Differentiation imbalance in single oesophageal progenitor cells causes clonal immortalization and field change.
Differentiation imbalance in single oesophageal progenitor cells causes clonal immortalization and field change.
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DOI：
10.1038/ncb2963
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发表时间：
2014-06
影响因子：
21.3
通讯作者：
中科院分区：
文献类型：
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作者：
多种癌症可能起源于癌前上皮的克隆区域，这种现象称为“场变化”。然而，目前尚不清楚现场变化如何发展。在这里，我们使用谱系追踪来研究这个问题，以追踪分散的单个食管上皮祖细胞的行为，这些细胞表达抑制 Notch 信号通路的突变。 Notch 在鳞状癌中经常发生失活突变。定量分析表明，突变祖细胞中不存在产生两个分化子代的细胞分裂。结果，突变克隆不再因分化而丢失，并且在功能上变得永生。此外，突变细胞促进邻近野生型细胞的分化，然后这些细胞从组织中消失。这些效应导致克隆扩张，突变细胞最终取代整个上皮。此外，携带 p53 稳定突变的祖细胞中的 Notch 抑制会产生大的双突变上皮汇合区域。因此，场变化是个体祖细胞分化不平衡的结果。
Multiple cancers may arise from within a clonal region of preneoplastic epithelium, a phenomenon termed ‘field change’. However, it is not known how field change develops. Here we investigate this question using lineage tracing to track the behaviour of scattered single oesophageal epithelial progenitor cells expressing a mutation that inhibits the Notch signaling pathway. Notch is frequently subject to inactivating mutation in squamous cancers. Quantitative analysis reveals that cell divisions which produce two differentiated daughters are absent in mutant progenitors. As a result mutant clones are no longer lost by differentiation and become functionally immortal. In addition, mutant cells promote the differentiation of neighbouring wild type cells, which are then lost from the tissue. These effects lead to clonal expansion, with mutant cells eventually replacing the entire epithelium. Furthermore, Notch inhibition in progenitors carrying p53 stabilizing mutations creates large confluent regions of doubly mutant epithelium. Field change is thus a consequence of imbalanced differentiation in individual progenitor cells.
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影响因子：
50.3
作者：
Quante M;Bhagat G;Abrams JA;Marache F;Good P;Lee MD;Lee Y;Friedman R;Asfaha S;Dubeykovskaya Z;Mahmood U;Figueiredo JL;Kitajewski J;Shawber C;Lightdale CJ;Rustgi AK;Wang TC
通讯作者：
Wang TC
影响因子：
64.5
作者：
Hu B;Castillo E;Harewood L;Ostano P;Reymond A;Dummer R;Raffoul W;Hoetzenecker W;Hofbauer GF;Dotto GP
通讯作者：
Dotto GP
影响因子：
50.3
作者：
Demehri, Shadmehr;Turkoz, Ahu;Kopan, Raphael
通讯作者：
Kopan, Raphael
DOI：
10.1098/rsta.1933.0009
发表时间：
1933-03-01
影响因子：
--
作者：
Neyman, J
通讯作者：
Neyman, J
影响因子：
11.2
作者：
Proweller, Aaron;Lili Tu;Parmacek, Mchael S.
通讯作者：
Parmacek, Mchael S.