Mixed Gastric- and Intestinal-type Metaplasia Is Formed by Cells with Dual Intestinal and Gastric Differentiation

Abstract

We have proposed to divide intestinal metaplasia (IM) into two categories, i.e., a mixed gastric and intestinal (GI) type, and a solely intestinal (I) type, based on the residual gastric phenotype cells. The GI-mixed-type IM can be identified by the presence of both cells with either gastric or intestinal phenotypes in a single gland. This study is conducted to elucidate whether cells in the GI-mixed-type IM glands can simultaneously present both gastric and intestinal phenotypes. MUC5AC, MUC2, CD10 and villin expressions were investigated in 20 samples from five gastric cancer cases, directly using either AlexaFluor 488- or 568-labeled specific monoclonal antibodies and observed by fluorescent microscopy and confocal laser-scanning microscopy. GI-mixed IM glands comprise a population expressing MUC5AC and MUC2, MUC5AC and villin, and MUC5AC and CD10. MUC2 and villin expressions were reciprocally increased with decreasing MUC5AC expression, while CD10 expression was limited to cells with only a residual MUC5AC expression or no expression. These results suggest that a heterogeneous cell population with both gastric and intestinal phenotypes would develop into a single intestinal phenotype, as reflected in the progression of intestinal metaplasia from GI-mixed-type- to I-type IM-type glands.

CDX2 does not suppress tumorigenicity in the human gastric cancer cell line MKN45

“…We found that loss of CDX2 resulted in loss of MUC2 transcripts, consistent with the notion that CDX2 is important for maintenance of MUC2 expression (Figure 4c). Concomitantly, we found that loss of CDX2 led to increased MUC5AC, which is specific to gastric surface mucous cells (Tsukashita et al, 2001;Niwa et al, 2005). These findings suggest that CDX2 regulates the expression of MUC2, which is associated with terminal differentiation of goblet cells and an intestinal mucous phenotype.…”

Comparison of six immunohistochemical markers for the histologic diagnosis of neoplasia in Barrett’s esophagus

“…In concordance to the findings of other groups, our data showed an absent MUC2 expression in normal gastroesophageal mucosa but a 92% positivity in Barrett's mucosa followed by a significant decrease from LG-IEN (22%) to HG-IEN (16%) to invasive carcinoma (9%) due to the increase in cellular atypia and decrease of the number of goblet cells. Villin is a candidate gene of CDX2 further downstream and an end-differentiated marker of intestinal cells [50] protein needs to be of sufficient quantity to result in a mature brush border [28]. We found villin to be present in 25% of normal mucosa and in 88% of the Barrett's mucosa cases.…”

“…Its expression can be induced by long-term acid exposure and is correlated with the development of differentiated polarized cells that contain a brush border and microvillus inclusions [27]. Villin is an end-differentiated marker of intestinal cells, and the protein needs to be of a sufficient quantity to result in a mature brush border [28]. An in vitro study demonstrated the rate of villin synthesis to be dramatically increased in the course of enterocyte differentiation, remaining remarkably stable after synthesis.…”

Pathophysiology of intestinal metaplasia of the stomach: emphasis on CDX2 regulation

“…Interestingly, mixture of the gastric and the intestinal phenotype can also occur at the cellular level. Niwa et al [9] showed that single cells can express both gastric and intestinal mucins, such as MUC5AC and MUC2.Common to both types of IM is the de novo expression of CDX2, a transcription factor that, in normal conditions, is expressed exclusively in the intestine, but is present in every focus of aberrant intestinal differentiation occurring in the human body. It is thus considered the master gene for intestinal differentiation and it is reviewed in detail below.…”