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. 2013 Jan 17;152(1-2):25-38.
doi: 10.1016/j.cell.2012.12.012. Epub 2012 Dec 27.

Intestinal tumorigenesis initiated by dedifferentiation and acquisition of stem-cell-like properties

Sarah Schwitalla  1 , Alexander A Fingerle, Patrizia Cammareri, Tim Nebelsiek, Serkan I Göktuna, Paul K Ziegler, Ozge Canli, Jarom Heijmans, David J Huels, Guenievre Moreaux, Rudolf A Rupec, Markus Gerhard, Roland Schmid, Nick Barker, Hans Clevers, Roland Lang, Jens Neumann, Thomas Kirchner, Makoto M Taketo, Gijs R van den Brink, Owen J Sansom, Melek C Arkan, Florian R Greten
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Free article

Intestinal tumorigenesis initiated by dedifferentiation and acquisition of stem-cell-like properties

Sarah Schwitalla et al. Cell. .
Free article

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.

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