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

By S. Pavlides, D. Whitaker-Menezes, Remedios Castelló-Cros, N. Flomenberg, A. Witkiewicz, P. G. Frank, Mathew C. Casimiro, Chenguang Wang, P. Fortina, S. Addya and 4 more. Cell Cycle, 2009

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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 up-regulation of both i) myo-fibroblast markers and ii) 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.

Subfields: Cancer Research, Cell Biology, Oncology

View Paper: https://www.semanticscholar.org/paper/3e832988aa80143522c65473ef31e6f1c4987b45

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Citations in the corpus

Adipose tissue and adipocytes supports tumorigenesis and metastasis (2013, methodology): “This is exemplified by the ground-breakingwork of the Lisanti group (Thomas JeffersonUniversity, Philadelphia) which showed that metabolites from CAF are transferred and utilized by cancer cells, promoting tumor growth and metastasis [53,81].”
Signaling pathways in cancer-associated fibroblasts and targeted therapy for cancer (2021, background): “In the noncanonical TGF-β signaling pathway, TGF-β superfamily ligands can activate Rho, extracellular signal-regulated kinase (ERK), Janus kinase/STAT3, and phosphoinositide 3-kinase (PI3K)/AKT pathways in CAFs.(51,82,83) Over the past nearly four decades, TGF-β has been further explored and found ”
The role of m6A RNA methylation in cancer metabolism (2022, background): “However, later researchers found that tumor cells have biphasic metabolism, which may be the reason of chemotherapy resistance of tumor cells, known as anti-Warburg effect or metabolic coupling [13].”
Stroma Cells in Tumor Microenvironment and Breast Cancer (2012, positive): “Similar results were also observed by another group [93], which shows that the loss of stromal Cav-1 in human breast cancers is associated with tumor recurrence, metastasis, and poor clinical outcome.”
Metabolic reprogramming: the emerging concept and associated therapeutic strategies (2015, background): “Furthermore, CAFs depend significantly on autophagy, and the activation of autophagy in tumor stroma leads to chemoresistance [18, 42] (Fig.”
Lactate metabolism in human lung tumors (2017, neutral): “Blocking lactate uptake with an MCT1 inhibitor reduces respiration and promotes glycolysis in some cancer cell lines and suppresses xenograft growth in mice (Pavlides et al., 2009; Sonveaux et al., 2008).”
The return of metabolism: biochemistry and physiology of the pentose phosphate pathway (2014, result): “…is an informative exception as its enzyme activity in tumours is well studied and was increased in various human cancer types when compared to the respective benign control tissue, e.g. cervix, uteri, prostate and breast (Pedersen, 1975; Zampella, Bradley & Pretlow, 1982; Bezwoda et al., 1985).”
Revisiting the Warburg effect: historical dogma versus current understanding (2020, background): “This phenomenon is called the ‘reverse Warburg effect’ (Pavlides et al. 2009; Fu et al. 2017).”
Metabolic Interactions in the Tumor Microenvironment (2017, background): “The phenomenon, whereby CAFs take in glucose and release lactate to cancer cells, has been coined the “reverse Warburg effect” [40, 55].”
Metabolic heterogeneity in human lung tumors (2016, neutral): “Other extrinsic effects include metabolic competition or cooperativity among stromal, immune, and tumor cells (Pavlides et al., 2009; Sonveaux et al., 2008).”
Energy metabolism of cancer: Glycolysis versus oxidative phosphorylation (Review). (2012, background): “In the reverse Warburg effect, epithelial cancer cells induce aerobic glycolysis in carcinoma‑associated fibroblasts (CAFs) which produce lactate, ketones and pyruvate that enter the TCA cycle in cancer cells for OXPHOS (22,23).”