The role of tumor metabolism as a driver of prostate cancer progression and lethal disease: results from a nested case-control study.

Understanding the biologic mechanisms underlying the development of lethal prostate cancer is critical for improved therapeutic and prevention strategies. In this study we explored the role of tumor metabolism in prostate cancer progression using mRNA expression profiling of seven metabolic pathways; fatty acid metabolism, glycolysis/gluconeogenesis, oxidative phosphorylation, pentose phosphate, purine metabolism, pyrimidine metabolism and the tricarboxylic acid cycle.

The study included 404 men with archival formalin-fixed, paraffin-embedded prostate tumor tissue from the prospective Health Professionals Follow-up Study and Physicians' Health Study. Lethal cases (n = 113) were men who experienced a distant metastatic event or died of prostate cancer during follow-up. Non-lethal controls (n = 291) survived at least 8 years post-diagnosis without metastases. Of 404 men, 202 additionally had matched normal tissue (140 non-lethal, 62 lethal). Analyses compared expression levels between tumor and normal tissue, by Gleason grade and by lethal status. Secondary analyses considered the association with biomarkers of cell proliferation, apoptosis and angiogenesis.

Oxidative phosphorylation and pyrimidine metabolism were identified as the most dysregulated pathways in lethal tumors (p < 0.007), and within these pathways, a number of novel differentially expressed genes were identified including POLR2K and APT6V1A. The associations were tumor specific as there was no evidence any pathways were altered in the normal tissue of lethal compared to non-lethal cases.

The results suggest prostate cancer progression and lethal disease are associated with alterations in key metabolic signaling pathways. Pathways supporting proliferation appeared to be of particular importance in prostate tumor aggressiveness.

Cancer & metabolism. 2016 Dec 07*** epublish ***

Rachel S Kelly, Jennifer A Sinnott, Jennifer R Rider, Ericka M Ebot, Travis Gerke, Michaela Bowden, Andreas Pettersson, Massimo Loda, Howard D Sesso, Philip W Kantoff, Neil E Martin, Edward L Giovannucci, Svitlana Tyekucheva, Matthew Vander Heiden, Lorelei A Mucci

Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA USA ; Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA USA ; Channing Division of Network Medicine, 181 Longwood Avenue, Boston, MA 02115 USA., Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA USA ; Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA USA., Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA USA ; Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA USA., Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA USA., Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA USA ; Department of Epidemiology, College of Medicine and College of Public Health and Health Professions, University of Florida, Gainesville, FL USA., Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA USA., Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA USA ; Clinical Epidemiology Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden., Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA USA ; Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA USA., Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA USA ; Division of Preventive Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA USA., Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA USA., Department of Radiation Oncology, Brigham and Women's Hospital/Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA USA., Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA USA ; Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA USA ; Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA USA., Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA USA., Koch Institute for Integrative Cancer Research at Massachusetts Institute of Technology, Cambridge, MA 02139 USA ; Dana-Farber Cancer Institute, Boston, MA USA ; Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA 02139 USA.

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