Hypoxia-inducible factor 1 alpha expression correlates with angiogenesis and unfavorable prognosis in bladder cancer.
OBJECTIVE
Hypoxia-inducible factor 1 alpha (HIF-1 alpha) 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-1 alpha was evaluated in 93 formalin-fixed paraffin-embedded primary transitional cell carcinoma tissue samples. HIF-1 alpha 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-1 alpha immunoreactivity and histological grade (p=0.009) was found. VEGF and MVD were closely related to tumor grade (p=0.06 and p<0.001) and clinical stage (p=0.04 and p<0.01, respectively). HIF-1 alpha was significantly correlated with VEGF expression (p=0.01) and MVD (p<0.001). Patients characterized by HIF-1 alpha overexpression had significantly worse overall (p=0.009) and disease-free survival (p=0.03). When HIF-1 alpha, histologic grade and stage were included in multivariate Cox regression analysis, HIF-1 alpha 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-1 alpha emerged as a significant negative predictor of the time to first recurrence.


CONCLUSIONS
HIF-1 alpha and angiogenesis markers may play an important predictive and prognostic role in patients with bladder cancer. HIF-1 alpha may be of biologic and clinical value as its overexpression is related to up-regulation of VEGF, the stimulation of angiogenesis and worse prognosis.
Theodoropoulos
Vasilios E
VE
Department of Urology, Agia Olga General Hospital, Ag. Olgas 3-5, Athens 14233, Greece. vastheodor@hotmail.com
Lazaris
Andreas Ch
ACh
Sofras
Fragiskos
F
Gerzelis
Ioannis
I
Tsoukala
Vasiliki
V
Ghikonti
Ioanna
I
Manikas
Konstantinos
K
Kastriotis
Ioannis
I
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D033441:Andrology; D002295:Carcinoma, Transitional Cell / Q000098:blood supply* / Q000378:metabolism* / Q000473:pathology; D004268:DNA-Binding Proteins / Q000096:biosynthesis*; D005260:Female; D006801:Humans; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009389:Neovascularization, Pathologic; D009687:Nuclear Proteins / Q000096:biosynthesis*; D011379:Prognosis; D012189:Retrospective Studies; D016019:Survival Analysis; D014157:Transcription Factors / Q000096:biosynthesis*; D001749:Urinary Bladder Neoplasms / Q000098:blood supply* / Q000378:metabolism* / Q000473:pathology
D004268:DNA-Binding Proteins; C497442:HIF1A protein, human; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009687:Nuclear Proteins; D014157:Transcription Factors