缺氧诱导因子1α的表达与膀胱癌的血管生成及不良预后相关。

Hypoxia-inducible factor 1 alpha expression correlates with angiogenesis and unfavorable prognosis in bladder cancer.

作者信息

Theodoropoulos Vasilios E, Lazaris Andreas Ch, Sofras Fragiskos, Gerzelis Ioannis, Tsoukala Vasiliki, Ghikonti Ioanna, Manikas Konstantinos, Kastriotis Ioannis

机构信息

Department of Urology, Agia Olga General Hospital, Ag. Olgas 3-5, Athens 14233, Greece.

出版信息

Eur Urol. 2004 Aug;46(2):200-8. doi: 10.1016/j.eururo.2004.04.008.

DOI:10.1016/j.eururo.2004.04.008

PMID:15245814

Abstract

INTRODUCTION AND OBJECTIVES

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.

摘要

引言与目的

缺氧诱导因子1α（HIF-1α）是细胞对缺氧反应的关键调节蛋白，与血管生成过程的触发密切相关。我们研究了缺氧与血管生成之间的关系，以及它们对膀胱尿路上皮癌患者的预后影响。

方法

对93例福尔马林固定石蜡包埋的原发性移行细胞癌组织样本进行HIF-1α免疫组化表达评估。通过阳性细胞核染色识别HIF-1α。使用抗血管内皮生长因子（VEGF）单克隆抗体免疫组化单独评估血管生成情况，并用内皮细胞黏附分子CD31免疫组化染色计算微血管密度（MVD）。

结果

发现HIF-1α免疫反应性与组织学分级之间存在显著正相关（p = 0.009）。VEGF和MVD与肿瘤分级（p = 0.06和p < 0.001）及临床分期（分别为p = 0.04和p < 0.01）密切相关。HIF-1α与VEGF表达（p = 0.01）和MVD（p < 0.001）显著相关。HIF-1α过表达的患者总生存期（p = 0.009）和无病生存期（p = 0.03）明显更差。当将HIF-1α、组织学分级和分期纳入多变量Cox回归分析时，HIF-1α与分级和分期一样成为独立的预后因素（p = 0.02），但在多变量模型中纳入血管生成因子后失去了其独立预后价值。在T1期疾病患者亚组中，HIF-1α成为首次复发时间的显著负性预测指标。