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

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 resistance to chemotherapy, radiotherapy, and poorer survival. Recently, it is shown that hypoxia induces the expression of hypoxia-inducible factor-1 and 2 (HIF-1 and HIF-2), which then up-regulates the expression 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, HIF-2, CA IX, and VEGF by immunohistochemistry in nasopharyngeal carcinoma (NPC) biopsies from 90 consecutive patients recruited between 1994 and 1997 in a randomized controlled trial of chemoradiation in locally advanced NPC and investigated their relationship with survival.

Results: HIF-1 was expressed in 52 of 90 (58%), HIF-2 in 6 of 89 (7%), CA IX in 51 of 90 (57%), and VEGF in 54 of 90 (60%) of tumors. Tumor HIF-1 expression correlated significantly with that of CA IX (P = 0.008) and VEGF (P = 0.003). High tumor HIF-1 expression was associated with a trend for poor overall survival (P = 0.06). Tumors with a positive hypoxic profile (defined as high expression of both HIF-1 and CA9) were associated with worse progression-free survival (P = 0.04). Tumors with both hypoxic and angiogenic profile (defined as high VEGF expression) were associated with a worse progression-free survival (P = 0.0095).

Conclusion: Overexpression of HIF-1, CA IX, and VEGF is common in NPC, which is probably related to hypoxia up-regulated expression involving a HIF-dependent pathway, and is associated with poor prognosis. Targeting the hypoxia pathway may be useful in the treatment of NPC.

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