Transmigration of human ovarian adenocarcinoma cells through endothelial extracellular matrix involves αv integrins and the participation of MMP2
Transmigration of human ovarian adenocarcinoma cells through endothelial extracellular matrix involves αv integrins and the participation of MMP2
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DOI：
10.1002/ijc.20778
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发表时间：
2005-04-20
影响因子：
6.4
通讯作者：
Carreiras, F
中科院分区：
文献类型：
--
作者：
Leroy-Dudal, J;Demeilliers, C;Carreiras, F
卵巢癌的生长依赖于其血管形成，但卵巢癌细胞与内皮的相互作用及其通过内皮环境的侵袭在分子水平上仍然知之甚少。为了研究这一过程背后的粘附事件，重点研究了α - v整合素和MT1MMP-MMP2蛋白酶的作用，我们使用了人卵巢腺癌细胞系（IGROV1和SKOV3）与人脐静脉内皮细胞（HUVECs）共培养的体外模型。HUVECs免疫染色显示纤维纤维连接蛋白（Fn）和细胞外玻璃体连接蛋白（Vn）的网络组织。在共培养过程中，IGROV1和SKOV3细胞可以进入HUVECs的内皮基底膜，并在不影响内皮细胞Vn的情况下使内皮细胞Fn脱位。迁移实验显示肿瘤细胞侵入Vn，并以更高的效率侵入Fn。我们的数据还强调了卵巢癌细胞通过富fn的HUVEC-ECM迁移。MMP2和MT1-MMP在内皮环境下的肿瘤细胞中表达。此外，我们发现细胞通过内皮细胞外基质的迁移几乎完全依赖于α - v整合素的功能，而β - a1整合素则不需要。此外，发现MMP2活性抑制剂（单独使用或与抗α - v整合素单抗联合使用）或TSRI265（阻断MMP2- α - β 3结合）可阻碍这一过程。最后，在移植IGROV1或SKOV3细胞系的裸鼠腹腔肿瘤淋巴结的三维结构内或人肿瘤组织内的卵巢癌细胞中发现了alphav整合素、MT1-MMP和MMP2。因此，α - v整合素似乎对人卵巢癌细胞的迁移特性至关重要，特别是在内皮环境中，MMP2参与了这一过程。(C) 2004 Wiley-Liss, Inc。
The growth of ovarian carcinoma is dependent upon their vascularistion, but the interaction of ovarian cancer cells with the endothelium and their invasion through an endothelial environment remain poorly understood at the molecular level. To investigate adhesive events underlying this process with focusing on the role of alphav integrins and MT1MMP-MMP2 proteinases, we used in vitro models of cocultures of human ovarian adenocarcinoma cell lines (IGROV1 and SKOV3) with human umbilical vein endothelial cells (HUVECs). Immunostaining of HUVECs revealed the network organisation of fibrillar fibronectin (Fn) and pericellular vitronectin (Vn). During coculture, IGROV1 and SKOV3 cells gain access to subendothelial basement membrane of HUVECs and dislocated endothelial Fn without affecting endothelial Vn. Transmigration assays revealed that tumour cells invade Vn and, with an higher efficiency, Fn. Our data also highlighted that ovarian carcinoma cells migrated through the Fn-rich HUVEC-ECM. The expression of MMP2 and MT1-MMP was revealed in tumour cells within an endothelial environment. Furthermore, we found that cell migration through the endothelial ECM was almost totally dependent on alphav integrin function, whereas beta1 integrins were not solicited. In addition, inhibitors of MMP2 activity (alone or combined with anti-alphav integrin MAb) or TSRI265 (which blocks MMP2-alphavbeta3 association) were found to impede this process. Finally, alphav integrins, MT1-MMP and MMP2 were found in ovarian carcinoma cells within the 3-dimensional architecture of intraperitoneal tumour nodes collected from nude mice xenografted with IGROV1 or SKOV3 cell lines or within human tumour tissues. alphav integrins therefore appear as essential to the migration properties of human ovarian carcinoma cells, especially in an endothelial environment, with MMP2 participating to this process. (C) 2004 Wiley-Liss, Inc.