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.

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.

The autophagic tumor stroma model of cancer proposes that epithelial cancer cells use oxidative stress as a “weapon” to extract recycled nutrients from adjacent stromal fibroblasts (i.e., connective tissue cells.[7][8][9][10][11][12][13][14][15][16]

The theory

The theory posits that oxidative stress in cancer associated fibroblasts forces these cells to eat themselves, by a process called “autophagy” or “self-cannibalism”. The resulting recycled nutrients, derived from catabolism in the tumor stroma, are then used to power the anabolic growth of cancer cells. Thus, cancer is a disease of “energy imbalance”, resulting from the vectorial and unilateral transfer of energy-rich nutrients from the tumor stroma to cancer cells. (This explains the phenomenon of cancer-associated cachexia (systemic wasting), in which patients with advanced cancer cannot maintain their normal body weight).

Oxidative stress in cancer associated fibroblasts also has other consequences. The amplification of ROS (reactive oxygen species) production feeds back upon the epithelial cancer cells, inducing DNA damage (double-strand breaks) and aneuploidy (abnormal chromosome number), which are characteristic of genomic instability. Thus, ROS production in the stroma fuels cancer cell evolution via a process of random mutagenesis.

Finally, the recycled nutrients produced by autophagy in stromal cells provide a steady-stream of energy-rich metabolites (chemical building blocks) to cancer cells, inducing mitochondrial biogenesis, and protecting these “well-fed” cancer cells against apoptosis.

Thus, cancer cells induce oxidative stress in adjacent fibroblasts, 1) to generate recycled nutrients via autophagy, 2) to mutagenize themselves and evolve, and 3) to protect themselves against cell death (apoptosis).

Implications

This new model has implications for both the diagnosis and treatment of cancer patients. For example, breast cancer patients with increased stromal autophagy (marked by a loss of stromal Cav-1), are more likely to undergo early tumor recurrence, lymph-node (LN) metastasis, and show drug-resistance. Conversely, breast cancer patients with little or no stromal autophagy (marked by high stromal Cav-1 levels), have a good clinical outcome. Thus, the use of stromal Cav-1 as a biomarker can identify high-risk cancer patients at diagnosis, for appropriate treatment stratification.

Epithelial cancer cells use oxidative mitochondrial metabolism to “fuel” tumor growth and metastasis. In support of this notion, two high energy-rich metabolites (ketones and L-lactate) which fuel the mitochondrial TCA cycle, dramatically promote tumor growth and metastasis, without an increase in tumor angiogenesis.

The model also explains why angiogenesis inhibitors don’t work, and instead induce lethal tumor recurrence, and metastasis. This is because angiogenesis inhibitors drive “hypoxia” in the tumor stromal micro-environment. Hypoxia, in turn, drives oxidative stress and autophagy. These are exactly the conditions that are necessary for the tumor to prosper, due to the increased stromal production of recycled nutrients via autophagy. Stromal autophagy, then promotes tumor growth and metastasis, via the availability of recycled nutrients to fuel mitochondrial metabolism in cancer cells. Furthermore, ketones are the ideal fuel to be used during hypoxia, as they burn more efficiently and require less oxygen, to drive the production of ATP via oxidative mitochondrial metabolism.

The prevailing view is that cancer cells have defective mitochondria, and undergo aerobic glycolysis the Warburg effect). The new theory is based on observations that stromal fibroblasts are undergoing the Warburg effect, due to mitophagy (the autophagic destruction of mitochondria). Thus, the Warburg effect occurs in fibroblasts, and not in cancer cells---just the opposite of what most cancer researchers have argued over the last 85 years. This new model has been called the "Reverse Warburg Effect”, to distinguish it from the conventional “Warburg Effect”, which was thought to take place in cancer cells.

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.

References

  1. ↑ Pavlides S, Whitaker-Menezes D, Castello-Cros R, Flomenberg N, Witkiewicz AK, Frank PG, Casimiro MC, Wang C, Fortina P, Addya S, Pestell RG, Martinez-Outschoorn UE, Sotgia F, Lisanti MP (December 2009). "The reverse Warburg effect: aerobic glycolysis in cancer associated fibroblasts and the tumor stroma". Cell Cycle 8 (23): 3984–4001. doi:10.4161/cc.8.23.10238. PMID 19923890.
  2. ↑ Pavlides S, Tsirigos A, Vera I, Flomenberg N, Frank PG, Casimiro MC, Wang C, Pestell RG, Martinez-Outschoorn UE, Howell A, Sotgia F, Lisanti MP (April 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"". Aging (Albany NY) 2 (4): 185–99. PMC 2881509. PMID 20442453.
  3. ↑ Bonuccelli G, Whitaker-Menezes D, Castello-Cros R, Pavlides S, Pestell RG, Fatatis A, Witkiewicz AK, Heiden MG, Migneco G, Chiavarina B, Frank PG, Capozza F, Flomenberg N, Martinez-Outschoorn UE, Sotgia F, Lisanti MP (December 2010). "The reverse Warburg Effect: Glycolysis inhibitors prevent the tumor promoting effects of caveolin-1 deficient cancer associated fibroblasts". Cell Cycle 9 (10): 1960–71. doi:10.4161/cc.9.10.11601. PMID 20495363.
  4. ↑ Pavlides S, Tsirigos A, Vera I, Flomenberg N, Frank PG, Casimiro MC, Wang C, Fortina P, Addya S, Pestell RG, Martinez-Outschoorn UE, Sotgia F, Lisanti MP (June 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". Cell Cycle 9 (11): 2201–19. doi:10.4161/cc.9.11.11848. PMID 20519932.
  5. ↑ Martinez-Outschoorn UE, Pavlides S, Whitaker-Menezes D, Daumer KM, Milliman JN, Chiavarina B, Migneco G, Witkiewicz AK, Martinez-Cantarin MP, Flomenberg N, Howell A, Pestell RG, Lisanti MP, Sotgia F (June 2010). "Tumor cells induce the cancer associated fibroblast phenotype via caveolin-1 degradation: Implications for breast cancer and DCIS therapy with autophagy inhibitors". Cell Cycle 9 (12): 2423–33. doi:10.4161/cc.9.12.12048. PMID 20562526.
  6. 1 2 3 Migneco G, Whitaker-Menezes D, Chiavarina B, Castello-Cros R, Pavlides S, Pestell RG, Fatatis A, Flomenberg N, Tsirigos A, Howell A, Martinez-Outschoorn UE, Sotgia F, Lisanti MP (June 2010). "Glycolytic cancer associated fibroblasts promote breast cancer tumor growth, without a measurable increase in angiogenesis: Evidence for stromal-epithelial metabolic coupling". Cell Cycle 9 (12): 2412–22. doi:10.4161/cc.9.12.11989. PMID 20562527.
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