Coexpression of Hypoxia-inducible Factors 1{alpha} and 2{alpha}, Carbonic Anhydrase IX, and Vascular Endothelial Growth Factor in Nasopharyngeal Carcinoma and Relationship to Survival

Molecular Oncology, Markers, Clinical Correlates

Coexpression of Hypoxia-inducible Factors 1 ${alpha}$ and 2 ${alpha}$ , Carbonic Anhydrase IX, and Vascular Endothelial Growth Factor in Nasopharyngeal Carcinoma and Relationship to Survival¹

Edwin P. Hui, Anthony T. C. Chan, Francesco Pezzella, Helen Turley, Ka-Fai To, Terence C. W. Poon, Benny Zee, Frankie Mo, Peter M. L. Teo, Dolly P. Huang, Kevin C. Gatter, Philip J. Johnson and Adrian L. Harris

Departments of Clinical Oncology [E. P. H., A. T. C. C., T. C. W. P., B. Z., F. M., P. M. L. T., D. P. H., P. J. J.] and Anatomical and Cellular Pathology [K- F. T.], The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, and Imperial Cancer Research Fund, Tumor Pathology Unit, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DU, United Kingdom [F. P., H. T., K. C. G., A. L. H.]

Purpose: Tumor hypoxia is known to be associated with resistanceto chemotherapy, radiotherapy, and poorer survival. Recently,it is shown that hypoxia induces the expression of hypoxia-induciblefactor-1 ${alpha}$ and 2 ${alpha}$ (HIF-1 ${alpha}$ and HIF-2 ${alpha}$ ), which then up-regulates theexpression of downstream genes such as carbonic anhydrase IX(CA IX) and vascular endothelial growth factor (VEGF).

Experimental Design: We examined the expression of HIF-1 ${alpha}$ , HIF-2 ${alpha}$ ,CA IX, and VEGF by immunohistochemistry in nasopharyngeal carcinoma(NPC) biopsies from 90 consecutive patients recruited between1994 and 1997 in a randomized controlled trial of chemoradiationin locally advanced NPC and investigated their relationshipwith survival.

Results: HIF-1 ${alpha}$ was expressed in 52 of 90 (58%), HIF-2 ${alpha}$ in 6 of89 (7%), CA IX in 51 of 90 (57%), and VEGF in 54 of 90 (60%)of tumors. Tumor HIF-1 ${alpha}$ expression correlated significantly withthat of CA IX (P = 0.008) and VEGF (P = 0.003). High tumor HIF-1 ${alpha}$ expression was associated with a trend for poor overall survival(P = 0.06). Tumors with a positive hypoxic profile (definedas high expression of both HIF-1 ${alpha}$ and CA9) were associated withworse progression-free survival (P = 0.04). Tumors with bothhypoxic and angiogenic profile (defined as high VEGF expression)were associated with a worse progression-free survival (P =0.0095).

Conclusion: Overexpression of HIF-1 ${alpha}$ , CA IX, and VEGF is commonin NPC, which is probably related to hypoxia up-regulated expressioninvolving a HIF-dependent pathway, and is associated with poorprognosis. Targeting the hypoxia pathway may be useful in thetreatment of NPC.

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