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

Stephanos Pavlides, Diana Whitaker-Menezes, Remedios Castello-Cros, Neal Flomenberg, Agnieszka K. Witkiewicz, Philippe G. Frank, Mathew C. Casimiro, Chenguang Wang, Paolo Fortina, Sankar Addya, Richard G. Pestell, Ubaldo E. Martinez-Outschoorn, Federica Sotgia, Michael P. Lisanti

Research output: Contribution to journalArticle

630 Scopus citations

Abstract

Here, we propose a new model for understanding the Warburg effect in tumor metabolism. Our hypothesis is that epithelial cancer cells induce the Warburg effect (aerobic glycolysis) in neighboring stromal fibroblasts. These cancer-associated fibroblasts, then undergo myo-fibroblastic differentiation, and secrete lactate and pyruvate (energy metabolites resulting from aerobic glycolysis). Epithelial cancer cells could then take up these energy-rich metabolites and use them in the mitochondrial TCA cycle, thereby promoting efficient energy production (ATP generation via oxidative phosphorylation), resulting in a higher proliferative capacity. In this alternative model of tumorigenesis, the epithelial cancer cells instruct the normal stroma to transform into a wound-healing stroma, providing the necessary energy-rich micro-environment for facilitating tumor growth and angiogenesis. In essence, the fibroblastic tumor stroma would directly feed the epithelial cancer cells, in a type of host-parasite relationship. We have termed this new idea the "Reverse Warburg Effect." In this scenario, the epithelial tumor cells "corrupt" the normal stroma, turning it into a factory for the production of energyrich metabolites. This alternative model is still consistent with Warburg's original observation that tumors show a metabolic shift towards aerobic glycolysis. In support of this idea, unbiased proteomic analysis and transcriptional profiling of a new model of cancer-associated fibroblasts [caveolin-1 (Cav-1) deficient stromal cells], shows the upregulation of both (1) myo-fibroblast markers and (2) glycolytic enzymes, under normoxic conditions. We validated the expression of these proteins in the fibroblastic stroma of human breast cancer tissues that lack stromal Cav-1. Importantly, a loss of stromal Cav-1 in human breast cancers is associated with tumor recurrence, metastasis, and poor clinical outcome. Thus, an absence of stromal Cav-1 may be a biomarker for the "Reverse Warburg Effect," explaining its powerful predictive value.

Original languageEnglish (US)
Pages (from-to)3984-4001
Number of pages18
JournalCell Cycle
Volume8
Issue number23
DOIs
StatePublished - Dec 1 2009

    Fingerprint

Keywords

  • Aerobic glycolysis
  • Cancer-associated fibroblast
  • Caveolin-1
  • Lactate dehydrogenase
  • M2-isoform of pyruvate kinase
  • Myo-fibroblast
  • Tumor stroma
  • Warburg effect

ASJC Scopus subject areas

  • Molecular Biology
  • Developmental Biology
  • Cell Biology

Cite this

Pavlides, S., Whitaker-Menezes, D., Castello-Cros, R., Flomenberg, N., Witkiewicz, A. K., Frank, P. G., Casimiro, M. C., Wang, C., Fortina, P., Addya, S., Pestell, R. G., Martinez-Outschoorn, U. E., Sotgia, F., & Lisanti, M. P. (2009). The reverse Warburg effect: Aerobic glycolysis in cancer associated fibroblasts and the tumor stroma. Cell Cycle, 8(23), 3984-4001. https://doi.org/10.4161/cc.8.23.10238