Figure 3.

Schematic representation of the coupling model or reverse Warburg effect. The coupling model proposes the integration of the various metabolic changes observed in cancer in a more functional manner. This model is based on the premise that most human tumors, such as those of the breast, stomach, and pancreas, are comprised of stroma. The Warburg effect preferentially occurs in the predominant stromal cell type, i.e., the CAFs, where it manifests as an increase in aerobic glycolysis and a hypofunctional tricarboxylic acid (TCA) cycle. This leads to a significant release of lactate and ketone bodies into the interstitium and their capture by tumor cells. Once inside the cells, these molecules feed and enhance TCA activity. Likewise, the activation of autophagy in CAFs releases a large quantity of amino acids into the interstitium, which is captured by the cells of the tumoral parenchyma for use in the anabolic synthesis of protein. Catabolic reactions, therefore, predominate in the stromal CAFs, favoring the preponderance of anabolism in the tumor cells. This is known as the reverse Warburg effect or the coupling model. Upward pointing arrows indicate increased levels or activity of that molecule or pathway. The downward pointing arrows indicate the opposite. Created using BioRender.