Editors' ChoiceCancer

Microbes make the cancer

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Science Translational Medicine  04 May 2016:
Vol. 8, Issue 337, pp. 337ec71
DOI: 10.1126/scitranslmed.aaf7827

Colorectal cancer (CRC) is the third most common type of cancer worldwide. Although the overall death rate from CRC is declining in the United States, in part because of effective screening, there is still a need to identify therapeutic targets for the prevention of this cancer. There are well-described roles for genetics, diet, environment, and gastrointestinal inflammation in the pathogenesis of CRC. All of these factors also markedly alter gut microbiota composition and function, and recent evidence even suggested a role for gut microbiota and their metabolites in CRC.

In a recent study, Peuker et al. found that epithelial calcineurin-NFAT (nuclear factor of activated T cells), an immune-associated signaling pathway, promotes intestinal tumorigenesis. Using genetically modified mice and antibiotic treatment, the authors identified a role for gut microbiota in Toll-like receptor (TLR)–induced activation of the epithelial calcineurin pathway, which results in development of intestinal tumors. Although the authors found that calcineurin did not affect microbial community structure, they observed perturbation of microbial stratification, impaired barrier function, increased expression of TLRs, and an altered community structure of mucosa-adherent microbiota in intestinal tumors compared with healthy epithelium. To investigate the translational relevance of their findings, the researchers expanded their studies to humans and found that calcineurin is required for the growth of human CRC cells in vitro and that calcineurin-NFAT pathway activation is associated with reduced survival in individuals with CRC.

These findings expand our understanding of the molecular mechanisms linking changes in microbiota to epithelial pathways contributing to CRC. Interestingly, Fusobacterium nucleatum, a bacterium previously implicated in CRC pathogenesis, did not activate the calcineurin pathway, suggesting the presence of additional microbiota-mediated pathways in development of CRC. Development of new therapies targeting either epithelial pathways or microbial signaling identified in this study may be able to reduce the incidence and mortality of CRC. These data also help fuel an old debate about infectious origin of cancer—but perhaps instead of considering pathogenic agents in all cases, we need to consider alterations in preexisting microbial communities as a potential inciting event for tumorigenesis.

K. Peuker et al., Epithelial calcineurin controls microbiota-dependent intestinal tumor development. Nat. Med. 10.1038/nm.4072 (2016). [Abstract]

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