|March 26, 2016|
The Reverse Warburg Effect in human breast cancers was first proposed by Dr. Michael P. Lisanti and colleagues (Drs. Sotgia, Martinez-Outschoorn, and Pavlides, among others) in December 2009. In these novel studies, the researchers show that aerobic glycolysis (a.k.a, the Warburg Effect) actually takes place in tumor associated fibroblasts, and NOT in cancer cells (1-5).
This has important consequences for tumor growth and progression. Aerobic glycolysis in cancer associated fibroblasts results in the production of high-energy metabolites (such as lactate and pyruvate), which can then be transferred to adjacent epithelial cancer cells, which are undergoing oxidative mitochondrial metabolism. This would then result in increased ATP production in cancer cells, driving tumor growth and metastasis. Essentially, in this new paradigm, stromal fibroblasts are literally ???feeding??? cancer cells via the transfer of high-energy metabolites, via a monocarboxylate transporter (MCT) (6-11).
The researchers termed this new idea ???The Reverse Warburg Effect???, to distinguish it from the conventional Warburg Effect, which was originally thought to take place in epithelial cancer cells (1).
These new findings reverse over 85 years of dogma surrounding cancer cell metabolism, and explain the lethality of a caveolin-1 (Cav-1) deficient tumor microenvironment. More specifically, a loss of Cav-1 in stromal fibroblasts drives onset of ???The Reverse Warburg Effect???, due to the autophagic destruction of mitochondria (mitophagy) in these stromal cells. Cancer cells induce ???The Reverse Warburg Effect??? in adjacent stromal fibroblasts by using oxidative stress, to promote aerobic glycolysis, under conditions of normoxia.
Importantly, a loss of stromal Cav-1 is a powerful biomarker for ???The Reverse Warburg Effect???, and predicts early tumor recurrence, lymph node metastasis, and drug-resistance in virtually all of the major subtypes of human breast cancer. For example, in triple negative (TN) breast cancer, patients with high stromal Cav-1 have a survival rate of >75% at 12 years post-diagnosis. In striking contrast, TN breast cancer patients with absent stromal Cav-1 have a survival rate of <10% at 5 years post-diagnosis. Similar results have also been obtained with DCIS and prostate cancer patients, suggesting that stromal Cav-1 could serve as a diagnostic marker for identifying the high-risk population in many different types of human cancer (12-16).
Thus, ???The Reverse Warburg Effect??? is a characteristic of a ???lethal??? tumor micro-environment. Importantly, researchers have shown, using a co-culture system, that a loss of stromal Cav-1 can be effectively prevented by treatment with anti-oxidants (such as N-acetyl cysteine (NAC); quercetin; and metformin), or with autophagy inhibitors (chloroquine). This is very promising as these drugs/supplements are now currently available off the shelf from health food stores, or are already FDA-approved drugs. All of these drugs have previously shown anti-tumor activity in pre-clinical models, however their mechanism of action was not attributed to ???The Reverse Warburg Effect???(6-11).
Similarly, a loss of stromal Cav-1 was prevented by treatments with HIF1 and NFkB inhibitors. HIF1 and NFkB are the upstream transcription factors that control the onset of autophagy/mitophagy in cancer associated fibroblasts. Genetic studies have now shown that activation of HIF1 or NFkB is sufficient to promote the cancer associated fibroblast phenotype, driving increased tumor growth and metastasis, without any increase in tumor angiogenesis (6-11).
Finally, Lisanti and colleagues propose that the conventional Warburg effect may still occur, but would be associated with a good clinical outcome, as the tumor cells would produce less energy due to defective mitochondrial metabolism. For example, IDH1/2 mutations, which occur in key mitochondrial enzymes associated with the TCA cycle, are associated with a better clinical outcome in patients with brain cancer (17).
1. Pavlides et al., 2009: The reverse Warburg effect: aerobic glycolysis in cancer associated fibroblasts and the tumor stroma
2. Pavlides et al., 2010: Transcriptional evidence for the "Reverse Warburg Effect" in human breast cancer tumor stroma and metastasis: similarities with oxidative stress, inflammation, Alzheimer's disease, and "Neuron-Glia Metabolic Coupling"
3. Bonuccelli et al., 2010: The reverse Warburg effect: Glycolysis inhibitors prevent the tumor promoting effects of caveolin-1 deficient cancer associated fibroblasts
4. Pavlides et al., 2010: Loss of stromal caveolin-1 leads to oxidative stress, mimics hypoxia and drives inflammation in the tumor microenvironment, conferring the "reverse Warburg effect": A transcriptional informatics analysis with validation
5. Martinez-Outschoorn et al., 2010: Tumor cells induce the cancer associated fibroblast phenotype via caveolin-1 degradation: Implications for breast cancer and DCIS therapy with autophagy inhibitors
6. Migneco et al., 2010: Glycolytic cancer associated fibroblasts promote breast cancer tumor growth, without a measurable increase in angiogenesis: Evidence for stromal-epithelial metabolic coupling
7. Pavlides et al., 2010: The autophagic tumor stroma model of cancer: Role of oxidative stress and ketone production in fueling tumor cell metabolism
8. Bonuccelli et al., 2010: Ketones and lactate ???fuel??? tumor growth and metastasis: Evidence that epithelial cancer cells use oxidative mitochondrial metabolism
9. Martinez-Outschoorn et al., 2010: Autophagy in cancer associated fibroblasts promotes tumor cell survival: Role of hypoxia, HIF1 induction and NFkB activation in the tumor stromal microenvironment
10. Chiavarina et al., 2010: HIF1-alpha functions as a tumor promoter in cancer associated fibroblasts, and as a tumor suppressor in breast cancer cells: Autophagy drives compartment-specific oncogenesis
11. Martinez-Outschoorn et al., 2010: Oxidative stress in cancer associated fibroblasts drives tumor-stroma co-evolution: A new paradigm for understanding tumor metabolism, the field effect and genomic instability in cancer cells
12. Witkiewicz et al., 2010: Loss of stromal caveolin-1 expression predicts poor clinical outcome in triple negative and basal-like breast cancers
13. Lisanti et al., 2010: Understanding the "lethal" drivers of tumor-stroma co-evolution: Emerging role(s) for hypoxia, oxidative stress, and autophagy/mitophagy in the tumor micro-environment
14. Sloan et al., 2009: Stromal cell expression of caveolin-1 predicts outcome in breast cancer.
15. Ghajar CM et al., 2009: Quis custodiet ipsos custodies: who watches the watchmen?
16. Witkiewicz et al., 2009: An Absence of Stromal Caveolin-1 Expression Predicts Early Tumor Recurrence and Poor Clinical Outcome in Human Breast Cancers
17. Yan et al., 2009: IDH1 and IDH2 Mutations in Gliomas (See Figure 3 within)
GNU Free Documentation License. It uses material from the Wikipedia article "The Reverse Warburg Effect".
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