Association of Angiogenesis Related Markers With Bladder Cancer Outcomes and Other Molecular Markers
Association of Angiogenesis Related Markers With Bladder Cancer Outcomes and Other Molecular Markers
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DOI：
10.1016/j.juro.2010.01.018
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发表时间：
2010-05-01
影响因子：
6.6
通讯作者：
Lotan, Yair
中科院分区：
文献类型：
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作者：
Shariat, Shahrokh F.;Youssef, Ramy F.;Lotan, Yair
目的：我们检测了血管生成相关标志物的免疫组化表达改变是否与膀胱尿路上皮癌患者的预后相关，并评估了血管生成相关标志物与膀胱尿路上皮癌中常见改变的分子标志物的相关性。收集血管内皮生长因子、碱性成纤维细胞生长因子和血小板反应蛋白1表达数据以及微血管密度数据。对204例膀胱尿路上皮癌行根治性膀胱切除术后标本进行免疫组化染色。我们还对标本的连续切片进行了细胞周期蛋白El、细胞周期蛋白D1、p53、p21、p27、pRB、Ki-67、Bc 1 -2、caspase-3、生存素和环氧合酶-2的染色。我们测量疾病复发和癌症特异性死亡率的时间，以及与临床和病理特征和其他分子markers.Results：血管内皮生长因子（过度表达），碱性成纤维细胞生长因子（过度表达）和血小板反应蛋白1（表达下降）的表达改变的相关性分别为86%，79%和63%。微血管密度中位数为20。所有4种标志物均与侵袭性膀胱尿路上皮癌的临床病理特征（如分期、淋巴管浸润和淋巴结转移）及其他分子标志物相关。在校正标准病理特征的多变量分析中，碱性成纤维细胞生长因子和血小板反应蛋白1是疾病复发（HR分别为3.6，p = 0.002和HR 2.2，p = 0.001）和癌症特异性死亡率（HR分别为2.8，p = 0.02和HR 2.3，p = 0.003）的独立预测因子。当所有4种标志物都包括在一个模型中时，碱性成纤维细胞生长因子和血小板反应蛋白1保留了它们与疾病复发的独立相关性（HR分别为2.9，p = 0.014和1.8，p = 0.022），只有血小板反应蛋白1与癌症特异性死亡率独立相关。结论：膀胱尿路上皮癌中血管生成相关分子标志物的表达普遍改变，使其成为治疗的靶点。血小板反应蛋白1的下调和碱性成纤维细胞生长因子的上调是膀胱尿路上皮癌患者临床预后的独立预测因子。
Purpose: We tested whether the altered immunohistochemical expression of angiogenesis related markers is associated with outcomes of patients with urothelial carcinoma of the bladder, and assessed the correlation of angiogenesis related markers with molecular markers commonly altered in urothelial bladder carcinoma.Materials and Methods: Vascular endothelial growth factor, basic fibroblast growth factor and thrombospondin 1 expression data were collected, as were microvessel density data. Immunohistochemical staining was performed on specimens from 204 patients treated with radical cystectomy for urothelial carcinoma of the bladder. We also stained serial sections of the specimens for cyclin El, cyclin D1, p53, p21, p27, pRB, Ki-67, Bc1-2, caspase-3, survivin and cyclooxygenase-2. We measured time to disease recurrence and cancer specific mortality, as well as the association with clinical and pathological features and other molecular markers.Results: The altered expression of vascular endothelial growth factor (over expression), basic fibroblast growth factor (over expression) and thrombospondin 1 (decreased expression) was 86%, 79% and 63%, respectively. Median microvessel density was 20. All 4 markers were associated with established clinicopathological features of aggressive urothelial carcinoma of the bladder (such as stage, lymphovascular invasion and lymph node metastasis) and other molecular markers. On multivariable analyses that adjusted for standard pathological features basic fibroblast growth factor and thrombospondin 1 were independent predictors of disease recurrence (HR 3.6, p = 0.002 and HR 2.2, p = 0.001, respectively) and cancer specific mortality (HR 2.8, p = 0.02 and HR 2.3, p = 0.003, respectively). When all 4 markers were included in 1 model basic fibroblast growth factor and thrombospondin 1 retained their independent association with disease recurrence (HR 2.9, p = 0.014 and HR 1.8, p = 0.022, respectively) and only thrombospondin 1 was independently associated with cancer specific mortality (HR 1.9, p = 0.031).Conclusions: Angiogenesis related molecular markers are commonly altered in urothelial carcinoma of the bladder, making them a target for therapy. Downregulation of thrombospondin 1 and up-regulation of basic fibroblast growth factor are independent predictors of clinical outcomes of patients with urothelial carcinoma of the bladder.