Abstract
BackgroundUnderstanding 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.MethodsThe 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.ResultsOxidative 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.ConclusionsThe 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s40170-016-0161-9) contains supplementary material, which is available to authorized users.
Highlights
Understanding the biologic mechanisms underlying the development of lethal prostate cancer is critical for improved therapeutic and prevention strategies
We recently reported that the pyrimidine biosynthesis pathway, which is responsible for production of nucleic acids needed for cell replication, is enriched in higher Gleason grade tumors [10]
Study population This study was nested among men with incident prostate cancer from the prospective US Health Professionals Follow-up Study (HPFS) or Physicians’ Health Study (PHS)
Summary
Understanding the biologic mechanisms underlying the development of lethal prostate cancer is critical for improved therapeutic and prevention strategies. It is well known that proliferating tumor cells have different metabolic requirements from normal, differentiated cells [1] These metabolic needs are reflected, at least in part, by a shift in metabolic phenotype including the increased conversion of glucose to lactate even when oxygen is abundant, a phenomenon termed aerobic glycolysis or the Warburg effect [2]. We recently reported that the pyrimidine biosynthesis pathway, which is responsible for production of nucleic acids needed for cell replication, is enriched in higher Gleason grade tumors [10]. We extend these analyses to explore other relevant metabolic pathways and to consider lethal disease as an endpoint
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