Introduction

The reverse Warburg effect in human breast cancer

Breast cancer

Breast cancer is cancer originating from breast tissue, most commonly from the inner lining of milk ducts or the lobules that supply the ducts with milk. Cancers originating from ducts are known as ductal carcinomas; those originating from lobules are known as lobular carcinomas...

s was first proposed by Dr. Michael P. Lisanti and colleagues in 2009. According to this model, aerobic glycolysis (a.k.a, the Warburg Effect

Warburg effect

The phrase "Warburg effect" is used for two unrelated observations in biochemistry, one in plant physiology and the other in oncology, both due to Nobel laureate Otto Heinrich Warburg.-Plant physiology:...

) actually takes place in tumor associated fibroblast

Fibroblast

A fibroblast is a type of cell that synthesizes the extracellular matrix and collagen, the structural framework for animal tissues, and plays a critical role in wound healing...

s, and not in cancer cells.

This has important consequences for tumor growth and progression. Aerobic glycolysis

Glycolysis

Glycolysis is the metabolic pathway that converts glucose C6H12O6, into pyruvate, CH3COCOO− + H+...

 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

Monocarboxylate transporter

Monocarboxylate transporters, or MCTs, constitute a family of proton-linkedplasma membrane transporters that carry molecules having one carboxylate group , such aslactate and pyruvate, across biological membranes....

 (MCT).

The researchers termed this new idea “The Reverse Warburg Effect”, to distinguish it from the conventional Warburg Effect

Warburg effect

The phrase "Warburg effect" is used for two unrelated observations in biochemistry, one in plant physiology and the other in oncology, both due to Nobel laureate Otto Heinrich Warburg.-Plant physiology:...

, which was originally thought to take place in epithelial cancer cells.

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.

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

Quercetin

Quercetin , a flavonol, is a plant-derived flavonoid found in fruits, vegetables, leaves and grains. It also may be used as an ingredient in supplements, beverages or foods.-Occurrence:...

; and metformin

Metformin

Metformin is an oral antidiabetic drug in the biguanide class. It is the first-line drug of choice for the treatment of type 2 diabetes, in particular, in overweight and obese people and those with normal kidney function. Its use in gestational diabetes has been limited by safety concerns...

), or with autophagy

Autophagy

In cell biology, autophagy, or autophagocytosis, is a catabolic process involving the degradation of a cell's own components through the lysosomal machinery. It is a tightly regulated process that plays a normal part in cell growth, development, and homeostasis, helping to maintain a balance...

 inhibitors (chloroquine

Chloroquine

Chloroquine is a 4-aminoquinoline drug used in the treatment or prevention of malaria.-History:Chloroquine , N'--N,N-diethyl-pentane-1,4-diamine, was discovered in 1934 by Hans Andersag and co-workers at the Bayer laboratories who named it "Resochin". It was ignored for a decade because it was...

). 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”.

Similarly, a loss of stromal Cav-1 was prevented by treatments with HIF1

HIF1A

Hypoxia-inducible factor 1, alpha subunit , also known as HIF1A, is a protein that in humans is encoded by the HIF1A gene...

 and NF-κB inhibitors. HIF1 and NF-κB are the upstream transcription factor

Transcription factor

In molecular biology and genetics, a transcription factor is a protein that binds to specific DNA sequences, thereby controlling the flow of genetic information from DNA to mRNA...

s 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.

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.

External links

• http://www.youtube.com/watch?v=xYmVrIDr7P0
• http://www.youtube.com/watch?v=i3wZ9je_XLk