Diego Iglesias-Gato1, Pernilla Wikström2, Stefka Tyanova3, Charlotte Lavallee4, Elin Thysell2, Jessica Carlsson5, Christina Hägglöf2, Jürgen Cox3, Ove Andrén5, Pär Stattin6, Lars Egevad7, Anders Widmark8, Anders Bjartell9, Colin C Collins10, Anders Bergh2, Tamar Geiger11, Matthias Mann12, Amilcar Flores-Morales13. 1. 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. Electronic address: diego.iglesias@sund.ku.dk. 2. Department of Medical Biosciences, Pathology, Umea University, Umea, Sweden. 3. Department of Proteomics and Signal Transduction, Max Planck Institute for Biochemistry, Martinsried, Germany. 4. 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. 5. School of Health and Medical Sciences, Department of Urology, University of Örebro, Sweden. 6. Departments of Surgery and Perioperative Sciences, Umea University, Umea, Sweden. 7. Section of Urology, Department of Surgical Science, Karolinska Institutet, Stockholm, Sweden. 8. Department of Radiation Sciences, Oncology, Umea University, Umea, Sweden. 9. Department of Translational Medicine, Division of Urological Cancers, University of Lund, Lund, Sweden. 10. Department of Urologic Sciences, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada. 11. Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel. 12. Novo Nordisk Foundation Centre for Protein Research, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark; Department of Proteomics and Signal Transduction, Max Planck Institute for Biochemistry, Martinsried, Germany. 13. 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. Electronic address: Amilcar.Flores@cpr.ku.dk.
Abstract
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.
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.
Authors: Ankit Sinha; Vincent Huang; Julie Livingstone; Jenny Wang; Natalie S Fox; Natalie Kurganovs; Vladimir Ignatchenko; Katharina Fritsch; Nilgun Donmez; Lawrence E Heisler; Yu-Jia Shiah; Cindy Q Yao; Javier A Alfaro; Stas Volik; Anna Lapuk; Michael Fraser; Ken Kron; Alex Murison; Mathieu Lupien; Cenk Sahinalp; Colin C Collins; Bernard Tetu; Mehdi Masoomian; David M Berman; Theodorus van der Kwast; Robert G Bristow; Thomas Kislinger; Paul C Boutros Journal: Cancer Cell Date: 2019-03-18 Impact factor: 31.743
Authors: Kelly V Ruggles; Karsten Krug; Xiaojing Wang; Karl R Clauser; Jing Wang; Samuel H Payne; David Fenyö; Bing Zhang; D R Mani Journal: Mol Cell Proteomics Date: 2017-04-29 Impact factor: 5.911
Authors: Thomas Stefan Worst; Jost von Hardenberg; Julia Christina Gross; Philipp Erben; Martina Schnölzer; Ingrid Hausser; Peter Bugert; Maurice Stephan Michel; Michael Boutros Journal: Mol Cell Proteomics Date: 2017-04-09 Impact factor: 5.911
Authors: Erez Persi; Davide Prandi; Yuri I Wolf; Yair Pozniak; Georgina D Barnabas; Keren Levanon; Iris Barshack; Christopher Barbieri; Paola Gasperini; Himisha Beltran; Bishoy M Faltas; Mark A Rubin; Tamar Geiger; Eugene V Koonin; Francesca Demichelis; David Horn Journal: Proc Natl Acad Sci U S A Date: 2019-08-06 Impact factor: 11.205