Evaluation of hypoxia-inducible factor 1alpha overexpression as a predictor of tumour recurrence and progression in superficial urothelial bladder carcinoma.
OBJECTIVE
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.


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.
Theodoropoulos
Vasilios E
VE
Department of Urology, Agia Olga General Hospital, National and Kapodistrian University of Athens, Athens, Greece. vastheodor@hotmail.com
Lazaris
Andreas C
AC
Kastriotis
Ioannis
I
Spiliadi
Chariclia
C
Theodoropoulos
George E
GE
Tsoukala
Vasiliki
V
Patsouris
Efstratios
E
Sofras
Frank
F
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis; D018450:Disease Progression; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007150:Immunohistochemistry; D019394:Ki-67 Antigen / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000098:blood supply / Q000175:diagnosis* / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000473:pathology; D011237:Predictive Value of Tests; D014157:Transcription Factors / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D001749:Urinary Bladder Neoplasms / Q000098:blood supply / Q000175:diagnosis* / Q000473:pathology; D019459:Urothelium / Q000378:metabolism / Q000473:pathology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D019394:Ki-67 Antigen; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D042461:Vascular Endothelial Growth Factor A