Characterization of the interface between normal and transformed epithelial cells
Characterization of the interface between normal and transformed epithelial cells
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DOI：
10.1038/ncb1853
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发表时间：
2009-04-01
影响因子：
21.3
通讯作者：
Fujita, Yasuyuki
中科院分区：
文献类型：
--
作者：
Hogan, Catherine;Dupre-Crochet, Sophie;Fujita, Yasuyuki
在大多数癌症中，转化始于上皮细胞片层中的单个细胞(1-3)。然而，一旦发生初始转化，尚不清楚非转化（正常）细胞和转化细胞之间的界面会发生什么。使用在四环素诱导系统中表达组成型活性致癌 Ras (Ras(V12)) 的 Madin-Darby 犬肾 (MDCK) 上皮细胞，我们研究了正常细胞和转化细胞之间界面处出现的细胞过程。我们表明，两种独立的现象以非细胞自主的方式发生：当被正常细胞包围时，Ras（V12）细胞要么从单层顶部挤出，要么形成动态基底突起并侵入基底基质。当 Ras(V12) 细胞被其他 Ras(V12) 细胞包围时，既没有观察到顶端突出，也没有观察到基底突出形成。我们证明 Cdc42 和 ROCK（也称为 Rho 激酶）在这些过程中发挥着至关重要的作用。我们还证明 Ras(V12) 细胞周围正常细胞中 E-钙粘蛋白的敲低降低了顶端突出的频率，同时促进基底突出的形成和侵袭。这些结果表明，Ras(V12) 转化细胞能够识别正常细胞和转化细胞之间的差异，从而以细胞环境依赖性方式在顶部或底部留下上皮片。
In most cancers, transformation begins in a single cell in an epithelial cell sheet(1-3). However, it is not known what happens at the interface between non-transformed (normal) and transformed cells once the initial transformation has occurred. Using Madin-Darby canine kidney (MDCK) epithelial cells that express constitutively active, oncogenic Ras (Ras(V12)) in a tetracycline-inducible system, we investigated the cellular processes arising at the interface between normal and transformed cells. We show that two independent phenomena occur in a non-cell-autonomous manner: when surrounded by normal cells, Ras(V12) cells are either apically extruded from the monolayer, or form dynamic basal protrusions and invade the basal matrix. Neither apical extrusion nor basal protrusion formation is observed when Ras(V12) cells are surrounded by other Ras(V12) cells. We show that Cdc42 and ROCK (also known as Rho kinase) have vital roles in these processes. We also demonstrate that E-cadherin knockdown in normal cells surrounding Ras(V12) cells reduces the frequency of apical extrusion, while promoting basal protrusion formation and invasion. These results indicate that Ras(V12)-transformed cells are able to recognize differences between normal and transformed cells, and consequently leave epithelial sheets either apically or basally, in a cell-context-dependent manner.