Large intestine embryogenesis: Molecular pathways and related disorders (Review)

Abstract

The large intestine, part of the gastrointestinal tract (GI), is composed of all three germ layers, namely the endoderm, the mesoderm and the ectoderm, forming the epithelium, the smooth muscle layers and the enteric nervous system, respectively. Since gastrulation, these layers develop simultaneously during embryogenesis, signaling to each other continuously until adult age. Two invaginations, the anterior intestinal portal (AIP) and the caudal/posterior intestinal portal (cIP), elongate and fuse, creating the primitive gut tube, which is then patterned along the antero-posterior (AP) axis and the radial (RAd) axis in the context of left-right (LR) asymmetry. These events lead to the formation of three distinct regions, the foregut, midgut and hindgut. All the above-mentioned phenomena are under strict control from various molecular pathways, which are critical for the normal intestinal development and function. Specifically, the intestinal epithelium constitutes a constantly developing tissue, deriving from the progenitor stem cells at the bottom of the intestinal crypt. Epithelial differentiation strongly depends on the crosstalk with the adjacent mesoderm. Major molecular pathways that are implicated in the embryogenesis of the large intestine include the canonical and non-canonical wingless-related integration site (Wnt), bone morphogenetic protein (BMP), Notch and hedgehog systems. The aberrant regulation of these pathways inevitably leads to several intestinal malformation syndromes, such as atresia, stenosis, or agangliosis. Novel theories, involving the regulation and homeostasis of intestinal stem cells, suggest an embryological basis for the pathogenesis of colorectal cancer (cRc). Thus, the present review article summarizes the diverse roles of these molecular factors in intestinal embryogenesis and related disorders.

The Role of IL-37 and IL-38 in Colorectal Cancer

“…Moreover, the right colon is derived from the midgut, while the left side is derived from the hindgut during embryonic development (46). Consequently, there are substantial differences in biological markers, genes and prognosis between left-and right-sided CRC (47).…”

“…As stated above, there are physiological and anatomic differences between the right and left sides of the colon (46), arising from embryonic development, which contributes to different clinical symptoms for left-and right-sided CRC patients, resulting in a later diagnosis of right-sided colon cancers (47). Colonic IL-38 expression has been shown to be nearly half the level in right-sided CRC compared to that of the left side (55).…”

Intertwined leukocyte balances in tumours and peripheral blood as robust predictors of right and left colorectal cancer survival

“…the right colon (comprising caecum, ascending colon, and proximal two-thirds of the transverse colon), derives from the embryonic midgut; whereas the left colon (comprising the distal third part of the transverse colon and descending and sigmoid colon) derives from the embryonic hindgut[ 21 ]. Distinct embryologic origin of right and left sides of the colon markedly determines important physiological differences, mainly: cell motility, vasculature, lymphatic drainage, extrinsic innervation, development of the endocrine components, and the expression and patterns of epigenetic marks of crucial molecular factors for cell development[ 21 , 22 ].…”

“…Since seminal contributions by Bufill et al [ 23 ], an increasing number of studies have supported the hypothesis that these differences in origin may explain why RCRC and LCRC constitute two distinct clinical entities, which arise through different pathogenetic mechanisms[ 22 , 24 , 25 ]. Thus, differential aspects such as incidence, presentation, microbiome composition, genetic burden, or immunogenicity could be explained on these grounds[ 26 - 31 ].…”

Infection with a hypervirulent strain of Helicobacter pylori primes gastric cells toward intestinal transdifferentiation

“…Both the stomach and the intestine originate from the same endodermal lineage in the early embryo 10 , and their fate is decided by a gradient of induction factors and speci c gene signatures for each tissue 11 . Normally, "master control genes" encoding transcription factors, control this development rather than a multitude of genes 12 . During gastric-to-intestinal transdifferentiation, a major alteration in gene expression, especially of tissuespeci c transcription factors, result in switching off one set of downstream genes and switching on another 13 .…”