Hypoxia-inducible factor (HIF1A and HIF2A), angiogenesis, and chemoradiotherapy outcome of squamous cell head-and-neck cancer

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Purpose : Hypoxia-inducible factors HIF1α and HIF2α (HIFαs) regulate the expression of a variety of genes encoding proteins related to angiogenesis and to anaerobic metabolism of cells exposed to hypoxic stress. Their putative role as markers of clinically relevant hypoxia and, therefore, as predictors of response to chemoradiotherapy is herein examined. Patients and Methods : Using immunohistochemistry, we assessed the expression of HIFαs in normal head-neck mucosa and in 75 cancer specimens from patients with locally advanced squamous cell head-and-neck cancer (SCHNC), treated with concurrent carboplatin chemoradiotherapy. Results : Head-and-neck mucosa from normal individuals did not show any HIF1α or HIF2α reactivity. SCHNC showed a varying expression of HIFαs ranging through negative reactivity, to weak or focally strong cytoplasmic reactivity, or to strong diffuse cytoplasmic/nuclear reactivity. Fifty-two percent and 33% of cancer samples showed the latter expression pattern for HIF1α and HIF2α, respectively, and were considered to bear “high” HIF reactivity. Bone/cartilage involvement was more frequent in tumors with high HIF1α expression ( p = 0.05). HIF1α and HIF2α overexpression were significantly associated with high microvessel density ( p = 0.002 and 0.02, respectively) and with VEGF expression ( p = 0.01 and 0.005, respectively). HIF1α was related to high thymidine phosphorylase expression ( p = 0.03), whereas VEGF/KDR-activated tumor vasculature was significantly more frequent in HIF2α-overexpressing tumors ( p = 0.02). High HIF1α and HIF2α were associated with incomplete response to chemoradiation ( p = 0.007 and p = 0.02, respectively). In univariate analysis, high HIF1α and HIF2α expression were significantly associated with poor local relapse-free survival ( p = 0.003 and 0.003, respectively) and with poor overall survival ( p = 0.05 and 0.001, respectively). In multivariate models, HIF2α expression was an independent prognostic factor. In biopsies performed after the delivery of 20 Gy of radiotherapy, upregulation of HIFαs was noted in some cases. Conclusions : It is concluded that the overexpression of HIFαs in SCHNC is related to locally aggressive behavior, to intensification of angiogenesis, and to an important resistance to carboplatin chemoradiotherapy.