, Mireia Olivan1
1 Group of Biomedical Research in Urology, Vall d’Hebron Research Institute (VHIR) and Universitat Autònoma de Barcelona (UAB), Barcelona, Spain
2 Proteomics Unit, Centre de Regulació Genòmica (CRG), Barcelona, Spain
3 Proteomics Unit, Universitat Pompeu Fabra, Barcelona, Spain
4 Department of Pathology, Vall d'Hebron University Hospital, Barcelona, Spain
5 Department of Urology, Vall d'Hebron University Hospital, Barcelona, Spain
6 Department of Urology, VU University Medical Center, Amsterdam, The Netherlands
7 Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands
8 Sanford-Burnham Medical Research Institute, La Jolla, California, USA
9 Sagetis-Biotech; Grup d'Enginyeria de Materials (GEMAT) Institut Químic de Sarrià, Barcelona, Spain
10 Departement of Basic Science, International University of Catalonia, Barcelona, Spain
11 IDIBELL-Bellvitge Biomedical Research Institute, Barcelona, Spain
Mireia Olivan, email: [email protected]
Keywords: prostate cancer, biomarkers, urine, extracellular vesicles, diagnosis
Received: September 22, 2016 Accepted: November 07, 2016 Published: November 26, 2016
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.
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