Expression of Cdx2 in Early GRCL of Barrett?s Esophagus Induced in Rats by Duodenal Reflux

Abstract

The intestine-specific caudal-related homeobox transcription factor Cdx2 is widely accepted to play a key role in intestinal development and differentiation in mammals. We studied the role of Cdx2 in the development of Barrett's esophagus (BE). In previous studies, we have shown a sequence of morphological changes of squamous epithelium leading to BE, found a peculiar metaplastic change common to other parts of gut, and proposed the concept of a "gut regenerative cell lineage" (GRCL). The GRCL is characterized by pyloric-foveolar metaplasia with goblet cell metaplasia, which occurs in the regenerative process in response to chronic inflammation. BE very likely develops through the GRCL, and we studied the expression of Cdx2 in various lesions of rat esophageal mucosa induced by duodenal reflux, using reverse transciptase-polymerase chain reaction and immunohistochemistry against Cdx2. We found that Cdx2 was expressed not only in specialized columnar epithelium (SCE) of BE, but also in several pyloric gland and foveolar metaplastic cells which developed in the basal layer of the squamous epithelium at an earlier stage of SCE development. These findings indicate that Cdx2 plays a crucial role in directing intestinal-type differentiation of the GRCL.

Interaction of Toll-like receptors with bacterial components induces expression of CDX2 and MUC2 in rat biliary epithelium in vivo and in culture

“…Among them, anti-CDX2 antibody against human tissue is reported to react with rat CDX2, 8,9 and our preliminary study also confirmed that this antibody reacted with the nuclei of cell of the small intestinal epithelium of PCK rats. Therefore, we used this antibody in this study using rat specimens.…”

“…2,4,5-8 CDX2-dependent intestinal metaplasia is noted in Barrett's esophagus with MUC2 expression, and bile acid and chronic acid exposure have been reported to induce CDX2 expression. 2,[4][5][6]8,9 Intestinal metaplasia is also involved in the pathogenesis of biliary diseases. For example, in chronic cholangitis such as hepatolithiasis, intestinal metaplasia with goblet cells occurs, and MUC2 is aberrantly expressed in goblet cells colocalized with CDX2.…”

Impact of Inflammation-Metaplasia-Adenocarcinoma Sequence and Prevention in Surgical Rat Models

“…This is an adaptive response to protect the epithelium, since metaplastic tissue is more resistant to change than natural tissue. Recent studies determined that the metaplastic changes are driven by increased expression of the homeobox genes related with intestinal development (Cdx2) [12]. These genes are activated by bile acids such as deoxycholic acid and cholic acids [13,14].…”

Barrett esophagus

“…The role of bile reflux has been established from surgical models in rats, where esophagojejunostomy and esophagogastroduodenostomy results in a mixed bile and gastric refluxate that leads to intestinal metaplasia, with many similarities to human BE, including early induction of Cdx1 and Cdx2 expression and the development of a columnar-lined epithelium containing intestinal mucin-secreting goblet cells, [21][22][23][24][25] and esophageal adenocarcinoma. 26,27 Bile acids, particularly unconjugated bile acids such as deoxycholate that induce DNA damage, are one component of gastroduodenal reflux that has been strongly linked to the development of BE, as well as to other cancers a leucine-rich orphan G protein-coupled receptor, was shown to specifically label stem cells in the small intestinal and colon crypts, the so-called crypt based columnar (CBC) cells.…”