The relation between hypoxia-inducible factor (HIF)-1alpha and HIF-2alpha expression with anemia and outcome in surgically treated head and neck cancer.
Winter SC., Shah KA., Han C., Campo L., Turley H., Leek R., Corbridge RJ., Cox GJ., Harris AL.
BACKGROUND: Hypoxia promotes tumorigenesis through the hypoxia-inducible factor (HIF) pathway. There are 2 main homologues of the regulatory proteins, HIF-1alpha and HIF-2alpha, which have different effects in genetic knock-out experiments. Anemia may contribute to hypoxia by reducing oxygen delivery, but it is not known whether this influences HIF-alpha expression in tumors. METHODS: The expression of HIF-1alpha, HIF-2alpha, carbonic anhydrase-9 (CA-9), and peripheral hemoglobin (Hb) levels in 151 patients who underwent surgery for head and neck squamous cell carcinoma (HNSCC) were analyzed and related to outcome. RESULTS: High HIF-1alpha was expressed in 45 of 140 tumors (30%), HIF-2alpha was expressed in 21 of 139 tumors (14%), and CA-9 was expressed in 56 of 149 tumors (62%). There was a positive correlation between HIF-1alpha expression and HIF-2alpha expression (P =.0001). HIF-1alpha alone was associated with a worse disease-specific survival (DSS) (P =.05) and disease-free survival (DFS) (P = .03) in multivariate analyses. Nine percent of tumors expressed both high HIF-1alpha and high HIF-2alpha. High HIF-1alpha/high HIF-2alpha expression was an independent prognostic factors in DSS (P = .04) and DFS (P =.005) in multivariate analyses. There was no correlation noted between Hb and HIF-1alpha, HIF-2alpha, or CA-9. CONCLUSIONS: HIF-1alpha alone was correlated with DSS and DFS. The additive effect of HIF-2alpha on poor prognosis suggested that different pathways may be regulated by HIF-2alph. Anemia that was not related to HIF-alpha expression suggests that tumor intrinsic factors regulate HIF-alpha therefore, anemia may be a surrogate marker for other factors that affect outcome.