John Murphy, MDLinx | October 06, 2017
Researchers have shown that lactate—long believed to be an excrement of cancer metabolism—also appears to fuel tumor cells, even exceeding glucose as a fuel. This discovery challenges the time-honored Warburg effect, and may also make finding therapies more complicated, according to a study published recently in Cell.
“We were completely shocked by our findings,” said lead investigator Ralph DeBerardinis, MD, PhD, Director of the Genetic and Metabolic Disease Program at Children’s Medical Center Research Institute and Chief of the Division of Pediatric Genetics and Metabolism at University of Texas Southwestern Medical Center, Dallas, TX.
“The oldest observation in cancer metabolism, the Warburg effect, says that lactate is a waste product of the tumor,” Dr. DeBerardinis explained. “This concept has driven the vast amount of research in the field. Our finding is a fundamental change in how we think about tumor metabolism.”
The Warburg effect has 3 main components: glucose is rapidly converted to lactate, glucose oxidation is suppressed even when oxygen is plentiful, and lactate is secreted into the extracellular space.
In this study, Dr. DeBerardinis and colleagues compared glucose and lactate metabolism in non-small cell lung cancer tumors in mice and humans in vivo. They showed that lactate is not just a waste product but, in addition to glucose, fuels tumor metabolism. Not only that, lactate is preferred over glucose as a fuel, they found.
“We believe that lactate is one of the fuels that supports growth, proliferation, and maybe even lung cancer metastases,” Dr. DeBerardinis said. “Cancer metabolism is clinically actionable, and understanding the lactate pathway could help us find therapeutic targets for lung cancer. Lactate uptake could also have predictive value when used as an imaging tracer.”
The researchers also found evidence that lactate uptake was highest in human lung tumors with “aggressive oncological behavior.”
“The findings are preliminary,” said lead author Brandon Faubert, PhD, a postdoctoral research fellow at Children's Research Institute. “But we did see a connection between lactate utilization and how quickly the tumors metastasized or recurred. This result suggests that there is something fundamental about the lactate utilization pathway that pertains to the clinical aggressiveness of the tumor.”
With multiple fuels involved in tumor metabolism—including glucose, lactate, and others—and the variation of fuel choices between and within tumors, it will be a challenge to develop universal therapies by targeting single fuels, the researchers concluded.