The reverse Warburg effect. (a) Via oxidative stress, cancer cells activate two major transcription factors in adjacent stromal fibroblasts (hypoxia-inducible factor (HIF)1α and NFκB). This leads to the onset of both autophagy and mitophagy, as well as aerobic glycolysis, which then produces recycled nutrients (such as lactate, ketones, and glutamine). These high-energy chemical building blocks can then be transferred and used as fuel in the tricarboxylic acid cycle (TCA) in adjacent cancer cells. The outcome is high ATP production in cancer cells, and protection against cell death. ROS, reactive oxygen species. (b) Homotypic cultures (upper panels) of MCF7 cells (right) and hTERT-fibroblasts (left) were immunostained with a mitochondrial membrane antibody (red). Note that mitochondrial mass is lower in mono-cultures of MCF7 cells compared to fibroblasts. However, co-culture of MCF7 cells with fibroblasts (lower panel) induces a dramatic increase in mitochondrial mass in the 'central MCF7 cell colony', outlined by the dotted white oval. In contrast, mitochondrial mass is decreased in co-cultured fibroblasts. Panel (b) was modified and reproduced with permission from [41, 78].