The relation between hypoxia-inducible factor (HIF)-1α and HIF-2α expression with anemia and outcome in surgically treated head and neck cancer

BACKGROUND. Hypoxia promotes tumorigenesis through the hypoxia-inducible factor (HIF) pathway. There are 2 main homologues of the regulatory proteins, HIF-1 alpha and HIF-2 alpha, 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-1 alpha, HIF-2 alpha, 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-1 alpha was expressed in 45 of 140 tumors (30%), HIF-2 alpha 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-1 alpha expression and HIF-2 alpha expression (P =.0001). HIF-1 alpha 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-1 alpha and high HIF-2 alpha. High HIF-1 alpha/high HIF-2 alpha 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-1 alpha, HIF-2 alpha, or CA-9. CONCLUSIONS. HIF-1 alpha alone was correlated with DSS and DFS. The additive effect of HIF-2 alpha on poor prognosis suggested that different pathways may be regulated by HIF-2 alpha. Anemia that was not related to HIF-a expression suggests that tumor intrinsic factors regulate HIF-alpha; therefore, anemia may be a surrogate marker for other factors that affect outcome.