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  Wnt and BMP signals control intestinal adenoma cell fates

Farrall, A., Riemer, P., Leushacke, M., Sreekumar, A., Grimm, C., Hermann, B. G., et al. (2012). Wnt and BMP signals control intestinal adenoma cell fates. International Journal of Cancer, 131(10), 2242-2252. doi:10.1002/ijc.27500.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-000E-B335-4 Version Permalink: http://hdl.handle.net/11858/00-001M-0000-000E-B337-F
Genre: Journal Article

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 Creators:
Farrall, Alexandra1, Author              
Riemer, Pamela1, Author              
Leushacke, Marc1, Author              
Sreekumar, Amulya2, Author
Grimm, Christina3, Author              
Hermann, Bernhard G.1, Author              
Morkel, Markus1, Author              
Affiliations:
1Dept. of Developmental Genetics (Head: Bernhard G. Herrmann), Max Planck Institute for Molecular Genetics, Max Planck Society, Ihnestr. 73, 14195 Berlin, ou_1433548              
2Charité Universitätsmedizin Berlin, Laboratory of Molecular Tumor Pathology, Berlin, Germany, ou_persistent22              
3In vitro Ligand Screening (Zoltán Konthur), Dept. of Vertebrate Genomics (Head: Hans Lehrach), Max Planck Institute for Molecular Genetics, Max Planck Society, Ihnestr. 73, 14195 Berlin, ou_1479653              

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Free keywords: cancer stem cells; colon cancer; mouse models; ex vivo culture; clonogenicity
 Abstract: Cellular hierarchies and signals that govern stemness and differentiation of intestinal adenoma cells are not well defined. In this study, we used organotypic culture to investigate the impact of β-catenin and BMP signals in cells that form intestinal adenoma in the mouse. We found that activation of β-catenin signaling by loss of APC or transgenic induction of oncogenic mutant β-catenin (Ctnnb1mut) initiates the conversion of untransformed intestinal cells to tumor cells. These tumor cells display cancer stem cell (CSC) traits such as increased expression of the CSC markers Cd133 and Cd44, a high capacity for self-renewal and unlimited proliferative potential. Subsequent inactivation of transgenic Ctnnb1mut results in the reversion of tumor cells to normal intestinal stem cells, which immediately reinstall the cellular hierarchy of the normal intestinal epithelium. Our data demonstrate that oncogenic activation of β-catenin signaling initiates the early steps of intestinal cellular transformation in the absence of irreversible genetic or epigenetic changes. Interestingly, we found that tumor cells in culture and in adenoma produce BMP4, which counteracts CSC-like traits by initiating irreversible cellular differentiation and loss of self-renewal capacity. We conclude that the opposition of stemness-maintaining oncogenic β-catenin signals and autocrine differentiating BMP signals within the adenoma cell provides a rationale for the formation of cellular hierarchies in intestinal adenoma and may serve to limit adenoma growth.

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Language(s): eng - English
 Dates: 2012-03-282012-11-15
 Publication Status: Published in print
 Pages: -
 Publishing info: -
 Table of Contents: -
 Rev. Method: -
 Identifiers: DOI: 10.1002/ijc.27500
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Title: International Journal of Cancer
Source Genre: Journal
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Publ. Info: John Wiley & Sons, Inc.
Pages: - Volume / Issue: 131 (10) Sequence Number: - Start / End Page: 2242 - 2252 Identifier: ISSN: 0020-7136