Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, USA.
Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, USA.
Ann Oncol. 2018 Jan 1;29(1):264-270. doi: 10.1093/annonc/mdx645.
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.
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.
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.
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.
关于瓦博格效应有两个最新观察结果：（i）干细胞的代谢是组成性（有氧）糖酵解，而正常细胞分化涉及向氧化磷酸化的转变；（ii）18F-氟脱氧葡萄糖正电子发射断层扫描（FDG-PET）成像显示的恶性肿瘤葡萄糖摄取程度与肿瘤分化的组织学测量有关。结合这些观察结果，我们假设在分化不良的癌症中观察到的高水平葡萄糖摄取可能反映了恶性细胞中未能完全分化的干细胞糖酵解代谢的持续存在。
通过 FDG-PET 测量了 552 名组织学不同的癌症患者的肿瘤葡萄糖摄取。我们使用正常混合模型探索 FDG-PET 标准化摄取值（SUV）分布，并测试葡萄糖摄取与组织学分化、淋巴结转移风险和生存之间的相关性。使用 RNA-seq 数据，我们进行了途径和转录因子分析，以比较葡萄糖摄取水平高和低的肿瘤。
我们发现，分化良好的肿瘤摄取 FDG 较低，而中度和低度分化的肿瘤摄取较高。每个组织学的 SUV 分布呈双峰模式，低峰约为 SUV 2-5，高峰约为 SUV 8-14。两种模式的癌症在淋巴结转移和死亡风险方面存在临床差异。在分化不良/高 SUV 簇中，碳水化合物代谢和戊糖相关途径升高。在分化不良/高 SUV 簇中，胚胎干细胞相关特征被激活。
我们的发现支持这样一种假设，即沃伯格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，这是由于未能从利用糖酵解的未分化细胞向利用氧化磷酸化的分化细胞转变。我们发现，癌症沿着分化途径聚类为两组，一组利用糖酵解，另一组利用氧化磷酸化。我们的结果对临床肿瘤学的多个领域具有重要意义。
