Reverse Warburg effect

The reverse Warburg effect in human breast cancers was first proposed by Dr. Michael P. Lisanti and colleagues in 2009. According to this model, aerobic glycolysis (a.k.a, the Warburg Effect) actually takes place in tumor associated fibroblasts, and not in cancer cells.[1][2][3][4][5] 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.

Contents

Description

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 feeding cancer cells via the transfer of high-energy metabolites, via a monocarboxylate transporter (MCT).[6][7][8][9][10][11]

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.

Clinical applications

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][13][14][15][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][7][8][9][10][11]

Similarly, a loss of stromal Cav-1 was prevented by treatments with HIF1 and NF-κB inhibitors. HIF1 and NF-κB 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 NF-κB is sufficient to promote the cancer associated fibroblast phenotype, driving increased tumor growth and metastasis, without any increase in tumor angiogenesis.[6][7][8][9][10][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]

References

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