Hypoxia-inducible factor-1α expression correlates with focal macrophage infiltration, angiogenesis and unfavourable prognosis in urothelial carcinoma

Background: Hypoxia inducible factor (HIF)-1 alpha is a critical regulatory protein of cellular response to hypoxia and is closely related to angiogenic process. Aims: To explore the potential role and the prognostic value of HIF-1 alpha in urothelial carcinoma (UC). Methods: Clinicopathological and follow-up data on 99 UC cases were reviewed and immunostained for HIF-1 alpha, CD68, vascular endothelial growth factor (VEGF) and CD34 antigen. Tumour-associated macrophage (TAM) counts and HIF-1 alpha expression were compared with clinicopathologic characteristics, overall survival (OS) and disease-free survival rates (DFS). Results: High expression of HIF-1 alpha was detected in 55 of 99 (55.6%) tumours. HIF-1 alpha expression was correlated with tumour size, histological grade, tumour invasiveness and recurrence. VEGF and microvessel density (MVD) demonstrated their positive correlation with HIF-1 alpha overexpression, supporting the correlation of HIF-1 alpha up-regulation with tumour angiogenesis. Higher TAM infiltration was identified in high expression of HIF-1 alpha cases rather than HIF-1 alpha low expression cases (p = 0.002). Kaplan-Meier analysis found that HIF-1 alpha overexpression and high TAM count was only associated with worse DFS (p = 0.009, p = 0.023) but was not associated with OS (p = 0.696, p = 0.141). Multivariate analyses indicated only tumour size (p = 0.038) to be an independently significant prognostic factor for OS, in addition, HIF-1 alpha expression (p = 0.011), as well as histological grade (p = 0.038), and MVD (p = 0.004), to be independently significant prognostic factors for DFS. Conclusions: Our results indicate that HIF-1 alpha is a key regulator of the angiogenic cascade. We show that HIF-1 alpha is an independent prognostic factor for disease-free survival.