title: The reverse Warburg effect: aerobic glycolysis in cancer associated fibroblasts and the tumor stroma.
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 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.
authors.affiliation: Department of Stem Cell Biology & Regenerative Medicine, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: Stephanos
authors.initials: S
authors.lastname: Pavlides
authors.forename: Diana
authors.initials: D
authors.lastname: Whitaker-Menezes
authors.forename: Remedios
authors.initials: R
authors.lastname: Castello-Cros
authors.forename: Neal
authors.initials: N
authors.lastname: Flomenberg
authors.forename: Agnieszka K
authors.initials: AK
authors.lastname: Witkiewicz
authors.forename: Philippe G
authors.initials: PG
authors.lastname: Frank
authors.forename: Mathew C
authors.initials: MC
authors.lastname: Casimiro
authors.forename: Chenguang
authors.initials: C
authors.lastname: Wang
authors.forename: Paolo
authors.initials: P
authors.lastname: Fortina
authors.forename: Sankar
authors.initials: S
authors.lastname: Addya
authors.forename: Richard G
authors.initials: RG
authors.lastname: Pestell
authors.forename: Ubaldo E
authors.initials: UE
authors.lastname: Martinez-Outschoorn
authors.forename: Federica
authors.initials: F
authors.lastname: Sotgia
authors.forename: Michael P
authors.initials: MP
authors.lastname: Lisanti
mesh_terms: 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
chemical_list: D017302:Annexins; D051242:Caveolin 1; D019063:Tenascin; D007770:L-Lactate Dehydrogenase; D011770:Pyruvate Kinase