Background Two recent observations regarding the Warburg effect are that (i) the metabolism of stem cells is constitutive (aerobic) glycolysis while normal cellular differentiation involves a transition to oxidative phosphorylation and (ii) the degree of glucose uptake of a malignancy as imaged by 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) is associated with histologic measures of tumor differentiation. Combining these observations, we hypothesized that the high levels of glucose uptake observed in poorly differentiated cancers may reflect persistence of the glycolytic metabolism of stem cells in malignant cells that fail to fully differentiate. Patients and methods Tumor glucose uptake was measured by FDG-PET in 552 patients with histologically diverse cancers. We used normal mixture modeling to explore FDG-PET standardized uptake value (SUV) distributions and tested for associations between glucose uptake and histological differentiation, risk of lymph node metastasis, and survival. Using RNA-seq data, we carried out pathway and transcription factor analyses to compare tumors with high and low levels of glucose uptake. Results We found that well-differentiated tumors had low FDG uptake, while moderately and poorly differentiated tumors had higher uptake. The distribution of SUV for each histology was bimodal, with a low peak around SUV 2-5 and a high peak at SUV 8-14. The cancers in the two modes were clinically distinct in terms of the risk of nodal metastases and death. Carbohydrate metabolism and the pentose-related pathway were elevated in the poorly differentiated/high SUV clusters. Embryonic stem cell-related signatures were activated in poorly differentiated/high SUV clusters. Conclusions Our findings support the hypothesis that the biological basis for the Warburg effect is a persistence of stem cell metabolism (i.e. aerobic glycolysis) in cancers as a failure to transition from glycolysis-utilizing undifferentiated cells to oxidative phosphorylation-utilizing differentiated cells. We found that cancers cluster along the differentiation pathway into two groups, utilizing either glycolysis or oxidative phosphorylation. Our results have implications for multiple areas of clinical oncology.

中文翻译：

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沃堡效应：癌症中干细胞代谢的持续性是分化失败的原因。

背景技术关于沃堡效应的两个最新观察结果是：（i）干细胞的代谢是组成型（有氧）糖酵解，而正常的细胞分化涉及向氧化磷酸化的转变，以及（ii）18F成像显示的恶性肿瘤的葡萄糖摄取程度-氟脱氧葡萄糖正电子发射断层扫描（FDG-PET）与肿瘤分化的组织学测量有关。结合这些观察结果，我们假设在分化较差的癌症中观察到的高水平的葡萄糖摄取可能反映了无法完全分化的恶性细胞中干细胞糖酵解代谢的持续性。患者和方法通过FDG-PET测定了552名组织学上不同的癌症患者的肿瘤葡萄糖摄取。我们使用正常的混合物模型来探索FDG-PET标准化摄取值（SUV）分布，并测试了葡萄糖摄取与组织学分化，淋巴结转移风险和生存之间的关联。利用RNA-seq数据，我们进行了途径和转录因子分析，以比较葡萄糖摄入量高和低的肿瘤。结果我们发现，高分化的肿瘤对FDG的摄取较低，而中度和低分化的肿瘤对FDG的摄取较高。每种组织学中SUV的分布都是双峰的，在SUV 2-5附近出现一个低峰，在SUV 8-14附近出现一个高峰。就淋巴结转移和死亡的风险而言，两种模式的癌症在临床上是截然不同的。在低分化/高SUV群中，碳水化合物的代谢和与戊糖有关的途径升高。胚胎干细胞相关的特征在低分化/高SUV簇中被激活。结论我们的发现支持以下假设：沃堡效应的生物学基础是癌症中干细胞代谢（即有氧糖酵解）的持续存在，因为无法从利用糖酵解的未分化细胞转变为利用氧化磷酸化的分化细胞。我们发现癌症利用糖酵解或氧化磷酸化沿分化途径聚集为两类。我们的结果对临床肿瘤学的多个领域都有影响。（有氧糖酵解）在癌症中无法从利用糖酵解的未分化细胞转变为利用氧化磷酸化的分化细胞的失败。我们发现癌症利用糖酵解或氧化磷酸化沿分化途径聚集为两类。我们的结果对临床肿瘤学的多个领域都有影响。（有氧糖酵解）在癌症中无法从利用糖酵解的未分化细胞转变为利用氧化磷酸化的分化细胞的失败。我们发现癌症利用糖酵解或氧化磷酸化沿分化途径聚集为两类。我们的结果对临床肿瘤学的多个领域都有影响。