Graesslin O, Cortez A, Fauvet R, Lorenzato M, Birembaut P, Daraï E
Service d'Anatomie Pathologique, Hôpital Tenon, AP-HP, Paris, France.
Ann Oncol. 2006 Apr;17(4):637-45. doi: 10.1093/annonc/mdj129. Epub 2006 Jan 11.
Matrix metalloproteinases (MMPs) and their inhibitors are key-players in extracellular matrix and basement membrane degradation, and are involved in both physiological and malignant processes. The aim of this study was to examine MMP-2, -7 and -9 and TIMP-1 and -2 expression in normal, hyperplastic and malignant endometrium, and their relation to clinical and histological prognostic factors.
We performed qualitative and semi-quantitative immunohistochemical analysis of 20 samples of normal endometrium (10 in the proliferative phase, 10 in the secretory phase), 39 samples of hyperplastic endometrium (17 without atypia and 22 with atypia) and 38 samples of endometrioid carcinoma, by using specific monoclonal antibodies.
In normal endometrium, epithelial expression of MMP-2 (P = 0.0007), MMP-7 (P = 0.0002) and TIMP-2 (P = 0.0004) was increased during the proliferative phase of the menstrual cycle. MMP-2 expression correlated negatively with TIMP-2 expression (P = 0.001, rho = 0.702). Endometrial stromal cells in the secretory phase showed strong MMP-2 expression (P = 0.004) and weak MMP-7 (P = 0.001) and TIMP-1 expression (P = 0.01). In hyperplastic endometrium, the presence of atypia was associated with lower TIMP-2 expression (P = 0.005) and was also associated with a trend towards higher MMP-2 expression. Endometrial stromal cell expression of MMP-2, -7 and -9 and TIMP-1 and -2 did not differ between hyperplastic endometrium with and without atypia. A gradient of MMP-2 and -9 expression was observed from hyperplastic endometrium to endometrial carcinomas. In endometrial carcinomas, MMP-2 expression increased (P = 0.0004) and TIMP-2 expression decreased (P = 0.0005) with the histological grade. TIMP-2 expression correlated with myometrial invasion (P = 0.005), lymphovascular space involvement (P = 0.008) and lymph node involvement (P = 0.007).
These results support the involvement of MMPs and TIMPs in endometrial carcinogenesis. Strong MMP-2 and weak TIMP-2 expression were the most potent markers of endometrial malignancies with a high risk of local and distant spread.
基质金属蛋白酶（MMPs）及其抑制剂是细胞外基质和基底膜降解的关键参与者，参与生理和恶性过程。本研究旨在检测MMP-2、-7和-9以及TIMP-1和-2在正常、增生和恶性子宫内膜中的表达，及其与临床和组织学预后因素的关系。
我们使用特异性单克隆抗体对20例正常子宫内膜样本（增殖期10例，分泌期10例）、39例增生性子宫内膜样本（无异型增生17例，有异型增生22例）和38例子宫内膜样癌样本进行了定性和半定量免疫组化分析。
在正常子宫内膜中，月经周期增殖期MMP-2（P = 0.0007）、MMP-7（P = 0.0002）和TIMP-2（P = 0.0004）的上皮表达增加。MMP-2表达与TIMP-2表达呈负相关（P = 0.001，rho = 0.702）。分泌期子宫内膜基质细胞显示出强烈的MMP-2表达（P = 0.004）、较弱的MMP-7（P = 0.001）和TIMP-1表达（P = 0.01）。在增生性子宫内膜中，异型增生的存在与较低TIMP-2表达相关（P = 0.005），也与MMP-2表达升高趋势相关。增生性子宫内膜有无异型增生之间，MMP-2、-7和-9以及TIMP-1和-2的子宫内膜基质细胞表达无差异。从增生性子宫内膜到子宫内膜癌观察到MMP-2和-9表达梯度。在子宫内膜癌中，MMP-2表达随组织学分级增加（P = 0.0004），TIMP-2表达降低（P = 0.0005）。TIMP-2表达与肌层浸润（P = 0.005）、淋巴管间隙受累（P = 0.008）和淋巴结受累（P = 0.007）相关。
这些结果支持MMPs和TIMPs参与子宫内膜癌发生。强烈的MMP-2和较弱的TIMP-2表达是具有局部和远处转移高风险的子宫内膜恶性肿瘤的最有效标志物。
