Diagnostic, prognostic and therapeutic implications of carbonic anhydrases in cancer

Abstract

The carbonic anhydrases (CAs) comprise a family of evolutionarily ancient enzymes found ubiquitously in nature. They have important roles in facilitating transport of carbon dioxide and protons in the intracellular space, across biological membranes and in the unstirred layers of the extracellular space. The tumour-associated isoenzymes, CAIX and CAXII, are expressed in a wide variety of malignancies and appear to be tightly regulated by microenvironmental hypoxia. CAIX expression is linked to poor prognosis in a number of human tumours, and may be a marker of aggressive malignant phenotype and a mechanism of progression. Inhibitors of CA may inhibit tumour growth and invasion, with consequent therapeutic potential.

Figure 1

(A) Hydrogen ion produced by anaerobic metabolism within the cell must first be converted to carbon dioxide to facilitate diffusion across the lipid bilayer. This reaction with bicarbonate is catalysed by cytoplasmic CA. Once carbon dioxide has diffused into the extracellular space, CA activity in the boundary layer may regenerate protons, maintaining the carbon dioxide diffusion gradient. (B) The NHE is one method by which protons may be actively pumped from the cell. Alternatively, bicarbonate in the extracellular space (regenerated from carbon dioxide hydration with CA catalysis) may be imported into the cell via the chloride–bicarbonate AE. This bicarbonate may recombine with a proton in the cytoplasm to undertake further shuttling across the membrane. This recycling of bicarbonate with net proton extrusion is known as a Jacobs–Stewart cycle. The AE has recently been shown to bind CAII on its intracellular surface