Figure 13.

Hydrogen peroxide and ROS production in the tumor micro-environment fuels the anabolic growth of cancer cells. Recently, we proposed a new mechanism for understanding the Warburg effect in tumor metabolism. In this new paradigm, cancer cells induce oxidative stress in neighboring cancer-associated fibroblasts. Then, oxidative stress, in cancer-associated fibroblasts, triggers the activation of two main transcription factors, NFκB and HIF-1α, leading to the onset of inflammation, autophagy, mitophagy and aerobic glycolysis in the tumor micro-environment. this type of stromal metabolism then produces high-energy nutrients (lactate, ketones and glutamine), as well as recycled chemical building blocks (nucleotides, amino acids, fatty acids), to literally “feed” cancer cells. these nutrients (such as lactate) stimulate mitochondrial biogenesis in adjacent cancer cells. In addition, the oxidative stress and ROS, produced in cancer-associated fibroblasts, has a “bystander effect” on adjacent cancer cells, leading to DNA damage, genomic instability and aneuploidy, driving tumor-stroma co-evolution. We have previously termed this new paradigm the “reverse Warburg effect,” as we see that aerobic glycolysis takes place in cancer-associated fibroblasts, rather than in tumor cells, as previously suspected. Here, we showed that tumor cells produce and secrete hydrogen peroxide, thereby “fertilizing” the tumor microenvironment and driving the “reverse Warburg effect.” As a consequence, oxidative stress initiated in tumor cells is transferred to cancer-associated fibroblasts, via hydrogen peroxide. Modified and reproduced with permission from reference ⁶.