Mouse fibroblasts lacking RB1 function form spheres and undergo reprogramming to a cancer stem cell phenotype.
Mouse fibroblasts lacking RB1 function form spheres and undergo reprogramming to a cancer stem cell phenotype.
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DOI：
10.1016/j.stem.2009.02.015
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发表时间：
2009-04-03
期刊：
影响因子：
23.9
通讯作者：
Dean DC
中科院分区：
文献类型：
--
作者：
Liu Y;Clem B;Zuba-Surma EK;El-Naggar S;Telang S;Jenson AB;Wang Y;Shao H;Ratajczak MZ;Chesney J;Dean DC
RB1通路的激活触发细胞周期阻滞，介导细胞-细胞接触抑制。因此，所有三个RB1家族成员的突变导致接触抑制的丧失和成纤维细胞生长成细胞-细胞接触为主的球体。我们提供的证据表明，这种生长触发重编程，以产生具有癌症干细胞特性的细胞。只有单个RB1突变的成纤维细胞保持接触抑制；然而，如果通过迫使RB1 - / -细胞在悬浮液中形成球体来绕过这种接触抑制，则也会产生具有癌症干细胞特性的细胞。这些细胞不仅能在裸鼠体内形成肿瘤，还能产生分化细胞。我们提出，RB1通路施加的接触抑制通过阻止细胞生长成具有癌症干细胞特性的细胞可以从晚期癌症的分化体细胞中产生的结构来实现意想不到的肿瘤抑制功能。
Activation of the RB1 pathway triggers the cell-cycle arrest that mediates cell-cell contact inhibition. Accordingly, mutation of all three RB1 family members leads to loss of contact inhibition and outgrowth of fibroblasts into spheres where cell-cell contacts predominate. We present evidence that such outgrowth triggers reprogramming to generate cells with properties of cancer stem cells. Fibroblasts with only a single RB1 mutation remain contact inhibited; however, if this contact inhibition is bypassed by forcing the RB1−/− cells to form spheres in suspension, cells with properties of cancer stem cells are also generated. These cells not only form tumors in nude mice but also generate differentiated cells. We propose that contact inhibition imposed by the RB1 pathway performs an unexpected tumor suppressor function by preventing cell outgrowth into structures where cells with properties of cancer stem cells can be generated from differentiated somatic cells in advancing cancers.
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