Fig. 1

The metabolic heterogeneity of cancer stem cells. Tumors are complex and dynamic structures encompassing populations of host cells (e.g., fibroblasts and immune cells) and cancer cells with different metabolic activities. These cells are affected in different ways by microenvironmental conditions and biological activities of other tumor cells. For example, cancer cells close to the vasculature show oxidative metabolism, whereas a shift toward a glycolytic metabolism is observed when glucose is present in cells residing in hypoxic areas. Despite metabolic heterogeneity, cancer cells cooperate to allow adaption to changes in conditions to ensure that metabolic requirements are met. Indeed, oxidative cancer cells, like proliferating cells, increase the consumption of glucose to produce ATP and generate biomass to support cell proliferation. The oxidative stress caused by rapidly proliferation of cancer cells induces glycolysis and autophagy/mitophagy in stromal cells and/or in glycolytic cancer cells leading to the release of high amounts of lactate, which fuels the metabolism of oxidative cancer cells. Key elements of lactate shuttles are the plasma membrane monocarboxylate transporters. MCT4 is involved in the export of lactate, and MCT1 and MCT2 are involved in the uptake of this catabolite. High levels of several factors including HIF-1α, NF-κB, TGF-β, and JNK/AP1 are associated with glycolytic phenotype. The metabolic status of a CSC depends on location. In actively growing regions of the tumor and in the presence of adequate levels of oxygen (normoxic conditions), CSCs rely on glycolytic and/or oxidative metabolism. Overexpression of HIF-1α in the hypoxic environment promotes upregulation of GLUT1, GLUT3, and glycolytic enzymes. In the metastatic niche, CSCs have increased utilization of extracellular catabolites. In nutrient-poor states, autophagy is activated to provide an alternative energy source. OXPHOS and the anabolic gluconeogenesis pathways control glucose homeostasis. Abbreviations: ATP, adenosine triphosphate; CSC, cancer stem cell; GLUT1/GLUT3, glucose transporter 1/3; HIF-1α, hypoxia-inducible factor 1α; HK2, hexokinase 2; JNK/AP1, c-Jun N-terminal kinases/activator protein 1; LDH, Lactate dehydrogenase; XMCT2/4, monocarboxylate transporter 2/4; NF-κB, nuclear factor-κB; OXPHOS, oxidative phosphorylation; PFKFB, phosphofructokinase/fructose bisphosphate; PKM2, pyruvate kinase isozyme M2; TGF-β, transforming growth factor β