Evidence supporting a 'lactate shuttle' in human tumors: compartmentalized distribution of monocarboxylate transporter (MCT)1/4. (a) MCT4 is expressed in the fibroblastic stromal compartment of human breast cancers. Note that MCT4 staining is absent from the tumor epithelial cells, but is present in the surrounding stroma. MCT4 staining outlines the cancer-associated fibroblasts that surround nests of epithelial cancer cells. (b) MCT1 is expressed in the epithelial compartment of human breast cancers. Note that MCT1 staining is present in the tumor epithelial cells, but is absent in the surrounding stroma. (c) The lactate shuttle: an energy transfer mechanism in normal tissue and human cancers. MCT4 functions primarily as a transporter that extrudes lactate from cells that are undergoing aerobic glycolysis and lack functional mitochondria. After lactate is extruded by MCT4 in cancer-associated fibroblasts (CAFs), lactate is then taken up by MCT1 in adjacent cancer cells. Similarly, ketones are transported by the same MCTs that handle lactate. Our studies suggest that metabolic coupling occurs between CAFs and adjacent tumor cells. Modified and reproduced with permission from .