Acidic extracellular pH is a major feature of
tumor tissue, extracellular acidification being primarily considered to be due to
lactate secretion from anaerobic glycolysis. Clinicopathological evidence shows that transporters and pumps contribute to H+ secretion, such as the Na+/H+ exchanger, the H+-
lactate co-transporter, monocarboxylate transporters, and the
proton pump (
H+-ATPase); these may also be associated with
tumor metastasis. An acidic extracellular pH not only activates secreted lysosomal
enzymes that have an optimal pH in the acidic range, but induces the expression of certain genes of pro-metastatic factors through an intracellular signaling cascade that is different from
hypoxia. In addition to
lactate, CO2 from the pentose phosphate pathway is an alternative source of acidity, showing that
hypoxia and extracellular acidity are, while being independent from each other, deeply associated with the cellular microenvironment. In this article, the importance of an acidic extracellular pH as a microenvironmental factor participating in
tumor progression is reviewed.