Lactate and Acidity in the Cancer Microenvironment

Fermentative glycoly%sis, m ancnent evolved metabolic pathway, is exploited by rapidly growing tissues and tumors but also occurs in response to the nutritional and energetic demands of differentiated tissues. The lactic acid it produces is transported across cell membranes through reversible H' /lactate symporters (MCTI and 1\1CT4) and is recycled in organs as a major metabolic precursor of gluconeogenesis and an energy source. Concentrations of lactate in the tumor environment, investigated utilizing an induced metabolic bioluminescence imaging (imBh) technique, appear to be dominant hiomarkers of tumor response to irradiation and resistance to treatment. Suppression of lactic acid formation by genetic disruption of lactate dehydrogenases A and B in aggressive tumors reactivated OXPHOS {oxidative phosphorylatini) to maintain xenograft tumor growth at a halved rate. In contrast, disruption of the lactic acid transporters NIChl /4 suppressed glycolysis, tuTORCI, and ttunor growth as a result of intracellular acidosis. Furthermore, the global reduction of tumor acidity contributes to activation of the antitumor immune responses, offering hope for future clinical applications.