Hypoxia-regulated carbonic anhydrase-9 (CA9) relates to poor vascularization and resistance of squamous cell head and neck cancer to chemoradiotherapy

Purpose: Carbonic anhydrases are proteins involved in the catalytic hydrati on of carbon dioxide to carbonic acid. Recent studies show that carbonic an hydrase 9 (CA9) is up-regulated by hypoxia and that its immunohistochemical tissue distribution follows the distribution of the radiosensitizer pimoni dazole (C. C. Wykoff et al., Cancer Res. 60: 7075-7083, 2001). Therefore, C A9 expression may show hypoxia levels of clinical importance. Experimental Design: We assessed the expression of CA9 and the microvessel density (MVD; CD31-positive) in 75 locally advanced squamous cell head and neck cancers treated with concurrent chemoradiotherapy with carboplatin. Results: Strong membrane/cytoplasmic CA9 expression, noted in 20/75 (26.6%) tumors, mainly occurred in tumors with very poor vascularization (expressi on in 63% versus 14%; P < 0.0001), was located around areas of focal necros is, and was related to poor complete response rate (40% versus 70%; P = 0.0 2). These observations suggested that CA9 might be a marker of clinically i mportant hypoxia. Combining the CA9 staining and the tumor angiogenicity (M VD), we identified three groups of patients: (a) hypoxic tumors; (b) euoxic highly angiogenic tumors; and (c) euoxic non-highly angiogenic tumors. Gro ups (a) and (b) had a very poor local relapse-free survival (P < 0.0001). Conclusions: Stratification of patients undergoing radical radiotherapy usi ng the CA9/MVD model may be useful for the individualization of therapeutic strategies combining antiangiogenesis and hypoxia targeting with radiother apy.