Recently, we proposed a new mechanism for understanding the Warburg effect in 
cancer metabolism. In this new paradigm, cancer-associated fibroblasts undergo 
aerobic glycolysis, and extrude lactate to "feed" adjacent cancer cells, which 
then drives mitochondrial biogenesis and oxidative mitochondrial metabolism in 
cancer cells. Thus, there is vectorial transport of energy-rich substrates from 
the fibroblastic tumor stroma to anabolic cancer cells. A prediction of this 
hypothesis is that cancer-associated fibroblasts should express MCT4, a 
mono-carboxylate transporter that has been implicated in lactate efflux from 
glycolytic muscle fibers and astrocytes in the brain. To address this issue, we 
co-cultured MCF7 breast cancer cells with normal fibroblasts. Interestingly, our 
results directly show that breast cancer cells specifically induce the 
expression of MCT4 in cancer-associated fibroblasts; MCF7 cells alone and 
fibroblasts alone, both failed to express MCT4. We also show that the expression 
of MCT4 in cancer-associated fibroblasts is due to oxidative stress, and can be 
prevented by pre-treatment with the anti-oxidant N-acetyl-cysteine. In contrast 
to our results with MCT4, we see that MCT1, a transporter involved in lactate 
uptake, is specifically upregulated in MCF7 breast cancer cells when co-cultured 
with fibroblasts. Virtually identical results were also obtained with primary 
human breast cancer samples. In human breast cancers, MCT4 selectively labels 
the tumor stroma, e.g., the cancer-associated fibroblast compartment. 
Conversely, MCT1 was selectively expressed in the epithelial cancer cells within 
the same tumors. Functionally, we show that overexpression of MCT4 in 
fibroblasts protects both MCF7 cancer cells and fibroblasts against cell death, 
under co-culture conditions. Thus, we provide the first evidence for the 
existence of a stromal-epithelial lactate shuttle in human tumors, analogous to 
the lactate shuttles that are essential for the normal physiological function of 
muscle tissue and brain. These data are consistent with the "reverse Warburg 
effect," which states that cancer-associated fibroblasts undergo aerobic 
glycolysis, thereby producing lactate, which is utilized as a metabolic 
substrate by adjacent cancer cells. In this model, "energy transfer" or 
"metabolic-coupling" between the tumor stroma and epithelial cancer cells 
"fuels" tumor growth and metastasis, via oxidative mitochondrial metabolism in 
anabolic cancer cells. Most importantly, our current findings provide a new 
rationale and novel strategy for anti-cancer therapies, by employing MCT 
inhibitors.