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

S. Schwitalla, A.A. Fingerle, P. Cammareri, T. Nebelsiek, S.I. Goktuna, P.K. Ziegler, O. Canli, J. Heijmans, D.J. Huels, G. Moreaux, R.A. Rupec, M. Gerhard, R. Schmid, N. Barker, H. Clevers, R. Lang, J. Neumann, T. Kirchner, M.M. Taketo, G.R. van den BrinkO.J. Sansom, M.C. Arkan, F.R. Greten

Research output: Contribution to journal/periodicalArticleScientificpeer-review

830 Citations (Scopus)

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-kappaB represents a key transcription factor within the inflammatory tumor microenvironment. However, NF-kappaB'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-kappaB modulates Wnt signaling and show that IEC-specific ablation of RelA/p65 retards crypt stem cell expansion. In contrast, elevated NF-kappaB 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.
Original languageEnglish
Pages (from-to)25-38
JournalCell
Volume152
Issue number1-2
DOIs
Publication statusPublished - 2013

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