the Relation Between Hypoxia-Inducible Factor (Hif)-1α and Hif-2α Expression With Anemia and Outcome in Surgically Treated Head and Neck Cancer

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Abstract

BACKGROUND.

Hypoxia promotes tumorigenesis through the hypoxia-inducible factor (HIF) pathway. There are 2 main homologues of the regulatory proteins, HIF-1α and HIF-2α, 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-α expression in tumors.

METHODS.

The expression of HIF-1α, HIF-2α, 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-1α was expressed in 45 of 140 tumors (30%), HIF-2α 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-1α expression and HIF-2α expression (P = .0001). HIF-1α 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-1α and high HIF-2α. High HIF-1α/high HIF-2α 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-1α, HIF-2α, or CA-9.

CONCLUSIONS.

HIF-1α alone was correlated with DSS and DFS. The additive effect of HIF-2α on poor prognosis suggested that different pathways may be regulated by HIF-2α. Anemia that was not related to HIF-α expression suggests that tumor intrinsic factors regulate HIF-α; therefore, anemia may be a surrogate marker for other factors that affect outcome.

CONCLUSIONS.

Hypoxia-inducible factor (HIF)-1α expression was correlated with a poor outcome in patients with squamous cell carcinoma of the head and neck, whereas HIF-2α had an additive effect on outcome. The results did not indicate that anemia influenced tumor hypoxia.

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