The role of enteric neurons in the development and progression of colorectal cancer

Abstract

The enteric nervous system (ENS) is the intrinsic neural network of the gastrointestinal tract, which is essential for regulating gut functions and intestinal homeostasis. The importance of the ENS is underscored by the existence of severe gastrointestinal diseases, such as Hirschsprung's disease and intestinal pseudo-obstruction, which arise when the ENS fails to develop normally or becomes dysregulated. Moreover, it is known that enteric neurons are involved in intestinal inflammation. However, the role of the ENS in colorectal cancer (CRC) carcinogenesis remains poorly understood, even though processes like perineural invasion and neoneurogenesis are important factors in CRC. Here we summarize how enteric neurons are affected during CRC and discuss the influence of enteric neurons, either direct or indirect, on the development and/or progression of CRC. Finally, we illustrate how the ENS could be targeted as a potential anti-cancer therapy, establishing the ENS as an integral part of the tumor microenvironment.

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“…This could indicate derepression due to loss of polycomb/REST activity leading to misregulation of neuronal genes in the tumor. Alternatively, it may indicate involvement of neuronal phenotype in these tissues 69 .…”

A combined literature and in silico analysis enlightens the role of the NDRG family in the gut

“…While it is well-known that the ENS is pivotal to maintain gut homeostasis, there is little evidence linking the ENS with CRC. In our recent review by Rademakers et al we summarized the preliminary evidence linking the ENS with CRC and hypothesized that enteric neurons communicate with the intestinal epithelium via the production and secretion of neurotrophic factors through vesicle transport [97]. Interestingly, NDRG4 has been shown to regulate some important SNARE-proteins of the vesicle trafficking machinery as (i) its interaction with BVES regulates docking and cargo delivery of VAMP-3 vesicles, and (ii) its knockdown is associated with a sharp reduction in the level of SNAP-25.…”