Institute of Molecular Immunology, Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany.
Cell. 2013 Jan 17;152(1-2):25-38. doi: 10.1016/j.cell.2012.12.012. Epub 2012 Dec 27.
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-κB represents a key transcription factor within the inflammatory tumor microenvironment. However, NF-κB'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-κB modulates Wnt signaling and show that IEC-specific ablation of RelA/p65 retards crypt stem cell expansion. In contrast, elevated NF-κB 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.
肿瘤内的细胞类型可塑性最近被认为是由炎症基质引发的，导致肿瘤起始干细胞和非干细胞之间的双向转化。NF-κB 是炎症肿瘤微环境中的关键转录因子。然而，NF-κB 在肿瘤起始细胞中的功能尚未被检测到。我们使用一种肠道上皮细胞 (IEC) 中组成性 Wnt 激活的遗传模型，该模型包含结肠癌起始的最常见事件，证明 NF-κB 调节 Wnt 信号，并表明 IEC 特异性删除 RelA/p65 会延迟隐窝干细胞的扩增。相反，升高的 NF-κB 信号增强了 Wnt 的激活，并诱导获得肿瘤起始能力的非干细胞去分化。因此，我们的数据支持双向转化的概念，并强调炎症信号对于体内去分化和产生肿瘤起始细胞的重要性。
