摘要
肿瘤细胞向周边组织中的侵袭,是肿瘤细胞转移的初始步骤,也是一个高度受控和多因子参与的复杂过程。这一过程包括癌细胞的趋化性迁移、细胞膜的伸展活性的引导、细胞与胞外基质之间粘附的能力以及蛋白酶的水解作用。在此过程中整合素家族以及基质金属蛋白酶家族对肿瘤细胞的黏附与迁移均发挥着重要的作用。
基质金属蛋白酶(MMPs)能够调节肿瘤的微环境,而与普通组织相比,基质金属蛋白酶的表达和活化在几乎所有的人类癌症中都有所增长。基质金属蛋白酶-2(MMP-2)是肿瘤细胞迁移过程中的关键调节者,也调节着肿瘤细胞的行为。整合素涉及到癌症发展分类(从基底膜的穿透、间质组织的侵袭、进入到循环系统,到血流中与血小板和内皮细胞的相互作用、外渗以及转移灶的产生)中的多个阶段。对于肿瘤细胞在其常态环境内的过度增殖并向间质侵袭的过程的改变,它们必须将水解蛋白酶活化来“挖掘”基底膜以获得提高能动性的行为。这种转变需要伴随整合素的表达上的改变。这样,基质金属蛋白酶和整合素之间就存在着必然联系。在以往的报道中,整合素αvβ3在肿瘤细胞黏附过程中扮演着的关键的角色,并且通过促进MMP-2的活化进而调节肿瘤细胞的迁移过程。然而,过去的报道中却少有MMP-2在肿瘤细胞αvβ3活化和αvβ3介导的黏附和迁移过程中的影响。在本研究中,我们侧重于对肿瘤细胞侵袭性迁移的初始阶段中MMP-2与整合素αvβ3二者之间的表达的位置关系的分析,从不同的视角分析二者之间可能存在的另一种相互作用关系。
在本文的研究中,我们将肿瘤细胞接种于琼脂糖迁移模型中,并在该模型上进行了肿瘤细胞迁移过程中的观察,且利用该模型进行了肿瘤细胞定向迁移过程中的免疫荧光实验,以观察MMP-2与整合素αvβ3之间的时空关系。运用静止黏附实验、迁移和Transwell侵袭实验进一步研究肿瘤细胞黏附与迁移过程中,活化的MMP-2与整合素αvβ3之间的关系。我们发现,MMP-2能够先于整合素αvβ3定位于铺展过程中的肿瘤细胞的侵袭前缘。实验中,我们通过运用MMP-2抑制剂抑制了整合素αvβ3介导的肿瘤细胞的粘附和迁移。通过纤连蛋白分解实验,我们发现MMP-2将纤连蛋白裂解成多个小片段后,能够促进肿瘤细胞的粘附和迁移能力。这些结果揭示出,MMP-2可能通过对胞外基质的降解引导着整合素αvβ3的簇集,并指导着肿瘤细胞的迁移方向。
综合以上结论,我们对基质金属蛋白酶MMP-2对整合素αvβ3的调节机制做出了这样的推断：活化的MMP-2首先募集于肿瘤细胞的侵袭前缘,然后将纤连蛋白分解为若干较小的纤连蛋白产物。这些纤连蛋白片段进而促进了整合素αvβ3在分解后的纤连蛋白产物处的募集,从而促进肿瘤细胞的黏附和迁移能力。
The invasion of tumor cells in the surrounding tissue is the initial steps of tumor cell metastasis, also a complex process of highly controlled and multiple factors involved in. This process requires chemotactic migration of cancer cells, steered by protrusive activity of the cell membrane and its attachment to the extracellular matrix, and also protease hydrolysis. Integrin family, and matrix metalloproteinases family play an important role in the process of tumor cell adhesion and migration.
Matrix metalloproteinases (MMPs) can regulate the tumour microenvironment, and their expression and activation is increased in almost all human cancers compared with normal tissue. Matrix metalloproteinase-2(MMP-2) is a key regulator in the migration of tumor cells and regulates tumor cell behaviors. Integrins have been implicated in the various steps of cancer progression ranging from penetration of basement membranes, invasion of stromal tissues, entry into the circulation, to interactions with platelets and endothelial cells in the blood stream, extravasation, and outgrowth of metastatic lesions. For tumor cells to change from hyperproliferation within their normal environment towards invasive growth into the stromal compartment, they must activate proteolytic enzymes to digest basement membranes and acquire enhanced motile behavior.Integrin αvβ3has been reported to play a critical role in cell adhesion and to regulate the migration of tumor cells by promoting MMP-2activation. However, little is known about the effects of MMP-2on integrin αvβ3activity and integrin αvβ3mediated adhesion and migration of tumor cells.
In this study, tumor cells were seeded using an agarose drop model and/or subjected to in vitro immunofluorescence, adhesion, migration and invasion assays to investigate the relationship between active MMP-2and integrin αvβ3in the adhesion and migration of tumor cells. We found that MMP-2was localized at the invasive front of spreading cells before integrin αvβ3. Integrin αvβ3mediated adhesion and migration of tumor cells were inhibited by a MMP-2inhibitor. MMP-2cleaved fibronectin into small fragments, which promoted the adhesion and migration of tumor cells. The results shows that MMP-2cleaved fibronectin into small fragments to enhance αvβ3mediated adhesion and migration of tumor cells. These results indicate that MMP-2may guide the direction of tumor cell migration.
Based on the above conclusions, we propose the following mechanism for the initial steps of invasion based on tumor cell adhesion and migration. Active MMP-2is first recruited to the leading edge of invasive tumor cells and cleaves fibronectin into shorter fibronectin products. The fibronectin fragments promote avb3integrin recruitment to the area of cleaved fibronectin products to facilitate tumor cell adhesion and migration. Collectively, avb3integrin-mediated adhesion and migration of tumor cells is regulated, at least in part, by MMP-2via fibronectin cleavage.
引文
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