Fig. 1

Molecular alterations cause metabolic switching in cancer cells and severe metabolic changes in the tumor microenvironment. a Non malignant (quiescent) cells rely on OXPHOS as primary ATP source under normoxic conditions. FAO also contributes to the cellular ATP pool. Without extrinsic stimuli the PI3K-Akt1 pathway is inactive. Downstream targets are also blocked, e.g. HK, PFK2, FOXO, HIF1α, mTOR, and NRF2. In addition, AMPK keeps HIF1α and mTOR in check. p53 participates in the repression of glycolysis by expression of TIGAR, PTEN, and SCO2. Myc as well as PGC1α are not active in quiescent cells and do not contribute to glycolysis. In order to sustain cellular homeostasis cells have a low energy demand and low biosynthetic activity. b Cancer cells acquire a series of mutations that foster glycolysis in several ways. Oncogenic PI3K-Akt1 signaling and inhibited AMPK signaling promote activation of pro-glycolytic events. These include activation of glycolytic enzymes namely HK and PFK2 and activation of transcription factors such as FOXO and in combination with hypoxia- HIF1α, which in turn induce the expression of glucose transporters glut1 and glut4 and other glycolytic enzymes. Moreover, mTOR signaling is elevated which causes an increase in biosynthetic precursors. PI3K-Akt1-activated NRF2 induces expression of glycolytic genes as well as NADPH and anti-oxidants. PGC1α can also contribute to the cellular anti-oxidant pool. Mutation or deletion of p53 causes loss of glycolytic inhibitors like TIGAR, PTEN, and SCO2. Oncogenic Myc induces the expression of glycolytic genes, glucose and glutamine transporters. Additionally, Myc enhances the amount of biosynthetic precursors by expression of GLS and the amount of cellular NAPDH and anti-oxidants via PKM2. Expression of IDO mediates the degradation of tryptophan to N-formylkynurenin, the first step of tryptophan catabolism in the kynurenin pathway. These mutations elevate nucleotide, amino acid, and lipid biosynthesis paired with enhanced catabolic pathways to enable cancer cells to proliferate rapidly