The Tumor Microenvironment: New Insights into Regulation of Tumor pH by Carbonic Anhydrases

Abstract

Intracellular pH (pHi) is a powerful modulator of cell function. There is a narrow range of pHi, usually between 7.0 and 7.5, over which cell growth and development is optimal. Metabolism, particularly cellular respiration, tends to disturb this favorable steady state. The survival of cells undergoing such an acid challenge relies on efficient mechanisms for regulating pHi. In solid tumors, pHi regulation is challenged by their heavy demand for energy and poor blood supply. Inadequately perfused cancer cells deprive the milieu of oxygen, forcing a switchover to the less energy efficient, anaerobic mode of respiration. To meet energy demands, cells upregulate respiration and excrete more acid which lowers extracellular pH (pHe). The tumor extracellular milieu is believed to exert Darwinian selection in favor of cancer cells and against normal cells, based on the cell’s capacity to protect pHi under hypoxia and low pHe. In this chapter, we describe the pathways operating in tumors for removing acid and regulating pHi, with particular emphasis on membrane transporters and carbonic anhydrase (CA) enzymes. We discuss these pathways in terms of survival adaptations and possible targets for anticancer therapy.