Bcl-2 is a critical mediator of intestinal transformation

Maartje van der Heijden, Cheryl D. Zimberlin, Anna M. Nicholson, Selcuk Colak, Richard Kemp, Sybren L. Meijer, Jan Paul Medema, Florian R. Greten, Marnix Jansen, Douglas J. Winton and Louis Vermeulen ()
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Maartje van der Heijden: Cancer Research UK, Cambridge Institute, University of Cambridge
Cheryl D. Zimberlin: Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for Experimental Molecular Medicine (CEMM), Academic Medical Center
Anna M. Nicholson: Cancer Research UK, Cambridge Institute, University of Cambridge
Selcuk Colak: Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for Experimental Molecular Medicine (CEMM), Academic Medical Center
Richard Kemp: Cancer Research UK, Cambridge Institute, University of Cambridge
Sybren L. Meijer: Academic Medical Center
Jan Paul Medema: Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for Experimental Molecular Medicine (CEMM), Academic Medical Center
Florian R. Greten: Institute for Tumor Biology and Experimental Therapy, Georg-Speyer-Haus
Marnix Jansen: Barts Cancer Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London
Douglas J. Winton: Cancer Research UK, Cambridge Institute, University of Cambridge
Louis Vermeulen: Cancer Research UK, Cambridge Institute, University of Cambridge

Nature Communications, 2016, vol. 7, issue 1, 1-11

Abstract: Abstract Intestinal tumour formation is generally thought to occur following mutational events in the stem cell pool. However, active NF-κB signalling additionally facilitates malignant transformation of differentiated cells. We hypothesized that genes shared between NF-κB and intestinal stem cell (ISCs) signatures might identify common pathways that are required for malignant growth. Here, we find that the NF-κB target Bcl-2, an anti-apoptotic gene, is specifically expressed in ISCs in both mice and humans. Bcl-2 is dispensable in homeostasis and, although involved in protecting ISCs from radiation-induced damage, it is non-essential in tissue regeneration. Bcl-2 is upregulated in adenomas, and its loss or inhibition impairs outgrowth of oncogenic clones, because Bcl-2 alleviates apoptotic priming in epithelial cells following Apc loss. Furthermore, Bcl-2 expression in differentiated epithelial cells renders these cells amenable to clonogenic outgrowth. Collectively, our results indicate that Bcl-2 is required for efficient intestinal transformation following Apc-loss and constitutes a potential chemoprevention target.

Date: 2016
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DOI: 10.1038/ncomms10916

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