2. Academic Validation
  3. Bcl-2 is a critical mediator of intestinal transformation

Bcl-2 is a critical mediator of intestinal transformation

  • Nat Commun. 2016 Mar 9;7:10916. doi: 10.1038/ncomms10916.
Maartje van der Heijden 1 2,  Cheryl D Zimberlin 2,  Anna M Nicholson 1,  Selcuk Colak 2,  Richard Kemp 1,  Sybren L Meijer 3,  Jan Paul Medema 2 4,  Florian R Greten 5,  Marnix Jansen 6,  Douglas J Winton 1,  Louis Vermeulen 1 2
Affiliations

Affiliations

  • 1 Cancer Research UK, Cambridge Institute, University of Cambridge, Robinson Way, Cambridge CB2 0RE, UK.
  • 2 Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for Experimental Molecular Medicine (CEMM), Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.
  • 3 Department of Pathology, Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.
  • 4 Cancer Genomics Center, Center for Molecular Medicine, HP Stratenum 3.217, Universiteitsweg 100, 3584 CG Utrecht, The Netherlands.
  • 5 Institute for Tumor Biology and Experimental Therapy, Georg-Speyer-Haus, Paul-Ehrlich-Straße 42-44, 60596 Frankfurt, Germany.
  • 6 Barts Cancer Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK.
PMID: 26956214 DOI: 10.1038/ncomms10916
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.

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