Carbonic anhydrase IX: a regulator of pH and participant in carcinogenesis

Carbonic anhydrase IX (CAIX) is a transmembrane metalloenzyme which is upregulated in tumour cells under hypoxic conditions. CAIX expression is induced by the accumulation of hypoxia-inducible factor-1α and has several downstream effects, including acidification of the extracellular pH, loss of cellular adhesion and increased tumour cell migration. CAIX is upregulated in a variety of solid organ tumours and has prognostic implications. High CAIX protein expression is a marker of poor prognosis in breast, lung, ovarian and bladder carcinomas. Conversely, low expression is an indicator of poor prognosis in clear cell renal cell carcinoma (CCRCC). CAIX immunohistochemistry is useful diagnostically to identify metastatic CCRCC, and the recently recognised clear cell papillary renal cell carcinoma. There is much interest in targeting CAIX with monoclonal antibodies and small molecule inhibitors. There are several small molecule inhibitors under development which have shown promising results in clinical trials. In this paper, we provide an overview of the role of CAIX in tumourigenesis and outline its use as a prognostic, diagnostic and therapeutic biomarker.