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

S Schwitalla, AA Fingerle, P Cammareri, T Nebelsiek… - Cell, 2013 - cell.com
S Schwitalla, AA Fingerle, P Cammareri, T Nebelsiek, SI Göktuna, PK Ziegler, O Canli
Cell, 2013cell.com
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 …
Summary
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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