Intestinal Tumorigenesis Initiated by Dedifferentiation and Acquisition of Stem-Cell-like Properties

被引:825
作者
Schwitalla, Sarah [1 ]
Fingerle, Alexander A. [2 ]
Cammareri, Patrizia [5 ]
Nebelsiek, Tim [1 ]
Goektuna, Serkan I. [1 ]
Ziegler, Paul K. [1 ]
Canli, Ozge [1 ]
Heijmans, Jarom [6 ]
Huels, David J. [5 ]
Moreaux, Guenievre [5 ]
Rupec, Rudolf A. [7 ]
Gerhard, Markus [3 ]
Schmid, Roland [4 ]
Barker, Nick [9 ]
Clevers, Hans [10 ,11 ]
Lang, Roland [12 ]
Neumann, Jens [8 ]
Kirchner, Thomas [8 ]
Taketo, Makoto M. [13 ]
van den Brink, Gijs R. [6 ]
Sansom, Owen J. [5 ]
Arkan, Melek C. [1 ]
Greten, Florian R. [1 ]
机构
[1] Tech Univ Munich, Klinikum Rechts Isar, Inst Mol Immunol, D-81675 Munich, Germany
[2] Tech Univ Munich, Klinikum Rechts Isar, Dept Radiol, D-81675 Munich, Germany
[3] Tech Univ Munich, Inst Med Microbiol Immunol & Hyg, D-81675 Munich, Germany
[4] Tech Univ Munich, Klinikum Rechts Isar, Dept Med 2, D-81675 Munich, Germany
[5] Beatson Inst Canc Res, Glasgow G61 1BD, Lanark, Scotland
[6] Acad Med Ctr, Tytgat Inst Liver & Intestinal Res, NL-1105 BK Amsterdam, Netherlands
[7] Univ Munich, Dept Dermatol & Allergol, D-80337 Munich, Germany
[8] Univ Munich, Inst Pathol, D-80337 Munich, Germany
[9] Inst Med Biol, Singapore 138648, Singapore
[10] Hubrecht Inst Dev Biol & Stem Cell Res, NL-3584 CT Utrecht, Netherlands
[11] Univ Med Ctr Utrecht, NL-3584 CT Utrecht, Netherlands
[12] Univ Hosp Erlangen, Inst Clin Microbiol Immunol & Hyg, D-91054 Erlangen, Germany
[13] Kyoto Univ, Grad Sch Med, Dept Pharmacol, Kyoto 6068501, Japan
基金
欧洲研究理事会;
关键词
NF-KAPPA-B; BETA-CATENIN; PANCREATIC-CANCER; TUMOR PROGRESSION; MOUSE MODEL; IN-VIVO; INFLAMMATION; EXPRESSION; IKK; APC;
D O I
10.1016/j.cell.2012.12.012
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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-kappa B represents a key transcription factor within the inflammatory tumor microenvironment. However, NF-kappa 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-kappa B modulates Wnt signaling and show that IEC-specific ablation of RelA/p65 retards crypt stem cell expansion. In contrast, elevated NF-kappa 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.
引用
收藏
页码:25 / 38
页数:14
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