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

561 Citations (Scopus)

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
StatePublished - Dec 1 2009

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Glycolysis
Caveolin 1
Neoplasms
Epithelial Cells
Fibroblasts
Cancer-Associated Fibroblasts
Breast Neoplasms
Host-Parasite Interactions
Oxidative Phosphorylation
Stromal Cells
Pyruvic Acid
Proteomics
Wound Healing
Lactic Acid
Carcinogenesis
Up-Regulation
Adenosine Triphosphate
Biomarkers
Observation
Neoplasm Metastasis

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

  • Cell Biology
  • Molecular Biology
  • Developmental Biology

Cite this

Pavlides, S., Whitaker-Menezes, D., Castello-Cros, R., Flomenberg, N., Witkiewicz, A. K., Frank, P. G., ... Lisanti, M. P. (2009). The reverse Warburg effect: Aerobic glycolysis in cancer associated fibroblasts and the tumor stroma. Cell Cycle, 8(23), 3984-4001.

The reverse Warburg effect : Aerobic glycolysis in cancer associated fibroblasts and the tumor stroma. / Pavlides, Stephanos; Whitaker-Menezes, Diana; Castello-Cros, Remedios; Flomenberg, Neal; Witkiewicz, Agnieszka K.; Frank, Philippe G.; Casimiro, Mathew C.; Wang, Chenguang; Fortina, Paolo; Addya, Sankar; Pestell, Richard G.; Martinez-Outschoorn, Ubaldo E.; Sotgia, Federica; Lisanti, Michael P.

In: Cell Cycle, Vol. 8, No. 23, 01.12.2009, p. 3984-4001.

Research output: Contribution to journalArticle

Pavlides, S, Whitaker-Menezes, D, Castello-Cros, R, Flomenberg, N, Witkiewicz, AK, Frank, PG, Casimiro, MC, Wang, C, Fortina, P, Addya, S, Pestell, RG, Martinez-Outschoorn, UE, Sotgia, F & Lisanti, MP 2009, 'The reverse Warburg effect: Aerobic glycolysis in cancer associated fibroblasts and the tumor stroma', Cell Cycle, vol. 8, no. 23, pp. 3984-4001.
Pavlides S, Whitaker-Menezes D, Castello-Cros R, Flomenberg N, Witkiewicz AK, Frank PG et al. The reverse Warburg effect: Aerobic glycolysis in cancer associated fibroblasts and the tumor stroma. Cell Cycle. 2009 Dec 1;8(23):3984-4001.
Pavlides, Stephanos ; Whitaker-Menezes, Diana ; Castello-Cros, Remedios ; Flomenberg, Neal ; Witkiewicz, Agnieszka K. ; Frank, Philippe G. ; Casimiro, Mathew C. ; Wang, Chenguang ; Fortina, Paolo ; Addya, Sankar ; Pestell, Richard G. ; Martinez-Outschoorn, Ubaldo E. ; Sotgia, Federica ; Lisanti, Michael P. / The reverse Warburg effect : Aerobic glycolysis in cancer associated fibroblasts and the tumor stroma. In: Cell Cycle. 2009 ; Vol. 8, No. 23. pp. 3984-4001.
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