Intestinal Tumorigenesis Initiated by Dedifferentiation and Acquisition of Stem-Cell-like Properties
Menée à l'aide d'un modèle murin, cette étude met en évidence un mécanisme par lequel l'activation d'une voie de signalisation inflammatoire dans le micro-environnement tumoral induit une dédifférenciation de cellules du côlon qui, ainsi, acquièrent des capacités de cellules souches cancéreuses
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-
κ
B represents a key transcription factor within the inflammatory tumor microenvironment. However, NF-
κ
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-
κ
B modulates Wnt signaling and show that IEC-specific ablation of RelA/p65 retards crypt stem cell expansion. In contrast, elevated NF-
κ
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. º Epithelial nonstem cells can be reprogrammed into tumor-initiating cells º Dedifferentiation depends on degree of Wnt signaling º Wnt signaling is enhanced by NF-
κ
B via the coactivator CBP º Differentiation of stem cells into nonstem cells is bidirectional Enhanced Wnt signaling causes postmitotic (nonstem) cells to dedifferentiate and reacquire stem cell characteristics, enabling the cells to initiate tumorigenesis. Reprogramming can thus occur in the context of carcinogenesis and may comprise an important mechanism for tumor initiation.