The influence of pH and hypoxia on tumor metastasis.

Rapid malignant proliferation, prior to effective tumor neoangiogenesis, creates a microenvironment around solid cancers, which is predominantly hypoxic and characterized by a high interstitial fluid pressure. Presumably as an adaptive response, tumor cells favor metabolic activity with apparently inefficient energy output, and production of intermediates that promote cellular replication, preferentially through anaerobic glycolysis, a phenomenon that persists even in re-established normoxic conditions (anomalously referred to as 'aerobic glycolysis'). Extrusion of the consequently excessive accumulation of lactate and protons decreases extracellular pH, leading to a microenvironment considered conducive to promotion of tumor motility, invasion and metastasis, and one that will invariably influence response to drug treatment. This review will critically assess the evidence forming the basis of current understanding of the precise pH conditions in the extracellular tumor matrix, its regulation by cancer cells and relationship with hypoxia, its relevance to malignant progression and its exploitation for therapeutic advantage.