Szarvas Tibor, Jäger Tobias, Tötsch Martin, vom Dorp Frank, Kempkensteffen Carsten, Kovalszky Ilona, Romics Imre, Ergün Süleyman, Rübben Herbert
Experimental Urology, Department of Urology, University of Duisburg-Essen, Essen, Germany.
Clin Cancer Res. 2008 Dec 15;14(24):8253-62. doi: 10.1158/1078-0432.CCR-08-0677.
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.
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.
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).
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.
血管内皮生长因子（VEGF）、血管生成素（Ang-1和Ang-2）及其受体Tie2在正常和病理性血管生成中都起着关键作用。本研究的目的是探讨Ang-1、Ang-2、VEGF和Tie2在膀胱癌发生发展中的作用，并检验它们在这种肿瘤类型中的预后价值。
通过定量实时PCR分析了113例膀胱癌患者的肿瘤样本、5例非癌患者的正常膀胱上皮以及两种低级别（UMUC3和RT4）和两种高级别（J82和T24）膀胱癌细胞系。对表达数据进行了Wilcoxon秩和检验、Kaplan-Meier对数秩检验以及单因素Cox分析和Cox比例风险回归模型分析。
在非侵袭性膀胱肿瘤组织中，Ang-1表达显著低于正常膀胱组织（P < 0.001），而VEGF表达显著高于正常膀胱组织（P = 0.031）。这些发现也通过免疫组织化学在蛋白水平得到了证实。相比之下，肿瘤中Tie2和Ang-2的丰度与正常膀胱组织没有显著差异。多因素分析确定Ang-2是肿瘤复发的一个强大且独立的预测因子[风险比（HR），10.18；95%置信区间（95%CI），2.69 - 38.49；P < 0.001]，而Tie2表达是转移（HR，0.31；95%CI，0.11 - 0.89；P = 0.029）和疾病特异性生存（HR，0.25；95%CI，0.10 - 0.62；P = 0.003）的一个独立的有利预后因素。
这些数据表明，与正常膀胱上皮和侵袭性肿瘤阶段相比，浅表性膀胱癌中VEGF和Ang-1的表达变化最为明显。Ang-2和Tie2的预后意义强调了血管生成素 - Tie2系统在膀胱癌进展中的重要作用。
