Intestinal Tumorigenesis Initiated by Dedifferentiation and Acquisition of Stem-Cell-like Properties
Intestinal Tumorigenesis Initiated by Dedifferentiation and Acquisition of Stem-Cell-like Properties
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DOI：
10.1016/j.cell.2012.12.012
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发表时间：
2013-01-17
期刊：
影响因子：
64.5
通讯作者：
Greten, Florian R.
中科院分区：
文献类型：
--
作者：
Schwitalla, Sarah;Fingerle, Alexander A.;Greten, Florian R.
肿瘤内的细胞型可塑性最近被认为是由炎性基质触发的肿瘤起始干细胞和非干细胞之间的双向转化。核因子-kappaB是炎症性肿瘤微环境中的关键转录因子。然而，核因子-kappaB在肿瘤启动细胞中的作用尚未被检测。利用肠上皮细胞(IEC)限制性的结构性Wnt激活的遗传模型，我们证明了NF-kappa B调节Wnt信号，并表明IEC特异性的RrelA/p65消融抑制了隐窝干细胞的扩张。相反，升高的核因子-kappaB信号增强了Wnt的激活，并诱导获得肿瘤启动能力的非干细胞的去分化。因此，我们的数据支持双向转化的概念，并强调了炎症信号对体内去分化和肿瘤启动细胞产生的重要性。
Cell-type plasticity within a tumor has recently been suggested to cause a bidirectional conversion between tumor-initiating stem cells and nonstem cells triggered by an inflammatory stroma. NF-kappa B represents a key transcription factor within the inflammatory tumor microenvironment. However, NF-kappa B's function in tumor-initiating cells has not been examined yet. Using a genetic model of intestinal epithelial cell (IEC)-restricted constitutive Wnt-activation, which comprises the most common event in the initiation of colon cancer, we demonstrate that NF-kappa B modulates Wnt signaling and show that IEC-specific ablation of RelA/p65 retards crypt stem cell expansion. In contrast, elevated NF-kappa B signaling enhances Wnt activation and induces dedifferentiation of nonstem cells that acquire tumor-initiating capacity. Thus, our data support the concept of bidirectional conversion and highlight the importance of inflammatory signaling for dedifferentiation and generation of tumor-initiating cells in vivo.