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.

The N-Myc downstream-regulated gene (NDRG) family consists of four members (NDRG1, NDRG2, NDRG3, NDRG4) that are differentially expressed in various organs and function in important processes, like cell proliferation and differentiation. In the last couple of decades, interest in this family has risen due to its connection with several disorders of the nervous system including Charcot-Marie-Tooth disease and dementia, as well as nervous system cancers. By combining a literature review with in silico data analysis of publicly available datasets, such as the Mouse Brain Atlas, BrainSpan, the Genotype-Tissue Expression (GTEx) project, and Gene Expression Omnibus (GEO) datasets, this review summarizes the expression and functions of the NDRG family in the healthy and diseased nervous system. We here show that the NDRGs have a differential, relatively cell typespecific, expression pattern in the nervous system. Even though NDRGs share functionalities, like a role in vesicle trafficking, stress response, and neurite outgrowth, other functionalities seem to be unique to a specific member, e.g., the role of NDRG1 in myelination. Furthermore, mutations, phosphorylation, or changes in expression of NDRGs are related to nervous system diseases, including peripheral neuropathy and different forms of dementia. Moreover, NDRG1, NDRG2, and NDRG4 are all involved in cancers of the nervous system, such as glioma, neuroblastoma, or meningioma. All in all, our review elucidates that although the NDRGs belong to the same gene family and share some functional features, they should be considered unique in their expression patterns and functional importance for nervous system development and neuronal diseases.

The role of the nervous system as a contributor in the tumor microenvironment has been recognized in different cancer types, including colorectal cancer (CRC). The gastrointestinal tract is a highly innervated organ system, which is not only innervated by the autonomic nervous system, but also contains an extensive nervous system of its own; the enteric nervous system (ENS). The ENS is important for gut function and homeostasis by regulating processes such as fluid absorption, blood flow, and gut motility. Dysfunction of the ENS has been linked with multiple gastrointestinal diseases, such as Hirschsprung disease and inflammatory bowel disease, and even with neurodegenerative disorders. How the extrinsic and intrinsic innervation of the gut contributes to CRC is not fully understood, although a mutual relationship between cancer cells and nerves has been described. Nerves enhance cancer progression through the secretion of neurotransmitters and neuropeptides, and cancer cells are capable of stimulating nerve growth. This review summarizes and discusses the nervous system innervation of the gastrointestinal tract and how it can influence carcinogenesis, and vice versa. Lastly, the therapeutic potential of these novel insights is discussed.

Similar effects of the NDRGs on the key-hallmarks of cancer, could implicate analogous functions in other tissue/cancer types.

The N‐Myc Downstream‐Regulated Gene 4 ( NDRG4 ), a prominent biomarker for colorectal cancer (CRC), is specifically expressed by enteric neurons. Considering that nerves are important members of the tumor microenvironment, we here establish different Ndrg4 knockout ( Ndrg4 −/− ) CRC models and an indirect co‐culture of primary enteric nervous system (ENS) cells and intestinal organoids to identify whether the ENS, via NDRG4, affects intestinal tumorigenesis. Linking immunostainings and gastrointestinal motility (GI) assays, we show that the absence of Ndrg4 does not trigger any functional or morphological GI abnormalities. However, combining in vivo , in vitro , and quantitative proteomics data, we uncover that Ndrg4 knockdown is associated with enlarged intestinal adenoma development and that organoid growth is boosted by the Ndrg4 −/− ENS cell secretome, which is enriched for Nidogen‐1 (Nid1) and Fibulin‐2 (Fbln2). Moreover, NID1 and FBLN2 are expressed in enteric neurons, enhance migration capacities of CRC cells, and are enriched in human CRC secretomes. Hence, we provide evidence that the ENS, via loss of Ndrg4 , is involved in colorectal pathogenesis and that ENS‐derived Nidogen‐1 and Fibulin‐2 enhance colorectal carcinogenesis.