Angiogenic switch of angiopietins-Tie2 system and its prognostic value in bladder cancer.
OBJECTIVE
Vascular endothelial growth factor (VEGF), angiopoietins (Ang-1 and Ang-2), and their receptor Tie2 are critically involved in both normal and pathologic angiogenesis. The aim of this study was to explore the role of Ang-1, Ang-2, VEGF, and Tie2 in the development and progression of bladder cancer as well as to examine their prognostic value in this tumor type.


METHODS
Tumor samples of 113 bladder cancer patients, normal bladder epithelium of 5 noncancer patients, and two low-grade (UMUC3 and RT4) and two high-grade (J82 and T24) bladder cancer cell lines were analyzed by quantitative real-time PCR. The expression data were analyzed performing Wilcoxon rank-sum and Kaplan-Meier log-rank tests as well as univariate Cox analyses and Cox proportional hazards regression model.


RESULTS
In tissues of noninvasive bladder tumors, Ang-1 expression was significantly lower (P < 0.001), whereas VEGF expression was significantly higher (P = 0.031) than in normal bladder tissue. These findings were also confirmed at the protein level by immunohistochemistry. In contrast, Tie2 and Ang-2 abundance in tumor did not differ significantly from that in normal bladder tissue. Multivariate analysis identified Ang-2 as a strong and independent predictor of tumor recurrence [hazard ratio (HR), 10.18; 95% confidence interval (95% CI), 2.69-38.49; P < 0.001] and Tie2 expression as an independent favorable prognostic factor for both metastasis (HR, 0.31; 95% CI, 0.11-0.89; P = 0.029) and disease-specific survival (HR, 0.25; 95% CI, 0.10-0.62; P = 0.003).


CONCLUSIONS
These data show the strongest change in expression of VEGF and Ang-1 in superficial bladder cancer in comparison with normal bladder epithelium and the invasive tumor stages. The prognostic significance of Ang-2 and Tie2 underlines the essential role of angiopoietins-Tie2 system in progression of bladder cancer.
Szarvas
Tibor
T
Experimental Urology, Department of Urology, University of Duisburg-Essen, Essen, Germany. sztibusz@gmail.com
Jäger
Tobias
T
Tötsch
Martin
M
vom Dorp
Frank
F
Kempkensteffen
Carsten
C
Kovalszky
Ilona
I
Romics
Imre
I
Ergün
Süleyman
S
Rübben
Herbert
H
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D042683:Angiopoietin-1 / Q000032:analysis / Q000235:genetics*; D042702:Angiopoietin-2 / Q000032:analysis / Q000235:genetics*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D011379:Prognosis; D042787:Receptor, TIE-2 / Q000032:analysis / Q000235:genetics*; D001749:Urinary Bladder Neoplasms / Q000098:blood supply* / Q000401:mortality*; D042461:Vascular Endothelial Growth Factor A / Q000032:analysis / Q000235:genetics
C467630:ANGPT1 protein, human; D042683:Angiopoietin-1; D042702:Angiopoietin-2; D042461:Vascular Endothelial Growth Factor A; D042787:Receptor, TIE-2