Involvement of Rac and Rho signaling in cancer cell motility in 3D substrates
Involvement of Rac and Rho signaling in cancer cell motility in 3D substrates
复制标题
DOI：
10.1038/onc.2009.2
复制
发表时间：
2009-04-01
期刊：
影响因子：
8
通讯作者：
Takenawa, T.
中科院分区：
文献类型：
--
作者：
Yamazaki, D.;Kurisu, S.;Takenawa, T.
3D 矩阵中癌细胞的运动有两种类型：间质运动（细胞拉长）和变形虫运动（细胞圆形）。变形虫运动由基于肌动球蛋白的收缩力驱动，该收缩力受 Rho/ROCK 通路调节。然而，细长细胞运动的分子机制仍然未知。在这里，我们发现拉长细胞的运动受到 Rac 信号传导的调节，通过 WAVE2/Arp2/3 依赖的拉长伪足的形成和 3D 基质中的细胞-基质粘附。在 3D 基质中表现出细长形态的细胞系中，Rac 信号传导对细胞运动的参与是不同的。在 U87MG 胶质母细胞瘤细胞中，大多数表现出间充质运动性，抑制 Rac 信号传导可阻止这些细胞对 3D 基质的侵袭。在 HT1080 纤维肉瘤细胞中，显示出涉及细长细胞和圆形细胞的混合细胞运动，抑制 Rac1 信号传导不仅阻断间充质运动，而且引起间充质-变形虫转变。此外，Rac1 和 RhoA 信号分别调节这些细胞中的间充质和阿米巴运动，抑制这两种途径可显着减少细胞侵袭。因此，我们可以得出结论，Rac1 和 RhoA 信号同时调节 3D 矩阵中的细胞侵袭。
The motility of cancer cells in 3D matrices is of two types: mesenchymal motility, in which the cells are elongated and amoeboid motility, in which the cells are round. Amoeboid motility is driven by an actomyosin-based contractile force, which is regulated by the Rho/ROCK pathway. However, the molecular mechanisms underlying the motility of elongated cells remain unknown. Here, we show that the motility of elongated cells is regulated by Rac signaling through the WAVE2/Arp2/3-dependent formation of elongated pseudopodia and cell-substrate adhesion in 3D substrates. The involvement of Rac signaling in cell motility was different in cell lines that displayed an elongated morphology in 3D substrates. In U87MG glioblastoma cells, most of which exhibit mesenchymal motility, inhibition of Rac signaling blocked the invasion of these cells in 3D substrates. In HT1080 fibrosarcoma cells, which display mixed cell motility involving both elongated and rounded cells, inhibition of Rac1 signaling not only blocked mesenchymal motility but also caused a mesenchymal-amoeboid transition. Additionally, Rac1 and RhoA signaling regulated the mesenchymal and amoeboid motility in these cells, respectively, and the inhibition of both pathways dramatically decreased cell invasion. Hence, we could conclude that Rac1 and RhoA signaling simultaneously regulate cell invasion in 3D matrices.