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Analysis of mechanisms involved in cohort migration of human colon carcinoma cells

人结肠癌细胞群体迁移机制分析

基本信息

批准号：
10670212
负责人：
NABESHIMA Kazuki
金额：
$ 1.34万
依托单位：
Miyazaki Medical College
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1998
资助国家：
日本
起止时间：
1998 至 1999
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10670212/
关键词：
cancer invasion migration HGF SF small G protein E-cadherin catenin complex MMP fibronectin E∞cadherin cell-cell contact TGF-β1

项目摘要

(I) Mechanisms of localized release from cell-cell adhesion during cohort migrationDuring cohort migration (CM) induced by hepatocyte growth factor/scatter factor (HGF/SF), migrating cells show localized release from cell-cell adhesion in the lower portion of the cells. This enables cells to extend leading edges and hence move. This localized release was associated with binding of IQGAP-1 to the E-cadherin/catenin complex. This caused release of α-catenin, which connects E-cadherin to actin filament cell skeleton, from the complex. This mechanism is now under investigation more in detail using dominant active/negative Rac 1 or cdc42-transfected cells.(ii) Enhanced induction of cohort migration of carcinoma cells in the co-presence of fibroblastsWe made in vitro CM assays which are more similar to the in vivo situation by coculturing carcinoma cells with fibroblasts. Coexistence of fibroblasts enhanced HGF/SF-induced CM of carcinoma cells. In the coculture, carcinoma cells stimulated secretion of TGF-β1 by fibroblasts, and the increased TGF-β1 induced more production of motility-stimulating EDA-containing fibronectin by cells. Thus, cell-cell interaction is shown to play an important role in CM..(iii) Front-cell-specific expression of matrix metalloproteinases (MMP) during cohort migrationDuring HGF/SF-induced CM, gelatinase A (GelA) and membrane type-1 matrix metalloproteinase (MT1-MMP) were positively demonstrated predominantly in front cells of the migrating sheets, with the following cells being negative. These MMPs caused rearrangement of gelatin matrix, which was essential for CM. Since the above front-cell-specific expression pattern of MMPs was effaced when scattering (single cell locomotion) of cells was induced instead of CM, cell-cell contact in migrating cell sheets appeared responsive for the pattern.

在肝细胞生长因子/散布因子(HGF/SF)诱导的队列迁移(CM)过程中，迁移细胞在细胞的下部表现为局部的细胞间黏附释放。这使单元格能够延伸前沿，从而移动。这种局部释放与IQGAP-1与E-钙粘蛋白/连环蛋白复合体的结合有关。这导致连接E-钙粘附素和肌动蛋白细丝细胞骨架的α-连环蛋白从复合体中释放出来。这一机制目前正在利用显性活性/阴性Rac 1或Cdc42转基因细胞进行更详细的研究。(Ii)在成纤维细胞共同存在的情况下，增强癌细胞的队列迁移诱导。我们通过将癌细胞与成纤维细胞共培养，进行了更接近体内情况的体外CM检测。成纤维细胞共存增强HGF/SF诱导的癌细胞CM。在共培养中，癌细胞刺激成纤维细胞分泌转化生长因子-β-1，且转化生长因子-β-1的增加诱导细胞产生更多的运动性刺激性EDA-纤维连接蛋白。在HGF/SF诱导的CM过程中，明胶酶A(Gela)和膜型基质金属蛋白酶-1(MT1-MMPs)主要呈阳性表达，后面的细胞呈阴性表达。这些MMPs可引起CM所必需的明胶基质的重排。由于当诱导细胞分散(单细胞运动)而不是CM时，上述MMPs的前端细胞特异性表达模式被消除，迁移细胞膜中的细胞-细胞接触似乎对该模式做出了响应。