Abstract
The intestinal epithelium has two distinct two stem cell populations, namely, crypt base columnar (CBC) cells and +4 cells. Several specific markers have been identified for each stem cell population. In this study, we examined the expression profiles of these markers in colitis-associated carcinogenesis (CAC) to investigate whether they can be used as biomarkers for the early detection of dysplasia. The expression of intestinal stem cell (ISC) markers was measured by real-time polymerase chain reaction during CAC that was induced by azoxymethane and dextran sodium sulfate treatment. CBC stem cell markers increased continuously with tumor development, whereas a +4 cell expression profile was not present. CBC stem cell population was suppressed in the acute colitis and then expanded to repopulate the crypts during the regeneration period. Notably, RNA in situ hybridization revealed that all dysplasia and cancer samples showed increased expression of CBC stem cell markers in more than one-third of the tumor height, whereas regenerative glands had CBC stem cell markers confined to the lower one-third of the crypt. These results suggest that CBC stem cell markers could be a useful tool for the early detection of colitis-induced tumors.
Highlights
Inflammatory bowel diseases (IBD) are chronic inflammatory disorders of the intestinal tract that affect millions of people around the world[1, 2]
Before we focused on the expression of crypt base columnar (CBC) stem cell markers in regenerative glands (RG) and tumors, we investigated alterations in the CBC stem cell population during regeneration after colitis-induced mucosal damage
With the discovery of robust intestinal stem cell markers by lineage tracing technologies, impressive breakthroughs have been made in understanding how intestinal stem cells interact with their local niche to maintain homeostasis and how they contribute to intestinal cancer initiation and progression
Summary
Inflammatory bowel diseases (IBD) are chronic inflammatory disorders of the intestinal tract that affect millions of people around the world[1, 2]. Two models of intestinal stem cell (ISC) identity have historically competed over the past four decades[11]. Remarkable advances have been made in the ISC research, and specific markers for these two candidate stem cell populations have been proposed through in vivo lineage tracing. The previous results on the lineage tracing and expression patterns of mouse ISC markers in small intestine and colon are summarized in Supplementary Table S1. There is no direct evidence that these stem cells give rise to colitis-associated colorectal cancers, and the expression of ISC markers in CAC has not been thoroughly studied. In this study, we aimed to reveal the expression patterns of the ISC markers during CAC using an AOM/DSS colitis-induced colon cancer model to identify ISC markers that could be used for the early detection of dysplasia
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