Regulation of the cancer cell motility by Racl GTPase: implications for metastasis of colon cancer

众所周知，癌细胞在生物学上具有异质性，转移能力是癌细胞最显著的异质性之一。最近的研究表明，癌细胞的运动性在肿瘤转移中起着核心作用，不同细胞之间的运动性有很大的不同。细胞迁移的最初步骤是主动膜过程的扩展，包括片状和丝状足细胞，主要发生在细胞前沿周围，细胞运动进行持续的随机行走。肌动蛋白细丝的组装驱动肿瘤细胞的运动。质膜下方致密的作用细丝网络的扩张提供了足够的力量来推动前沿。这些过程都是受调控的Rho家族GTP酶。Rho GTP酶的两个主要亚类-Rac和CDC42亚家族的基本信号特性在有核生物中高度保守，但它们在癌细胞中的作用方式尚不清楚。最近的证据表明，Rho激活在肝癌和前列腺癌细胞的迁移和侵袭中起着一定的作用。虽然在体外将Rac或CDC42 CDNA活性突变的细胞获得了较高的运动能力，但尚未发现任何肿瘤组织或细胞系存在类似的Rac或CDC42基因突变，因此对Rac和CDC42亚家族在癌细胞中的作用尚不清楚。在这里，我们报告了一些结肠癌细胞系保持高GTP结合，形成RAC活性RAC和高侵袭能力。有趣的是，诱导某些肝癌细胞高运动的Rho激活抑制了具有高活性Rac的结肠癌细胞的运动。另一个意想不到的发现是，在结肠癌细胞系中，CDC42的活性状态没有显著差异。这一发现表明，Rac和Rho而不是CDC42是调节结肠癌细胞运动的主要Rho家族GTP酶。

It is well accepted that cancer cells are biologically heterogeneous and metastatic capability is one of the most prominent heterogeneous property of cancer cells. Recent progress revealed that cancer cell motility, which is quite different from cell to cell, plays a central role in a tumor metastasis. Initial step of cell migration is extension of active membrane processes, including both lamellipodia and filopodia, which takes place primarily around cell front with cell locomotion taking on a persistent random walk. Assembly of actin filament drives the locomotion of tumor cells. Expansion of dense net work of action filaments underlying the plasma membrane provides sufficient force to push forward the leading edge. These processes are regulated Rho family GTPases. The basic signaling properties of two major subgroups of Rho GTPases-the Rac and Cdc42 sub families-are highlyconserved among alleukaryotes, but the means by which they act in cancer cell are not well understood. Recent evidence indicated that Rho activationplay some role in hepatoma and prostate cancer cell migration and invasion. Although cells transfected with active mutant Rac or Cdc42 CDNA in vitroacquired high motility, any cancer tissues or cell lines have not been found to have similar mutations in Rac or Cdc42 gene so that the roles of Racand Cdc42 sub families in cancer cells are not well understood. Here we report that some colon cancer cell lines maintains high GTP bound form Rac-active Rac-and high invasive ability. Interestingly Rho activation which induces high motility of some hepatoma inhibited motility of those colon cancer cells with high active Rac. Another unexpected finding was that there were no significant differences in Cdc42 active state in colon cancer celllines. This finding indicates that Rac as well as Rho not cdc42 are the major Rho family GTPases to regulate colon cancer cell motility.