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Bcl-2 is a critical mediator of intestinal transformation

Author

Listed:
  • Maartje van der Heijden

    (Cancer Research UK, Cambridge Institute, University of Cambridge
    Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for Experimental Molecular Medicine (CEMM), Academic Medical Center)

  • 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
    Cancer Genomics Center, Center for Molecular Medicine)

  • 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
    Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for Experimental Molecular Medicine (CEMM), Academic Medical Center)

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.

Suggested Citation

  • 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 & Louis Ver, 2016. "Bcl-2 is a critical mediator of intestinal transformation," Nature Communications, Nature, vol. 7(1), pages 1-11, April.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms10916
    DOI: 10.1038/ncomms10916
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    Cited by:

    1. Arezo Torang & Aleksandar B. Kirov & Veerle Lammers & Kate Cameron & Valérie M. Wouters & Rene F. Jackstadt & Tamsin R. M. Lannagan & Joan H. Jong & Jan Koster & Owen Sansom & Jan Paul Medema, 2025. "Enterocyte-like differentiation defines metabolic gene signatures of CMS3 colorectal cancers and provides therapeutic vulnerability," Nature Communications, Nature, vol. 16(1), pages 1-16, December.

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