Hypoxia-inducible factor 1α expression correlates with angiogenesis and unfavorable prognosis in bladder cancer

Introduction and objectives: Hypoxia-inducible factor 1alpha (HIF-1alpha) is a critical regulatory protein of cellular response to hypoxia and is closely related to the triggering of the angiogenic process. We examined the relationship between hypoxia and angiogenesis, as well as their prognostic impact in patients with urothelial bladder cancer. Methods: The immunohistochemical expression of HIF-1alpha was evaluated in 93 formalin-fixed paraffin-embedded primary transitional cell carcinoma tissue samples. HIF-1alpha was recognized through nuclear staining of positive cells. The angiogenic profile was individually assessed immunohistochemically using a monoclonal antibody to vascular endothelial growth factor (VEGF) and microvessel density (MVD) was calculated with immunohistochemical staining of the adhesion molecule CD31 of the endothelial cells. Results: A significant positive association between HIF-1alpha immunoreactivity and histological grade (p = 0.009) was found. VEGF and MVD were closely related to tumor grade (p = 0.006 and p < 0.001) and clinical stage (p = 0.04 and p < 0.001, respectively). HIF-1alpha was significantly correlated with VEGF expression (p = 0.01) and MVD (p < 0.001). Patients characterized by HIF-1alpha overexpression had significantly worse overall (p = 0.009) and disease-free survival (p = 0.03). When HIF-1alpha, histologic grade and stage were included in multivariate Cox regression analysis, HIF-1alpha emerged as an independent prognostic factor (p = 0.02) along with grade and stage, but lost its independent prognostic value after the inclusion of angiogenic factors in the multivariate model. In the subgroup of patients with T1 disease, HIF-1alpha emerged as a significant negative predictor of the time to first recurrence. Conclusions: HIF-1alpha and angiogenesis markers may play an important predictive and prognostic role in patients with bladder cancer. HIF-1alpha maybe of biologic and clinical value as its overexpression is related to up-regulation of VEGF, the stimulation of angiogenesis and worse prognosis. (C) 2004 Elsevier B.V. All rights reserved.