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


METHODS
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.
Koukourakis
M I
MI
Tumour and Angiogenesis Research Group, Department of Radiotherapy/Oncology, Democritus University of Thrace, Alexandroupolis 68100, Greece. targ@her.forthnet.gr
Giatromanolaki
A
A
Sivridis
E
E
Simopoulos
K
K
Pastorek
J
J
Wykoff
C C
CC
Gatter
K C
KC
Harris
A L
AL
D000951:Antigens, Neoplasm; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases / Q000378:metabolism*; D002294:Carcinoma, Squamous Cell / Q000378:metabolism / Q000473:pathology* / Q000628:therapy; D003131:Combined Modality Therapy; D019008:Drug Resistance, Neoplasm; D004358:Drug Therapy; D006258:Head and Neck Neoplasms / Q000378:metabolism / Q000473:pathology* / Q000628:therapy; D006801:Humans; D000860:Hypoxia / Q000503:physiopathology*; D007150:Immunohistochemistry; D009363:Neoplasm Proteins / Q000378:metabolism*; D009389:Neovascularization, Pathologic / Q000473:pathology*; D011878:Radiotherapy; D016019:Survival Analysis
D000951:Antigens, Neoplasm; D009363:Neoplasm Proteins; C089226:CA9 protein, human; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases