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.

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肿瘤代谢作为前列腺癌进展和致死疾病的驱动因素的作用：来自嵌套病例对照研究的结果

背景了解致死性前列腺癌发展的生物学机制对于改进治疗和预防策略至关重要。在这项研究中，我们使用七种代谢途径的 mRNA 表达谱探讨了肿瘤代谢在前列腺癌进展中的作用；脂肪酸代谢、糖酵解/糖异生、氧化磷酸化、磷酸戊糖、嘌呤代谢、嘧啶代谢和三羧酸循环。研究和医师健康研究。致死病例（n = 113）是在随访期间经历过远处转移事件或死于前列腺癌的男性。非致死对照（n = 291）在诊断后至少存活 8 年而没有转移。在 404 名男性中，还有 202 名具有匹配的正常组织（140 名非致死性，62 名致死性）。分析比较了肿瘤和正常组织之间的表达水平，按照格里森等级和致死状态。二次分析考虑与细胞增殖、凋亡和血管生成的生物标志物的关联。 结果氧化磷酸化和嘧啶代谢被确定为致死性肿瘤中最失调的途径 (p < 0.007)，并且在这些途径中，确定了许多新的差异表达基因包括 POLR2K 和 APT6V1A。这种关联是肿瘤特异性的，因为与非致死病例相比，没有证据表明致死病例的正常组织中任何途径发生了改变。结论结果表明前列腺癌的进展和致死性疾病与关键代谢信号通路的改变有关。支持增殖的途径似乎在前列腺肿瘤侵袭性中特别重要。