pH regulators of the tumoral microenvironment: A general overview

Abstract Cancer cells need to adapt to an ever-evolving environment to meet energy demands in an ecosystem where nutrient and oxygen levels are in constant flux. Rapid growth, enhanced metabolic rates, and the preference of glycolysis for energy production lead to increased production of metabolic byproducts in the form of lactate, protons, and carbonic acids. In order to survive, cancer cells adapt by upregulating expression of membrane transporters and enzymes that facilitate extrusion of lactate and protons and hydrate carbon dioxide to maintain an alkaline intracellular pH. Increased expression of MCT1/4, CAII/IX/XII, NHE1, and sodium bicarbonate transporters facilitate buffering of intracellular pH while acidifying the extracellular milieu. Defects in blood supply and perfusion exacerbate extracellular acidosis, which has implications for metabolic activity, therapy response, and migration/invasion/metastasis. Here we will review the current state of pH regulation in the tumor microenvironment, advantages to interfering with the function of pH regulatory machinery, the impact of pH homeostasis on response to therapy and its impact on metabolism.