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Colocalization of Carbonic Anhydrase 9 Expression and Cell Proliferation in Human Head and Neck Squamous Cell Carcinoma

Departments of ¹ Radiation Oncology, ² Otorhinolaryngology/Head-Neck Surgery; and ³ Urology, University Medical Center, St. Radboud, Nijmegen, the Netherlands

Requests for reprints: Ilse J. Hoogsteen, Department of Radiation Oncology, 341 University Medical Center, St. Radboud, P.O. Box 9101, 6500 HB Nijmegen, the Netherlands. Phone: 31-24-361-7822/4515; Fax: 31-24-356-8350; E-mail: i.hoogsteen{at}rther.umcn.nl

Purpose: Tumor cells undergo a variety of biological changes under sustained hypoxic conditions, allowing cells to survive and retain their clonogenic potential. The purpose of this study is to relate the expression of the hypoxia marker carbonic anhydrase 9 (CA9) to the uptake of iododeoxyuridine (IdUrd), a marker of proliferation, in head and neck squamous cell carcinomas. Colocalization of IdUrd and CA9 may identify an important subpopulation of tumor cells that might be responsible for repopulation and disease progression.

Experimental Design: Expression of CA9, IdUrd labeling, and colocalization between IdUrd and CA9 was examined by immunohistochemistry in biopsies of head and neck squamous cell carcinomas. Biopsies were taken from 51 patients recruited between 1998 and 2001 after administration of the proliferation marker IdUrd.

Results: A large variation was observed between the tumors in CA9 expression (range 0-39%), IdUrd labeling (range 0-81%), and colocalization between IdUrd and CA9 [FId_(CA9); range 0-53%]. FId_(CA9), the fraction of IdUrd-labeled cells positive for CA9, was highest at an intermediate distance from the blood vessels (100-150 µm). IdUrd labeling was higher in T4 carcinomas relative to lower stage tumors (P = 0.04). High FId_(CA9) correlated with the worst disease-free survival rates (P = 0.04).

Conclusions: Colocalization between IdUrd labeling and CA9 expression was observed in head and neck squamous cell carcinomas, suggesting the presence of a population of tumor cells under intermediate hypoxic conditions which still has proliferative capacity. The size of this subpopulation may be indicative of tumor aggressiveness and is associated with the worst disease-free survival rates.

Key Words: Iododeoxyuridine • hypoxia • proliferation • head and neck cancer

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