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Hypoxia-regulated Carbonic Anhydrase-9 (CA9) Relates to Poor Vascularization and Resistance of Squamous Cell Head and Neck Cancer to Chemoradiotherapy

Tumour and Angiogenesis Research Group, Departments of Radiotherapy/Oncology, Pathology and Surgery, Democritus University of Thrace, Alexandroupolis 68100, Greece [M. I. K., A. G., E. S., K. S.]; Institute of Virology, Slovak Academy of Sciences, Bratislava, Slovak Republic, 84246 [J. P.]; and Departments of Cellular Science and Institute of Molecular Medicine, Oxford Radcliffe Hospital, Headington, Oxford, OX3 9DS, United Kingdom [C. C. W., K. C. G., A. L. H.]

Purpose: Carbonic anhydrases are proteins involved in the catalytic hydration of carbon dioxide to carbonic acid. Recent studies show that carbonic anhydrase 9 (CA9) is up-regulated by hypoxia and that its immunohistochemical tissue distribution follows the distribution of the radiosensitizer pimonidazole (C. C. Wykoff et al., Cancer Res. 60: 7075–7083, 2001). Therefore, CA9 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 (expression in 63% versus 14%; P < 0.0001), was located around areas of focal necrosis, and was related to poor complete response rate (40% versus 70%; P = 0.02). These observations suggested that CA9 might be a marker of clinically important hypoxia. Combining the CA9 staining and the tumor angiogenicity (MVD), we identified three groups of patients: (a) hypoxic tumors; (b) euoxic highly angiogenic tumors; and (c) euoxic non-highly angiogenic tumors. Groups (a) and (b) had a very poor local relapse-free survival (P < 0.0001).

Conclusions: Stratification of patients undergoing radical radiotherapy using the CA9/MVD model may be useful for the individualization of therapeutic strategies combining antiangiogenesis and hypoxia targeting with radiotherapy.

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