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Nat Med. 2016 May;22(5):506-15. doi: 10.1038/nm.4072. Epub 2016 Apr 4.

Epithelial calcineurin controls microbiota-dependent intestinal tumor development.

Author information

1
Department of Internal Medicine I, University Medical Center Schleswig-Holstein, Kiel, Germany.
2
Center for Regenerative Therapies, Technical University Dresden, Dresden, Germany.
3
Max Planck Institute for Evolutionary Biology, Plön, Germany.
4
Institute for Experimental Medicine, Christian-Albrechts University of Kiel, Kiel, Germany.
5
Department of General Pediatrics, University Medical Center Schleswig-Holstein, Kiel, Germany.
6
Department of Pediatrics, University Medical Center Dresden, Technical University Dresden, Dresden, Germany.
7
Institute for Laboratory Animal Science and Central Animal Facility, Hannover Medical School, Hannover, Germany.
8
Division of Gastroenterology, Addenbrooke Hospital, University of Cambridge, Cambridge, UK.
9
Department of Clinical Pathobiochemistry, Faculty of Medicine, Technical University Dresden, Dresden, Germany.
10
Institute of Clinical Chemistry and Laboratory Medicine, Faculty of Medicine, Technical University Dresden, Dresden, Germany.
11
Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, Amsterdam, the Netherlands.
12
Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, the Netherlands.
13
Department of General Surgery and Thoracic Surgery, University Hospital Schleswig-Holstein, Kiel, Germany.
14
San Raffaele University and Scientific Institute, Milan, Italy.
15
Institute of Pathology, University Medical Center Schleswig-Holstein, Kiel, Germany.
16
Department of Medicine I, University Medical Center Dresden, Technical University Dresden, Dresden, Germany.
17
Division of Gastroenterology, Hepatology and Endoscopy, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.

Abstract

Inflammation-associated pathways are active in intestinal epithelial cells (IECs) and contribute to the pathogenesis of colorectal cancer (CRC). Calcineurin, a phosphatase required for the activation of the nuclear factor of activated T cells (NFAT) family of transcription factors, shows increased expression in CRC. We therefore investigated the role of calcineurin in intestinal tumor development. We demonstrate that calcineurin and NFAT factors are constitutively expressed by primary IECs and selectively activated in intestinal tumors as a result of impaired stratification of the tumor-associated microbiota and toll-like receptor signaling. Epithelial calcineurin supports the survival and proliferation of cancer stem cells in an NFAT-dependent manner and promotes the development of intestinal tumors in mice. Moreover, somatic mutations that have been identified in human CRC are associated with constitutive activation of calcineurin, whereas nuclear translocation of NFAT is associated with increased death from CRC. These findings highlight an epithelial cell-intrinsic pathway that integrates signals derived from the commensal microbiota to promote intestinal tumor development.

Comment in

PMID:
27043494
PMCID:
PMC5570457
DOI:
10.1038/nm.4072
[Indexed for MEDLINE]
Free PMC Article

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