Stromal fibroblasts mediate extracellular matrix remodeling and invasion of scirrhous gastric carcinoma cells.
Stromal fibroblasts mediate extracellular matrix remodeling and invasion of scirrhous gastric carcinoma cells.
复制标题
DOI：
10.1371/journal.pone.0085485
复制
发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Sakai R
中科院分区：
文献类型：
--
作者：
Yamaguchi H;Yoshida N;Takanashi M;Ito Y;Fukami K;Yanagihara K;Yashiro M;Sakai R
scrnous胃癌（SGC）是所有胃癌中预后最差的一种，因其侵袭扩张迅速且经常在腹膜传播。由于间质成纤维细胞（SFs）在SGC病变和腹膜转移部位的增殖增加，SFs被认为支持该疾病的进展。然而，SGC细胞与SFs细胞间相互作用的生物学和分子基础以及病理作用在很大程度上仍不清楚。在这项研究中，我们研究了SFs在SGC细胞侵袭细胞外基质（ECM）中的作用。当SGC细胞与来自SGC组织的SFs在三维（3D） Matrigel上共培养时，它们被吸引在一起形成大的细胞聚集体，侵入Matrigel内部。延时成像显示这一过程与ECM的广泛收缩和重塑有关。免疫荧光和生化分析表明，SGC细胞通过SFs刺激肌球蛋白轻链磷酸化和肌动球蛋白介导的ECM机械重塑。通过使用该检测系统进行抑制剂文库筛选，我们发现了几种抑制SGC细胞和SFs之间合作形成侵袭性结构的抑制剂。其中，Src抑制剂达沙替尼在体外和体内均破坏SGC细胞与sf的相互作用，有效阻断SGC细胞的腹膜播散。这些结果表明，SFs介导SGC细胞对ECM的机械重塑，从而促进SGC的侵袭和腹膜播散。
Scirrhous gastric carcinoma (SGC) has the worst prognosis of all gastric cancers, owing to its rapid expansion by invasion and frequent peritoneal dissemination. Due to the increased proliferation of stromal fibroblasts (SFs) that occurs within SGC lesions and the peritoneal metastatic sites, SFs have been proposed to support the progression of this disease. However, the biological and molecular basis and the pathological role of the intercellular interaction between SGC cells and SFs remain largely unknown. In this study, we investigated the role of SFs in the invasion of the extracellular matrix (ECM) by SGC cells. When SGC cells were cocultured with SFs derived from SGC tissue on three-dimensional (3D) Matrigel, they were attracted together to form large cellular aggregates that invaded within the Matrigel. Time-lapse imaging revealed that this process was associated with extensive contraction and remodeling of the ECM. Immunofluorescence and biochemical analysis showed that SGC cells stimulate phosphorylation of myosin light chain and actomyosin-mediated mechanical remodeling of the ECM by SFs. By utilizing this assay system for inhibitor library screening, we have identified several inhibitors that potently suppress the cooperation between SGC cells and SFs to form the invasive structures. Among them, a Src inhibitor dasatinib impaired the interaction between SGC cells and SFs both in vitro and in vivo and effectively blocked peritoneal dissemination of SGC cells. These results indicate that SFs mediate mechanical remodeling of the ECM by SGC cells, thereby promoting invasion and peritoneal dissemination of SGC.
登录
查看更多内容
影响因子：
7.5
作者：
Calvo, Fernando;Sahai, Erik
通讯作者：
Sahai, Erik
DOI：
10.1038/nrm2786
发表时间：
2009-11
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
通讯作者：
--
影响因子：
5.7
作者：
Fuyuhiro, Yuhiko;Yashiro, Masakazu;Hirakawa, Kosei
通讯作者：
Hirakawa, Kosei
影响因子：
21.3
作者：
通讯作者：
--
影响因子：
5.7
作者：
Yanagihara, K;Takigahira, M;Hirohashi, S
通讯作者：
Hirohashi, S