School of Biochemistry, University of Bristol, Bristol, BS8 1TD, UK.
Nat Cell Biol. 2010 Dec;12(12):1194-204. doi: 10.1038/ncb2122. Epub 2010 Nov 14.
Metastatic cancer cells typically fail to halt migration on contact with non-cancer cells. This invasiveness is in contrast to normal mesenchymal cells that retract on contact with another cell. Why cancer cells are defective in contact inhibition of locomotion is not understood. Here, we analyse the dynamics of prostate cancer cell lines co-cultured with fibroblasts, and demonstrate that a combinatorial code of Eph receptor activation dictates whether cell migration will be contact inhibited. The unimpeded migration of metastatic PC-3 cells towards fibroblasts is dependent on activation of EphB3 and EphB4 by ephrin-B2, which we show activates Cdc42 and cell migration. Knockdown of EphB3 and EphB4 restores contact inhibition of locomotion to PC-3 cells. Conversely, homotypic collisions between two cancer cells results in contact inhibition of locomotion, mediated by EphA-Rho-Rho kinase (ROCK) signalling. Thus, the migration of cancer cells can switch from restrained to invasive, depending on the Eph-receptor profile of the cancer cell and the reciprocal ephrin ligands expressed by neighbouring cells.
转移性癌细胞通常在与非癌细胞接触时无法停止迁移。这种侵袭性与正常间充质细胞形成鲜明对比，正常间充质细胞在与另一个细胞接触时会回缩。为什么癌细胞在接触抑制运动方面存在缺陷尚不清楚。在这里，我们分析了前列腺癌细胞系与成纤维细胞共培养的动力学，并证明 Eph 受体激活的组合密码决定了细胞迁移是否会受到接触抑制。转移性 PC-3 细胞不受阻碍地向成纤维细胞迁移依赖于 EphB3 和 EphB4 被 Ephrin-B2 激活，我们发现 Ephrin-B2 激活了 Cdc42 和细胞迁移。EphB3 和 EphB4 的敲低使 PC-3 细胞恢复了接触抑制运动。相反，两个癌细胞之间的同源性碰撞会导致运动受到抑制，这是由 EphA-Rho-Rho 激酶 (ROCK) 信号介导的。因此，癌细胞的迁移可以根据癌细胞的 Eph 受体谱和相邻细胞表达的相互 Ephrin 配体从受约束转变为侵袭性。
