In an article published in the Nature Medicine, German researchers describe a novel epithelial pathway that integrates signals derived from the commensal microbiota to promote intestinal tumour development and that may be amenable to therapeutic targeting. Their findings demonstrate that epithelial calcineurin does not regulate intestinal tumour development through effects on the composition of the commensal microbiota but rather through control of the epithelial response to changes in microbial composition and stratification along the adenoma-carcinoma sequence.
Recent work documented alterations in the composition of the commensal microbiota associated with colorectal cancer (CRC) development, which were characterised by an increase in the abundance of bacteria that are known to promote tumour growth. Tumour-promoting alterations in microbial composition thereby act together with defects in epithelial barrier function and microbial stratification to enhance tumour growth in a manner dependent on signaling pathways in myeloid and epithelial cells.
Intestinal inflammation as observed in inflammatory bowel disease is a risk factor for the development of CRC. Increasing evidence suggests that inflammation-associated pathways also contribute to CRC development in the absence of clinically overt intestinal inflammation. Thus, signaling pathways with central roles in myeloid and lymphoid cells, such as those associated with STAT3 and NF-κB, are also active in the transformed intestinal epithelium and promote tumour development.
Calcineurin is a phosphatase with central functions in immunity, many of which are elicited by dephosphorylation and activation of the nuclear factor of activated T cells (NFAT) family of transcription factors. In this study, the researchers from the Department of Internal Medicine I, University Medical Center Schleswig-Holstein, Kiel, Germany investigated the role of calcineurin in intestinal tumour development.
They wrote in the Nature Medicine that according an important role of calcineurin in immunity, calcineurin inhibitors are widely used to suppress undesired immune responses, particularly in solid organ transplantation. The pharmacological inhibition of calcineurin therefore leads to an increase in the incidence of solid cancers including CRC. In contrast to these observations in vivo, the blockade of calcineurin and NFAT in isolated CRC cell lines in vitro inhibits, rather than promotes, CRC cell growth, thus raising the question of whether epithelial calcineurin and NFAT exhibit cell-intrinsic oncogenic roles in CRC.
The investigators showed that calcineurin and NFAT are constitutively expressed by intestinal epithelial cells (IECs) and undergo toll-like receptor (TLR)-induced activation in response to impaired stratification of the tumour-associated microbiota and increased TLR expression by tumour cells. Epithelial calcineurin promotes intestinal tumour development through the regulation of cancer stem cell function in mice, and its activation in human CRC is associated with increased death from CRC.
Using mice as a model of genetically driven intestinal tumour formation, they found bacterial translocation into intestinal adenomas, as well as an increase in the relative abundance of bacteria known to signal via TLR4 and Myd88. This suggests that defects in microbial stratification, as well as specific alterations in the composition of the commensal microbiota, contribute to the activation of oncogenic epithelial calcineurin. Notably, alterations in the tumour-associated microbiota were observed regardless of the IEC-specific deletion of calcineurin.
The study team demonstrated that calcineurin and NFAT factors are constitutively expressed by primary IECs and selectively activated in intestinal tumours as a result of impaired stratification of the tumour-associated microbiota and TLR signaling. Epithelial calcineurin supports the survival and proliferation of cancer stem cells in an NFAT-dependent manner and promotes the development of intestinal tumours 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 tumour development. The results support a role for microbial elements in the regulation of CRC and provide novel insight into the molecular pathways linking tumour-associated changes in the microbiota to oncogenic epithelial signaling.