title: Intestinal tumorigenesis initiated by dedifferentiation and acquisition of stem-cell-like properties.
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.
authors.affiliation: Institute of Molecular Immunology, Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany.
authors.forename: Sarah
authors.initials: S
authors.lastname: Schwitalla
authors.forename: Alexander A
authors.initials: AA
authors.lastname: Fingerle
authors.forename: Patrizia
authors.initials: P
authors.lastname: Cammareri
authors.forename: Tim
authors.initials: T
authors.lastname: Nebelsiek
authors.forename: Serkan I
authors.initials: SI
authors.lastname: Göktuna
authors.forename: Paul K
authors.initials: PK
authors.lastname: Ziegler
authors.forename: Ozge
authors.initials: O
authors.lastname: Canli
authors.forename: Jarom
authors.initials: J
authors.lastname: Heijmans
authors.forename: David J
authors.initials: DJ
authors.lastname: Huels
authors.forename: Guenievre
authors.initials: G
authors.lastname: Moreaux
authors.forename: Rudolf A
authors.initials: RA
authors.lastname: Rupec
authors.forename: Markus
authors.initials: M
authors.lastname: Gerhard
authors.forename: Roland
authors.initials: R
authors.lastname: Schmid
authors.forename: Nick
authors.initials: N
authors.lastname: Barker
authors.forename: Hans
authors.initials: H
authors.lastname: Clevers
authors.forename: Roland
authors.initials: R
authors.lastname: Lang
authors.forename: Jens
authors.initials: J
authors.lastname: Neumann
authors.forename: Thomas
authors.initials: T
authors.lastname: Kirchner
authors.forename: Makoto M
authors.initials: MM
authors.lastname: Taketo
authors.forename: Gijs R
authors.initials: GR
authors.lastname: van den Brink
authors.forename: Owen J
authors.initials: OJ
authors.lastname: Sansom
authors.forename: Melek C
authors.initials: MC
authors.lastname: Arkan
authors.forename: Florian R
authors.initials: FR
authors.lastname: Greten
mesh_terms: D000818:Animals; D054337:Cell Dedifferentiation; D002471:Cell Transformation, Neoplastic; D003106:Colon / Q000473:pathology; D003110:Colonic Neoplasms / Q000473:pathology*; D004847:Epithelial Cells / Q000473:pathology; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000473:pathology*; D060449:Wnt Signaling Pathway
chemical_list: D016328:NF-kappa B