Author/Authors :
Sarah Schwitalla، نويسنده , , Alexander A. Fingerle، نويسنده , , Patrizia Cammareri، نويسنده , , Tim Nebelsiek، نويسنده , , Serkan I. G?ktuna، نويسنده , , Paul K. Ziegler، نويسنده , , Ozge Canli، نويسنده , , Jarom Heijmans، نويسنده , , David J. Huels، نويسنده , , Guenievre Moreaux، نويسنده , , Rudolf A. Rupec، نويسنده , , Markus Gerhard، نويسنده , , Roland Schmid، نويسنده , , Nick Barker، نويسنده , , Hans Clevers، نويسنده , , Roland Lang، نويسنده , , Jens Neumann، نويسنده , , Thomas Kirchner، نويسنده , , Makoto M. Taketo، نويسنده , , Gijs R. van den Brink، نويسنده , , et al.، نويسنده ,
Abstract :
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.
