Tumor suppression by cell competition through regulation of the Hippo pathway
Tumor suppression by cell competition through regulation of the Hippo pathway
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DOI：
10.1073/pnas.1113882109
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发表时间：
2012-01-10
影响因子：
11.1
通讯作者：
Halder, Georg
中科院分区：
文献类型：
--
作者：
Chen, Chiao-Lin;Schroeder, Molly C.;Halder, Georg
体内平衡机制可以消除异常细胞，预防癌症等疾病。然而，这种监测的潜在机制却知之甚少。在这里，我们研究了肿瘤抑制基因Scrible(Scrib)突变的细胞克隆是如何从果蝇成像盘中消除的。当想象中的视盘中的所有细胞都是Scrib的突变细胞时，它们会过度激活河马通路效应器York kie(Yki)，从而推动视盘生长成巨大的肿瘤性肿块。值得注意的是，当椎间盘也含有正常细胞时，Scrib(-)细胞不会过度增殖，并最终通过JNK依赖的机制发生凋亡。然而，诱导凋亡并不能解释Scrib(-)细胞是如何防止过度增殖的。我们报道，Scrib-和野生型细胞之间的细胞竞争通过抑制Scrib(-)细胞中的yki活性来防止过度增殖。抑制yki的激活是通过细胞竞争消除Scrib(-)克隆的关键，实验中提高Scrib(-)细胞中的yki活性足以刺激其肿瘤生长。因此，细胞竞争通过调节Scrib(-)细胞中的Hippo途径而起到抑制肿瘤的作用。
Homeostatic mechanisms can eliminate abnormal cells to prevent diseases such as cancer. However, the underlying mechanisms of this surveillance are poorly understood. Here we investigated how clones of cells mutant for the neoplastic tumor suppressor gene scribble (scrib) are eliminated from Drosophila imaginal discs. When all cells in imaginal discs are mutant for scrib, they hyper-activate the Hippo pathway effector Yorkie (Yki), which drives growth of the discs into large neoplastic masses. Strikingly, when discs also contain normal cells, the scrib(-) cells do not overproliferate and eventually undergo apoptosis through JNK-dependent mechanisms. However, induction of apoptosis does not explain how scrib(-) cells are prevented from overproliferating. We report that cell competition between scrib- and wild-type cells prevents hyperproliferation by suppressing Yki activity in scrib(-) cells. Suppressing Yki activation is critical for scrib(-) clone elimination by cell competition, and experimental elevation of Yki activity in scrib(-) cells is sufficient to fuel their neoplastic growth. Thus, cell competition acts as a tumor-suppressing mechanism by regulating the Hippo pathway in scrib(-) cells.