Objectives: To investigate the possible role of hypoxia-inducible factor 1alpha (HIF-1alpha, a transcription factor important in regulating O(2) homeostasis and physiological responses to oxygen deprivation) in the recurrence and progression of superficial urothelial bladder cancer, and to examine its expression in relation to proliferation status, apoptotic activity and intratumoral angiogenesis.
Patients and methods: Paraffin wax-embedded tissue from 140 patients with superficial primary urothelial bladder carcinoma was immunostained for HIF-1alpha, Ki-67, single-stranded DNA antibody for apoptotic cells, p53, bcl-2, vascular endothelial growth factor and CD31 antigen. We calculated the proliferative rate, the apoptotic index and the microvessel density (MVD). The mean (sem) follow-up was 46 (3.5) months, within which 86 patients relapsed while 18 progressed to a higher tumour stage and/or grade.
Results: HIF-1alpha expression was more common in high-grade superficial urothelial carcinomas. The positivity was related to increased proliferative activity (P = 0.012), apoptotic rate (P = 0.006) and MVD (P < 0.001). HIF-1alpha overexpression had a marginal adverse influence on progression-free survival (P = 0.058; univariate analysis), but when combined with p53 overexpression, the unfavourable impact was statistically important (P = 0.028). In multivariate analysis, only grade and the high Ki-67 labelling index were significant predictors of recurrence-free survival, while T-stage and the HIF-1alpha+/p53+ phenotype emerged as the only independent variables of adverse prognostic significance for time to progression.
Conclusions: HIF-1alpha overexpression combined with aberrant mutant p53 nuclear protein accumulation seem to indicate an aggressive phenotype, suggesting a potential biological model predictive of future risk of disease progression in patients with superficial urothelial bladder carcinoma. These indicators may be helpful in clinical practice to discriminate superficial bladder cancer worth a more intensive follow-up, or more aggressive treatment.