Figure 4.

The Reverse Warburg effect. In the “Reverse Warburg Effect”, which was initially characterized in breast cancer cells, anabolic cancer cells import lactate, ketones and fatty acids released by either adjacent cancer associated fibroblasts (CAF), other stromal cell types or catabolic cancer cells, in response to oxidative stress. In CAFs, hypoxia, nutrient deprivation and oxidative stress stabilize HIF1α, which in turn causes catabolic autophagy, mitophagy and glycolysis, together with expression of the monocarboxylate transporter (MCT) 4 that exports lactate. Aerobic glycolysis in cancer associated fibroblasts (CAFs) generates energy-rich metabolites (such as lactate, ketone bodies and pyruvate) that are transferred to adjacent cancer cells, where they then enter the TCA cycle, promoting oxidative phosphorylation and increased ATP production.