Multi-scale computational study of the Warburg effect, reverse Warburg effect and glutamine addiction in solid tumors
Fig 2
Metabolic profiles of various cell types in different hypotheses.
Values of metabolic fluxes [mmol/g-DW-hr] under different metabolic phenotypes obtained from the FBA are shown in boxes. Blue: normoxic phenotype. Orange: hypoglycemic phenotype. Black: hypoxic phenotype. (A) Representation of the Warburg Effect hypothesis includes: (i) Stromal cell: Normoxic stromal cells are quiescent and aerobic (use mainly OXPHOS to generate ATP for maintenance) (blue values). Hypoxic stromal cells are quiescent and anaerobic (use primarily glycolysis to generate ATP for maintenance) (black values). (ii) Warburg tumor cell: Normoxic Warburg tumor cells are highly proliferative and aerobically glycolytic (use mainly glycolysis to generate ATP to grow—blue values). The values of flux shown represent the metabolic phenotype of Warburg Number, WN = 2. Hypoxic Warburg tumor cells are quiescent and anaerobically glycolytic (use glycolysis to generate ATP for maintenance—black values). (B) Representation of the Reverse Warburg effect includes: (i) Hijacked stromal cell: Normoxic hijacked stromal cells are quiescent and undergo aerobic glycolysis (use mainly glycolysis to generate ATP for maintenance—blue values). Hypoxic hijacked stromal cells are quiescent and anaerobic (use mainly glycolysis to generate ATP for maintenance—black values). (ii) Reverse Warburg tumor cell: Normoxic reverse Warburg tumor cells are highly proliferative and uptake lactate aerobically; however they utilize OXPHOS to generate ATP to grow, fueled by lactate and oxygen instead of undergoing glycolysis using glucose (blue values). Hypoglycemic reverse Warburg tumor cells are quiescent and consume lactate to fuel mitochondria for maintenance (orange values). Hypoxic reverse Warburg tumor cells are quiescent and undergo anaerobic glycolysis to produce lactate (black values). Note the different directions of arrows for lactate fluxes. (C) Representation of Glutamine Addiction includes: (i) Stromal cell: Normoxic stromal cells are quiescent and aerobic (use mainly OXPHOS to generate ATP for maintenance—blue values). Hypoxic stromal cells are quiescent and anaerobic (use primarily glycolysis to generate ATP for maintenance—black values. (ii) “Glutamine-addicted” tumor cell: Normoxic “glutamine-addicted” tumor cells are highly proliferative and aerobic; instead of utilizing glucose in glycolysis, they undergo OXPHOS to generate ATP to grow, fueled by glutamine and oxygen (blue values). Hypoglycemic “glutamine-addicted” tumor cells are quiescent and consume glutamine to fuel mitochondria for maintenance (orange values). Hypoxic “glutamine-addicted” tumor cells do not consume glutamine. They are quiescent and undergo anaerobic glycolysis (black values). Note the different directions of arrows for glutamine flux.