Clinical studies have previously established high CAIX expression as a diagnostic and prognostic indicator in ccRCC (reviewed by ). VHL mutation results in persistently elevated HIF1a expression, and subsequent upregulation of HIF-regulated genes, including CAIX. The elevated expression of CAIX, however, has been independently associated with poor prognosis in a growing number of tumor types, including those of breast, lung, cervix, head and neck, rectal and brain, ,, ,, making it an attractive target for diagnostic non-invasive imaging and also as a potential biomarker of treatment response.ĬAIX is also constitutively expressed at high levels in clear cell renal carcinoma (ccRCC), due an inactivating mutation in the Von Hippel Landau E3 ligase protein (VHL). Whilst pre-clinical and early clinical studies have shown strong correlations between CAIX expression and tumor hypoxia (assessed by both Eppendorf pO2 probe measurements and the exogenous hypoxia tracer pimonidazole), ,, the general usefulness of CAIX as an endogenous marker of tumor hypoxia remains to be fully established. This has led to suggestions that CAIX expression may serve as an endogenous marker of tumor hypoxia. The expression of CAIX is regulated by HIF1 and is strongly-inducible under hypoxic conditions. Hypoxia results in an increase in the level of expression of Hypoxia-Inducible Factor 1α (HIF-1α), which, as part of the dimeric transcription factor HIF1, regulates the expression of a large number of genes involved in cell proliferation apoptosis, glucose metabolism, pH regulation and angiogenesis.
Reduced pO 2 (hypoxia) is a phenomenon of solid tumors resulting from an insufficient vascular network, and has been associated with tumor propagation, malignant progression and resistance to chemo- and radiotherapy in many tumor types.
The elevated expression of CAIX is restricted to malignant tissue, with normal tissue expression restricted to epithelia of the stomach, small intestine and gall bladder. Malignancies of the gastrointestinal tract have been the most widely studied, with high CAIX expression observed in esophageal, hepatobiliary, pancreatic, gastral and colorectal tumors. Immunohistochemical determination of CAIX has revealed elevated expression in an increasing number of diverse tumor types including those of kidney, breast, bladder, head and neck, cervix, soft tissue sarcoma and in non-small cell lung carcinoma, ,,. Carbonic Anhydrase 9 (CAIX, G250/MN) is a membrane-spanning protein involved in the enzymic regulation of tumor acid-base balance (reviewed by ).