Hypoxia inducible carbonic anhydrase IX, marker of tumor hypoxia, survival pathway and therapy target

Abstract

Over 50 genes are inducible by hypoxia, via hypoxia inducible factor 1α (HIF-1α). Carbonic anhydrase IX (CAIX) is one of the most inducible and most uniformly induced genes and because of its stability and membrane location provides a reliable histochemical marker of hypoxia. Recent studies have shown the importance of pH in cell death under hypoxia; thus mechanisms of pH regulation are likely to be vital pathways for survival. Carbonic anhydrases have a widespread role in normal tissues in regulating pH, with 14 isoforms described, so inhibition may have substantial normal tissue toxicity. Selective non-membrane permeable inhibitors are available and may synergize with chemotherapy agents more active in acid conditions. CAIX has a major role in regulating hydrogen ion (H+) Flux and blockade of CAIX results in increased cell death under hypoxia, indicating that it is one mechanism of hypoxic adaptation. As it is commonly expressed in tumors with the worst prognosis it is a potential target for therapy.