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Schlagwörter:
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Zusammenfassung:
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.
