Calpain 2 and Src dependence distinguishes mesenchymal and amoeboid modes of tumour cell invasion: a link to integrin function
Calpain 2 and Src dependence distinguishes mesenchymal and amoeboid modes of tumour cell invasion: a link to integrin function
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DOI：
10.1038/sj.onc.1209582
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发表时间：
2006-09-21
期刊：
影响因子：
8
通讯作者：
Frame, M. C.
中科院分区：
文献类型：
--
作者：
Carragher, N. O.;Walker, S. M.;Frame, M. C.
癌细胞可以通过不同的机制侵入三维基质，最近被定义为依赖于细胞外蛋白酶，包括基质金属蛋白酶。在用蛋白酶抑制剂治疗后，一些肿瘤细胞经历了“间充质向变形虫”的转变，在没有细胞周围蛋白水解和基质降解的情况下允许侵袭。我们在这里表明，在HT1080细胞中，这种转变与整合素依赖性粘附减弱、α 2 β 1整合素胶原受体的细胞表面表达持续降低以及下游信号传导受损有关，这可以通过局灶黏附激酶（FAK）的自磷酸化降低来判断。在研究使用明确的侵袭策略的癌细胞时，我们发现与间充质侵袭不同，变形虫侵袭不依赖于细胞内钙蛋白酶2蛋白水解活性，而钙蛋白酶2蛋白水解活性通常是在二维平面迁移过程中整合素连接的粘附转换所必需的。此外，一种Rho/ROCK信号传导抑制剂（特异性地损害变形虫样侵袭）可以恢复细胞表面α 2 β 1整合素的表达、下游FAK自磷酸化和钙蛋白酶2敏感性——这些都是间质侵袭的特征。这些发现将整合素功能减弱与变形虫侵袭过程中缺乏钙蛋白酶2介导的整合素粘附转换的需求联系起来。为了与整合素粘附转换的需要保持一致，间充质浸润对Src抑制剂非常敏感。因此，需要一个控制整合素粘附转换的主要途径来定义和区分癌细胞的入侵策略。
Cancer cells can invade three-dimensional matrices by distinct mechanisms, recently defined by their dependence on extracellular proteases, including matrix metalloproteinases. Upon treatment with protease inhibitors, some tumour cells undergo a 'mesenchymal to amoeboid' transition that allows invasion in the absence of pericellular proteolysis and matrix degradation. We show here that in HT1080 cells, this transition is associated with weakened integrin-dependent adhesion, consistently reduced cell surface expression of the alpha 2 beta 1 integrin collagen receptor and impaired signalling downstream, as judged by reduced autophosphorylation of focal adhesion kinase (FAK). On examining cancer cells that use defined invasion strategies, we show that distinct from mesenchymal invasion, amoeboid invasion is independent of intracellular calpain 2 proteolytic activity that is usually needed for turnover of integrin-linked adhesions during two-dimensional planar migration. Moreover, an inhibitor of Rho/ROCK signalling, which specifically impairs amoeboid-like invasion, restores cell surface expression of alpha 2 beta 1 integrin, downstream FAK autophosphorylation and calpain 2 sensitivity - features of mesenchymal invasion. These findings link weakened integrin function to a lack of requirement for calpain 2-mediated integrin adhesion turnover during amoeboid invasion. In keeping with the need for integrin adhesion turnover, mesenchymal invasion is uniquely sensitive to Src inhibitors. Thus, the need for a major pathway that controls integrin adhesion turnover defines and distinguishes cancer cell invasion strategies.