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The Proteome of Primary Prostate Cancer
IVS, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark; Novo Nordisk Foundation Centre for Protein Research, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark; Danish Cancer Society, Copenhagen, Denmark.
Department of Medical Biosciences, Pathology, Umeå University, Umeå, Sweden.
Department of Proteomics and Signal Transduction, Max Planck Institute for Biochemistry, Martinsried, Germany.
IVS, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark; Novo Nordisk Foundation Centre for Protein Research, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark; Danish Cancer Society, Copenhagen, Denmark.
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2016 (English)In: European Urology, ISSN 0302-2838, E-ISSN 1873-7560, Vol. 69, no 5, p. 942-952Article in journal (Refereed) Published
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Abstract [en]

Background: Clinical management of the prostate needs improved prognostic tests and treatment strategies. Because proteins are the ultimate effectors of most cellular reactions, are targets for drug actions and constitute potential biomarkers; a quantitative systemic overview of the proteome changes occurring during prostate cancer (PCa) initiation and progression can result in clinically relevant discoveries.

Objectives: To study cellular processes altered in PCa using system-wide quantitative analysis of changes in protein expression in clinical samples and to identify prognostic biomarkers for disease aggressiveness.

Design, setting, and participants: Mass spectrometry was used for genome-scale quantitative proteomic profiling of 28 prostate tumors (Gleason score 6-9) and neighboring nonmalignant tissue in eight cases, obtained from formalin-fixed paraffin-embedded prostatectomy samples. Two independent cohorts of PCa patients (summing 752 cases) managed by expectancy were used for immunohistochemical evaluation of proneuropeptide-Y (pro-NPY) as a prognostic biomarker.

Results and limitations: Over 9000 proteins were identified as expressed in the human prostate. Tumor tissue exhibited elevated expression of proteins involved in multiple anabolic processes including fatty acid and protein synthesis, ribosomal biogenesis and protein secretion but no overt evidence of increased proliferation was observed. Tumors also showed increased levels of mitochondrial proteins, which was associated with elevated oxidative phosphorylation capacity measured in situ. Molecular analysis indicated that some of the proteins overexpressed in tumors, such as carnitine palmitoyltransferase 2 (CPT2, fatty acid transporter), coatomer protein complex, subunit alpha (COPA, vesicle secretion), and mitogen-and stress-activated protein kinase 1 and 2 (MSK1/2, protein kinase) regulate the proliferation of PCa cells. Additionally, pro-NPY was found overexpressed in PCa (5-fold, p < 0.05), but largely absent in other solid tumor types. Pro-NPY expression, alone or in combination with the ERG status of the tumor, was associated with an increased risk of PCa specific mortality, especially in patients with Gleason score <= 7 tumors.

Conclusions: This study represents the first system-wide quantitative analysis of proteome changes associated to localized prostate cancer and as such constitutes a valuable resource for understanding the complex metabolic changes occurring in this disease. We also demonstrated that pro-NPY, a protein that showed differential expression between high and low risk tumors in our proteomic analysis, is also a PCa specific prognostic biomarker associated with increased risk for disease specific death in patients carrying low risk tumors.

Patient summary: The identification of proteins whose expression change in prostate cancer provides novel mechanistic information related to the disease etiology. We hope that future studies will prove the value of this proteome dataset for development of novel therapies and biomarkers. (C) 2015 European Association of Urology. Published by Elsevier B.V. All rights reserved.

Place, publisher, year, edition, pages
Elsevier, 2016. Vol. 69, no 5, p. 942-952
Keywords [en]
Prostate cancer, Quantitative proteomics, Formalin-fixed paraffin-embedded, Proneuropeptide-Y, Watchful waiting
National Category
Urology and Nephrology
Identifiers
URN: urn:nbn:se:oru:diva-50278DOI: 10.1016/j.eururo.2015.10.053ISI: 000374171700037PubMedID: 26651926OAI: oai:DiVA.org:oru-50278DiVA, id: diva2:927774
Funder
Swedish Research Council, K2013-64X-20407-04-3Swedish Cancer Society, CAN 2013/845 CAN 2013/1324
Note

Funding Agencies:

Danish Research Council

Movember Foundation

Danish Cancer Society

Novo Nordisk Foundation of The Novo Nordisk Foundation Center for Protein Research, University of Copenhagen NNF14CC0001

Terry Fox Research Institute New Frontiers Program TFF 116129

Erling-Persson Family Foundation

Available from: 2016-05-13 Created: 2016-05-13 Last updated: 2017-11-30Bibliographically approved

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Carlsson, JessicaAndrén, Ove

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