Comprehensive metabolomics analysis of prostate cancer tissue in relation to tumor aggressiveness and TMPRSS2-ERG fusion status
Comprehensive metabolomics analysis of prostate cancer tissue in relation to tumor aggressiveness and TMPRSS2-ERG fusion status
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DOI：
10.1186/s12885-020-06908-z
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发表时间：
2020-05-18
期刊：
影响因子：
3.8
通讯作者：
Grobner, Gerhard
中科院分区：
文献类型：
--
作者：
Dudka, Ilona;Thysell, Elin;Grobner, Gerhard
背景前列腺癌(PC)可以表现出非常不同的表型，从惰性的无症状到侵袭性的致命性形式。了解这些PC亚型在争取能量和合成代谢分子的过程中是如何变化的，对于开发更有效的治疗和诊断是至关重要的。在这里，我们对前列腺组织样本进行了广泛的分析，以揭示PC发育和疾病进展过程中的代谢变化，以及TMPRSS2-ERG重排阳性和阴性PC亚类之间的代谢变化。方法采用非破坏性高分辨魔角旋转核磁共振(H-1HR MAS核磁共振)对前列腺组织进行全面代谢组学分析。随后，样品进行了适度提取，保留了组织形态完整的组织病理学特征。用H-1/P-31核磁共振和液质联用鉴定组织提取物中的代谢物。通过化学计量学工具分析这些代谢组学特征，并使用来自单独样本队列的蛋白质组数据进一步验证结果。结果前列腺癌与良性组织、高Gleason评分(GS)和低Gleason评分(GS)样本之间的代谢产物图谱有显著差异。确定了五种关键代谢物(磷胆碱、谷氨酸、次黄嘌呤、精氨酸和α-葡萄糖)，它们足以区分癌症和良性组织以及高到低GS。在ERG阳性的PC中，分析显示在增加的代谢物中有几种酰肉碱，同时参与β-氧化的蛋白质水平下降；这表明ERG阳性肿瘤的酰基-COAS氧化减少。ERG阳性组还显示参与嘌呤分解代谢的代谢物和蛋白质水平增加；这是DNA损伤和氧化应激增加的潜在迹象。结论我们的综合代谢分析有力地表明，ERG阳性PC和ERG阴性PC应被视为不同的PC亚型；这一事实需要针对受影响的患者采取不同的亚型特异性治疗策略。
Background Prostate cancer (PC) can display very heterogeneous phenotypes ranging from indolent asymptomatic to aggressive lethal forms. Understanding how these PC subtypes vary in their striving for energy and anabolic molecules is of fundamental importance for developing more effective therapies and diagnostics. Here, we carried out an extensive analysis of prostate tissue samples to reveal metabolic alterations during PC development and disease progression and furthermore between TMPRSS2-ERG rearrangement-positive and -negative PC subclasses. Methods Comprehensive metabolomics analysis of prostate tissue samples was performed by non-destructive high-resolution magic angle spinning nuclear magnetic resonance (H-1 HR MAS NMR). Subsequently, samples underwent moderate extraction, leaving tissue morphology intact for histopathological characterization. Metabolites in tissue extracts were identified by H-1/P-31 NMR and liquid chromatography-mass spectrometry (LC-MS). These metabolomics profiles were analyzed by chemometric tools and the outcome was further validated using proteomic data from a separate sample cohort. Results The obtained metabolite patterns significantly differed between PC and benign tissue and between samples with high and low Gleason score (GS). Five key metabolites (phosphocholine, glutamate, hypoxanthine, arginine and alpha-glucose) were identified, who were sufficient to differentiate between cancer and benign tissue and between high to low GS. In ERG-positive PC, the analysis revealed several acylcarnitines among the increased metabolites together with decreased levels of proteins involved in beta-oxidation; indicating decreased acyl-CoAs oxidation in ERG-positive tumors. The ERG-positive group also showed increased levels of metabolites and proteins involved in purine catabolism; a potential sign of increased DNA damage and oxidative stress. Conclusions Our comprehensive metabolomic analysis strongly indicates that ERG-positive PC and ERG-negative PC should be considered as different subtypes of PC; a fact requiring different, sub-type specific treatment strategies for affected patients.