Mini-Review: Enteric glia of the tumor microenvironment: An affair of corruption

Abstract

The tumor microenvironment corresponds to a complex mixture of bioactive products released by local and recruited cells whose normal functions have been "corrupted" by cues originating from the tumor, mostly to favor cancer growth, dissemination and resistance to therapies. While the immune and the mesenchymal cellular components of the tumor microenvironment in colon cancer have been under intense scrutiny over the last two decades, the influence of the resident neural cells of the gut on colon carcinogenesis has only very recently begun to draw attention. The vast majority of the resident neural cells of the gastrointestinal tract belong to the enteric nervous system and correspond to enteric neurons and enteric glial cells, both of which have been understudied in the context of colon cancer development and progression. In this review, we especially discuss available evidence on enteric glia impact on colon carcinogenesis. To highlight "corrupted" functioning in enteric glial cells of the tumor microenvironment and its repercussion on tumorigenesis, we first review the main regulatory effects of enteric glial cells on the intestinal epithelium in homeostatic conditions and we next present current knowledge on enteric glia influence on colon tumorigenesis. We particularly examine how enteric glial cell heterogeneity and plasticity require further appreciation to better understand the distinct regulatory interactions enteric glial cell subtypes engage with the various cell types of the tumor, and to identify novel biological targets to block enteric glia pro-carcinogenic signaling.

Keywords: Cancer stem cell; Colon cancer; Enteric glial cell; Intestinal stem cell; Tumor microenvironment.

Figure 1.. Enteric glial network of the tumor front exhibits profound structural alterations.

Light-sheet microscopy imaging of full thickness human colonic wall at distance (>10 cm) from tumor (healthy) or at the tumor front stained against the enteric glial cell marker S-100β (white) and the epithelial cell marker EpCAM (green) using the iDISCO+ method. Tumor shown is a stage II colon adenocarcinoma.

Figure 2.. Putative heterogeneity and plasticity of enteric glial cells in the TME.

Schematic proposing that, in light of (1) the heterogeneity of enteric glia in homeostatic conditions and (2) the plasticity events triggered by tumor epithelial cell-derived IL-1 in enteric glia, different subtypes of enteric glial cells may subsist in the tumor microenvironment and may be differentially “corrupted” by the tumor, resulting in the existence of pro-tumorigenic (PGE2 producing; predominant) and anti-tumorigenic (marginal) enteric glial cell subpopulations in the tumor microenvironment (represented as red enteric glia and blue enteric glia, respectively). Some other enteric glial cell subpopulation(s) may not undergo any phenotypic changes in response to tumor-derived cues (purple enteric glia). Dotted rectangles indicate items for which there is no direct evidence available in the literature. The figure was created with BioRender.com.