Carbonic anhydrase 9 in clear cell renal cell carcinoma: A marker for diagnosis, prognosis and treatment

Carbonic anhydrase 9 (CA9) is a transmembrane member of the carbonic anhydrase family. It catalyses the reversible hydration of carbon dioxide into bicarbonate and a proton, thus enabling tumour cells to maintain a neutral pH despite an acidic microenvironment. CA9 is not expressed in healthy renal tissue but is expressed in most clear cell renal cell carcinomas (CCRCC) through HIF-1α accumulation driven by hypoxia and inactivation of the VHL gene. CA9 expression can be detected in the tumour by immunohistochemistry (IHC), in blood and tissue by ELISA assay and RT-PCR. It has a 100% diagnostic specificity in solid renal tumours, while ELISA assays on aspiration fluids may help in atypical cysts. Blood-based assays, ELISA for CA9 antigen and RT-PCR for CA9 mRNA are promising for the prognosis and follow-up of localised CCRCC. In metastatic disease, high CA9 expression by IHC was reported to be a powerful prognostic marker with better survival and sensitivity to IL-2, but this is still debated. Almost no data are currently available on the association of CA9 expression and outcome to targeted drugs. The prognostic value of CA9 in CCRCC could be explained by the frequent VHL gene inactivation driving an early activation of the HIF pathway. The poorer prognosis associated with low CA9 expressing tumours could be due to the simultaneous overexpression of EGFR contributing to the activation of AkT and mTOR pathways. Targeting CA9 by inhibitors, radioimmunotherapy, monoclonal antibodies or vaccination is promising and offers new avenues for clinical research.