子宫内膜癌患者中血管生成的“血管内皮生长因子/flk-1（KDR）受体”通路：预后及治疗意义

The angiogenic "vascular endothelial growth factor/flk-1(KDR) receptor" pathway in patients with endometrial carcinoma: prognostic and therapeutic implications.

作者信息

Giatromanolaki A, Sivridis E, Brekken R, Thorpe P E, Anastasiadis P, Gatter K C, Harris A L, Koukourakis M I

机构信息

Department of Pathology, Democritus University of Thrace, Alexandroupolis, Greece.

出版信息

Cancer. 2001 Nov 15;92(10):2569-77. doi: 10.1002/1097-0142(20011115)92:10<2569::aid-cncr1609>3.0.co;2-3.

DOI:10.1002/1097-0142(20011115)92:10<2569::aid-cncr1609>3.0.co;2-3

PMID:11745191

Abstract

BACKGROUND

Vascular endothelial growth factor (VEGF) is an important endothelial cell mitogen associated with increased angiogenesis and aggressive tumor behavior. Its stimulating effect on endothelial cells basically is dependent on the presence of specific VEGF receptors, such as the flk-1(KDR) receptor. This study investigates the roles of VEGF and of a functionally intact angiogenic pathway, "VEGF/flk-1(KDR)," in patients with endometrial carcinoma and their significance in prognosis and therapy.

METHODS

A series of 121 endometrial carcinomas were studied. The expression of VEGF by endometrial tumor cells was assessed using the monoclonal antibody (MoAb) VG1. VEGF/KDR complexes on tumor endothelium or activated microvessel density (aMVD) were identified using the MoAb 11B5. In addition, the standard microvessel density (sMVD) was assessed with anti-CD31. In all tumors, the alkaline phosphatase/antialkaline phosphatase technique was employed. A Fisher exact test or an unpaired, two-tailed t test was used for testing correlations between categoric tumor variables, whereas a log-rank test was used to determine statistical differences between life tables. A Cox proportional hazards model was used to assess the effect of tumor variables on overall survival.

RESULTS

Cytoplasmic VEGF expression in > 50% of tumor cells was associated significantly with aMVD (P < 0.0001) and with sMVD (P < 0.003). In univariate survival analysis, VEGF (P = 0.0002), aMVD (P = 0.001), and sMVD (P = 0.0009) were significant prognostic variables. Equally important were the histologic parameters tumor type (P = 0.03), tumor grade (P = 0.003), and disease stage (P < 0.0001). In multivariate analysis, disease stage was the most important independent prognostic factor (P < 0.0001), followed by VEGF/KDR (P < 0.01), and VEGF (P < 0.04). Furthermore, VEGF and VEGF/KDR were the only independent prognostic variables for patients with Stage I endometrioid adenocarcinoma.

CONCLUSIONS

sMVD and the angiogenic factor VEGF are important indicators of a poor prognosis in patients with endometrial carcinoma. VEGF/KDR complexes define a subgroup of patients with endometrial carcinoma with an even worse prognosis.

摘要

背景

血管内皮生长因子（VEGF）是一种重要的内皮细胞促有丝分裂原，与血管生成增加和肿瘤侵袭性行为相关。其对内皮细胞的刺激作用基本上取决于特定VEGF受体的存在，如flk-1（KDR）受体。本研究调查VEGF以及功能完整的血管生成途径“VEGF/flk-1（KDR）”在子宫内膜癌患者中的作用及其在预后和治疗中的意义。

方法

对121例子宫内膜癌进行了一系列研究。使用单克隆抗体（MoAb）VG1评估子宫内膜肿瘤细胞中VEGF的表达。使用MoAb 11B5识别肿瘤内皮上的VEGF/KDR复合物或活化微血管密度（aMVD）。此外，用抗CD31评估标准微血管密度（sMVD）。在所有肿瘤中，采用碱性磷酸酶/抗碱性磷酸酶技术。采用Fisher精确检验或非配对双尾t检验来检验分类肿瘤变量之间的相关性，而采用对数秩检验来确定生命表之间的统计学差异。采用Cox比例风险模型评估肿瘤变量对总生存的影响。

结果

超过50%肿瘤细胞的细胞质VEGF表达与aMVD（P<0.0001）和sMVD（P<0.003）显著相关。在单因素生存分析中，VEGF（P = 0.0002）、aMVD（P = 0.001）和sMVD（P = 0.0009）是显著的预后变量。同样重要的是组织学参数肿瘤类型（P = 0.03）、肿瘤分级（P = 0.003）和疾病分期（P<0.0001）。在多因素分析中，疾病分期是最重要的独立预后因素（P<0.0001），其次是VEGF/KDR（P<0.01）和VEGF（P<0.04）。此外，VEGF和VEGF/KDR是I期子宫内膜样腺癌患者唯一的独立预后变量。