Glucose Metabolism in Cancer-Associated Fibroblasts

Abstract

Under normal conditions, non-transformed cells rely on glycolysis followed by oxidative phosphorylation to generate ATPs. When oxygen is scarce or when cells are actively proliferating, cellular ATPs come mainly from glycolysis. Pyruvate is converted into lactate to allow glycolysis to continue. Interestingly, cancer cells have adapted to favor lactate production even at normal oxygen tensions, exhibiting a metabolic shift known as the Warburg effect. However, the metabolic state of other cellular constituents within the tumor remains mostly unknown. Cancer-associated fibroblasts (CAFs) are the most abundant stromal cells. They aid tumor growth and metastasis by providing growth factors, cytokine, ECM remodeling proteins and interacting with other tumor stromal cells. Here I show that the Warburg effect also operates in stromal fibroblasts of the tumor microenvironment. Using mass spectrometry, genetic mouse models, gene expression and methylation studies, I demonstrate that CAFs from human and mouse mammary tumors exhibit hyperactive glycolysis and a metabolic shift towards lactate production. Furthermore, this phenotype may be sustained through epigenetic modifications of endogenous hypoxia-inducible factor 1α, key regulatory enzymes fructose-bisphosphatase 1 and pyruvate kinase M2. Depletion of stromal fibroblasts or suppression of lactate production specifically in these cells alters the metabolic profile of not only the tumors but also the cancer cells and results in impeded tumor growth. These results collectively suggest that tumor growth is dependent on metabolic state and metabolic support of stromal fibroblasts, highlighting these cells as attractive therapeutic targets in controlling cancer progression.