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.

Keywords: FDG–PET standardized uptake values; bimodal distributions; epithelial malignancies; metabolism; stem cell.

Figure 1

. The relationship between ¹⁸F-FDG PET SUV_max and histologic differentiation of previously untreated cancer types before resection (A–E). ***P < 0.001, **P < 0.01.

Figure 2.

The distribution of SUV_max of diverse untreated cancer types (A–E). The red vertical lines mark the two modes of the bimodal distributions.

Figure 3.

SUV score is a predictor of lymph node metastases in untreated cancer types (A–E). Patients with lymph node metastases have a high ¹⁸F-FDG PET SUV_max. ***P < 0.001, **P < 0.01.

Figure 4.

The distribution of SUV_max pre- and post-induction chemotherapy for esophageal carcinoma (A and B) and non small cell lung carcinoma (C and D).

Figure 5.

Heat map combined with regression analysis of metabolism-related pathways for the 20 MSKCC Director’s Challenge samples of lung adenocarcinoma with available PET SUV data. (A) Red represents the low SUV mode, blue the high SUV mode. There is a significant (P < 0.01, Fisher’s exact) separation of the SUV modes where the left cluster contains 9 of the 13 samples with low SUV (SUV <6.0) and the right cluster has 7 of 7 samples with high SUV (SUV >6.0). In the heat map, red represents activation of the pathways, and blue represents repression of the pathways. Most of the ES cell-related pathways are activated in the high SUV cluster and display statistically highly significant correlation with SUV_max. Carbohydrate-/pentose-related pathway is also elevated in the high SUV cluster. (B) Regression analysis for SUV with signature enrichment score of ES cell-related pathways. ***P < 0.001, **P < 0.01, *P < 0.05 (FDR of signature enrichment score and SUV).