The reverse Warburg effect: Aerobic glycolysis in cancer associated fibroblasts and the tumor stroma

• DOI: 10.4161/cc.8.23.10238
• Publication Date: 2011-01-20T16:24:57Z
• Authors: Stephanos Pavlides; Diana Whitaker-Me...; Remedios Castello...; Neal Flomenberg; Agnieszka K. Witk...; Philippe G. Frank; Mathew C. Casimiro; Chenguang Wang; Paolo Fortina; Sankar Addya; Richard G. Pestell; Ubaldo E. Martine...; Federica Sotgia; Michael P. Lisanti
• Keywords: Warburg Effect; Anaerobic glycolysis; Cancer-Associated Fibroblasts; Tumor progression

Here, we propose a new model for understanding the Warburg effect in tumor metabolism. Our hypothesis is that epithelial cancer cells induce (aerobic glycolysis) neighboring stromal fibroblasts. These cancer-associated fibroblasts, then undergo myo-fibroblastic differentiation, and secrete lactate pyruvate (energy metabolites resulting from aerobic glycolysis). Epithelial could take up these energy-rich use them mitochondrial TCA cycle, thereby promoting efficient energy production (ATP generation via oxidative phosphorylation), higher proliferative capacity. In this alternative of tumorigenesis, instruct normal stroma to transform into wound-healing stroma, providing necessary micro-environment facilitating growth angiogenesis. essence, fibroblastic would directly feed cells, type host-parasite relationship. We have termed idea "Reverse Effect." scenario, "corrupt" turning it factory metabolites. This still consistent with Warburg's original observation tumors show metabolic shift towards glycolysis. support idea, unbiased proteomic analysis transcriptional profiling fibroblasts (caveolin-1 (Cav-1) deficient cells), shows up-regulation both i) myo-fibroblast markers ii) glycolytic enzymes, under normoxic conditions. validated expression proteins human breast tissues lack Cav-1. Importantly, loss Cav-1 cancers associated recurrence, metastasis, poor clinical outcome. Thus, an absence may be biomarker Effect", explaining its powerful predictive value.