Presence of active gelatinases in endometrial carcinoma and correlation of matrix metalloproteinase expression with increasing tumor grade and invasion
Presence of active gelatinases in endometrial carcinoma and correlation of matrix metalloproteinase expression with increasing tumor grade and invasion
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DOI：
10.1002/cncr.10355
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发表时间：
2002-03-01
期刊：
影响因子：
6.2
通讯作者：
Salamonsen, LA
中科院分区：
文献类型：
--
作者：
Di Nezza, LA;Misajon, A;Salamonsen, LA
背景。细胞外基质降解酶基质金属蛋白酶（MMPs）的作用与肿瘤的发生有关。研究了子宫内膜癌组织中MMP-2、MMP-9、膜1型(MT1)-MMP、组织金属蛋白酶抑制剂（TIMPs） 1-3的细胞定位以及活性明胶酶的存在。子宫内膜癌根据组织学分级（1-3级）、肌层浸润深度（0、< 50%、> 50%）和是否存在血管/淋巴浸润进行分组。对29例子宫内膜癌活检进行免疫组织化学研究，以确定MMP-2（明胶酶A）、MMP-9（明胶酶13）、MT1-MMP和TIMPs - 1-3的组织定位。原位杂交定位MMP-2和MMP-9 mRNA。使用原位酶谱法评估活性明胶酶的存在。上皮肿瘤细胞是MMP-2、MMP-9和MT1-MMP蛋白的主要表达部位。还观察到不同的间质细胞定位，特别是在肿瘤巢附近的区域。半定量分析显示，在肿瘤上皮细胞从组织学一级到二级和三级的转变过程中，MMP-9和MMP-2评分升高，但MT1-MMP染色评分未见升高。肿瘤细胞的基质金属蛋白酶-9和MT1-MMP染色评分与肌层浸润和血管/淋巴浸润存在显著相关，而MMP-2与这些因素无关。此外，MT1-MMP与MMP-2共定位，支持其在proMMP-2激活中的作用。所有组织学级别的肿瘤细胞都强烈染色TIMP-2和TIMP-3蛋白，同时观察到可变基质染色。在1级癌中，TIMP-1主要免疫定位于间质室，在2级和3级癌中观察到不同的肿瘤细胞定位。基质金属蛋白酶-9和MMP-2 mrna在turner上皮细胞和基质中均有不同程度的表达。原位酶谱图显示细胞表面明胶酶的活性形式，并与子宫内膜癌组织内的肿瘤上皮细胞有关。这些数据表明MMPs的表达增加与子宫内膜癌的进展密切相关。活性明胶酶存在于子宫内膜癌中，导致微环境的改变，促进肿瘤的侵袭和转移。(C) 2002年美国癌症协会。
BACKGROUND. The actions of the extracellular-matrix degrading enzymes, matrix metalloproteinases (MMPs), are implicated in tumorigenesis. The cellular localization of MMP-2, MMP-9, membrane type 1 (MT1)-MMP, tissue Inhibitors of metalloproteinases (TIMPs) 1-3, and the presence of active gelatinases were investigated in endometrial carcinoma.METHODS. Endometrial carcinomas were grouped according to histologic grade (Grades 1-3), depth of myometrial invasion (0, < 50%, > 50%) and the presence of vascular/lymphatic invasion. Twenty-nine endometrial carcinoma biopsies were investigated immunohistochemically to determine the tissue localization of MMP-2 (gelatinase A), MMP-9 (gelatinase 13), MT1-MMP, and TIMPs 1-3. In situ hybridization was performed to localize MMP-2 and MMP-9 mRNA. The presence of active gelatinases was assessed using in situ zymography.RESULTS. Epithelial tumor cells were the main site of MMP-2, MMP-9, and MT1-MMP protein. Variable stromal cell localization was also observed, particularly in areas adjacent to tumor nests. Semiquantitative analysis revealed increases in MMP-9 and MMP-2 but not MT1-MMP staining scores in tumor epithelial cells in the transition from histologic Grade I to Grades 2 and 3. Matrix metalloproteinase-9 and MT1-MMP staining scores in tumor cells were significantly associated with the presence of myometrial invasion and vascular/lymphatic invasion, while MMP-2 did not correlate with these factors. In addition, MT1-MMP was colocalized with MMP-2, supporting its role in the activation of proMMP-2. Tumor cells from all histologic grades stained intensely for TIMP-2 and TIMP-3 proteins, while variable stromal staining was observed. In Grade 1 carcinomas TIMP-1 was predominantly immunolocalized to the stromal compartment with variable tumor cell localization being observed in Grades 2 and 3 carcinomas. Matrix metalloproteinase-9 and MMP-2 mRNAs were predominantly observed in turner epithelial cells as well as in the stroma to varying degrees. In situ zymography revealed active forms of gelatinases at the cellular surface and in association with tumor epithelial cells within endometrial carcinoma tissues.CONCLUSIONS. These data Suggest that increasing expression of MMPs and endometrial carcinoma progression are closely related. Active gelatinases are present in endometrial carcinoma, resulting in alterations to the microenvironment that promote tumor invasion and metastasis. (C) 2002 American Cancer Society.