The Warburg effect: Persistence of stem-cell metabolism in cancers as a failure of differentiation Journal Article

Authors: Riester, M.; Xu, Q.; Moreira, A.; Zheng, J.; Michor, F.; Downey, R. J.
Article Title: The Warburg effect: Persistence of stem-cell metabolism in cancers as a failure of differentiation
Abstract: 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. © The Author 2017.
Keywords: cancer survival; human cell; major clinical study; cancer risk; positron emission tomography; lymph node metastasis; metabolism; embryo; embryonic stem cell; cohort analysis; transcription factor; cell differentiation; histology; stem cell; cancer cell; cancer stem cell; fluorodeoxyglucose f 18; cell metabolism; glucose transport; oxidative phosphorylation; rna sequence; aerobic glycolysis; human; priority journal; article; patient risk; bimodal distributions; epithelial malignancies; fdg-pet standardized uptake values
Journal Title: Annals of Oncology
Volume: 29
Issue: 1
ISSN: 0923-7534
Publisher: Oxford University Press  
Date Published: 2018-01-01
Start Page: 264
End Page: 270
Language: English
DOI: 10.1093/annonc/mdx645
PROVIDER: scopus
PUBMED: 29045536
PMCID: PMC6658717
Notes: Article -- Export Date: 1 March 2018 -- Source: Scopus
Citation Impact
MSK Authors
  1. Junting Zheng
    180 Zheng
  2. Robert J Downey
    236 Downey