The reverse Warburg effect: aerobic glycolysis in cancer associated fibroblasts and the tumor stroma.
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 energy-rich 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.
Pavlides
Stephanos
S
Department of Stem Cell Biology & Regenerative Medicine, Thomas Jefferson University, Philadelphia, PA, USA.
Whitaker-Menezes
Diana
D
Castello-Cros
Remedios
R
Flomenberg
Neal
N
Witkiewicz
Agnieszka K
AK
Frank
Philippe G
PG
Casimiro
Mathew C
MC
Wang
Chenguang
C
Fortina
Paolo
P
Addya
Sankar
S
Pestell
Richard G
RG
Martinez-Outschoorn
Ubaldo E
UE
Sotgia
Federica
F
Lisanti
Michael P
MP
D000818:Animals; D017302:Annexins / Q000378:metabolism; D001943:Breast Neoplasms / Q000378:metabolism*; D051242:Caveolin 1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000378:metabolism*; D006019:Glycolysis; D006801:Humans; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D040901:Proteomics; D011770:Pyruvate Kinase / Q000378:metabolism; D017154:Stromal Cells / Q000378:metabolism; D019063:Tenascin / Q000378:metabolism; D015854:Up-Regulation
D017302:Annexins; D051242:Caveolin 1; D019063:Tenascin; D007770:L-Lactate Dehydrogenase; D011770:Pyruvate Kinase