Original contributionPaneth cell differentiation in colonic epithelial neoplasms: evidence for the role of the Apc/β-catenin/Tcf pathway
Introduction
Paneth cell differentiation may occur in colonic epithelial neoplasms, particularly adenomas. In fact, Paneth cell differentiation in adenomas is more common in lesions from the proximal colon and in patients with familial adenomatous polyposis [1], [2], [3]. The prevalence of Paneth cell differentiation in adenomas varies from 0.2% to 70% [1]. In 1984, Bansal and Fenoglio [1] reported Paneth cells (“Paneth cell metaplasia”) in 0.2% of colonic adenomas from 3215 patients. These authors suggested that Paneth cells in colonic adenomas represent terminal differentiation of neoplastic cells. Since their study, there have been few studies that have evaluated Paneth cells in association with colonic neoplasms. Thus, it remains uncertain whether Paneth cell differentiation reveals a relationship with specific types of colonic tumors. The possible mechanism for Paneth cell differentiation in human colonic epithelial tumorigenesis is also poorly understood.
Human defensin 5 (HD-5) is a member of the α-defensin family of antimicrobial peptides and is mostly sequestered in lysozyme-rich granules of intestinal Paneth cells (also termed Paneth cell–specific defensin) [4]. HD-5 is a specific and reliable marker for Paneth cells [4]. Previous immunohistochemical studies have shown HD-5 expression in normal small intestinal Paneth cells, as well as in metaplastic Paneth cells in Barrett's esophagus, gastric intestinal metaplasia, and chronically injured colonic mucosa [4], [5], [6]. Recently, it was reported that some Paneth cell–related genes, including α-defensin and matrix metalloproteinase 7 (matrilysin), are up-regulated in both human and animal colonic cancers [7], [8].
There are at least 2 independent and well-known pathways of colorectal tumorigenesis: (1) the conventional adenoma-carcinoma pathway beginning with biallelic inactivation of APC and (2) the serrated neoplasia pathway associated with DNA microsatellite instability, BRAF-activating mutations, and extensive DNA methylation [9], [10], [11], [12], [13], [14]. A recent transgenic study showed that a promoter fragment of the HD-5 gene is activated by an endogenous Tcf associated with β-catenin [15], and activation of the β-catenin signaling pathway could promote Paneth cell differentiation during the process of intestinal tumorigenesis in the APC-mutant animal colon cancer model [7], [15], [16].
The aim of this pilot study was to evaluate the frequency and significance of Paneth cell differentiation in precursor colonic polyps and in adenocarcinomas using HD-5 immunohistochemistry. We evaluated a broad variety of colonic epithelial neoplasms, including hyperplastic polyps (HPs), sessile serrated adenomas (SSAs), traditional serrated adenomas (TSAs), mixed hyperplastic and adenomatous polyps (MPs), conventional adenomas (CAs), and adenocarcinomas (AC). Furthermore, we correlated HD-5 expression with nuclear β-catenin staining in order to determine whether activation of the β-catenin signaling pathway could be involved in the induction of Paneth cell differentiation in colonic tumor cells.
Section snippets
Study groups
This study consisted of 169 specimens, including 29 samples of normal colonic mucosa, 18 HPs, 10 SSAs, 12 TSAs, 21 MPs, 39 CAs, and 40 ACs. All cases, except CAs and ACs, were retrieved by a retrospective search through the surgical pathology files of the Brigham and Women's Hospital, Boston, MA, between 2003 and 2006. Cases of CA and AC were collected from the Ilsan Paik Hospital, Goyang, Korea, between 2005 and 2006. All cases, from both institutions, were identified in a consecutive manner
Clinical data
The clinical and pathologic characteristics of the study patients and their samples are summarized in Table 1. The age of the patients was not significantly different between each patient group. The male-female ratios in all patient groups were also statistically similar, except for patients with MPs, who showed a female predominance (male-female ratio: 5/16). Regarding location, HPs, TSAs, and ACs showed a predilection for the left colon, and patients with SSAs showed a propensity for the
Discussion
The significance and mechanism of Paneth cell differentiation in colonic adenomas and in other types of colonic polyps and neoplasms remain unclear [1], [20]. HD-5 has been previously shown to be a specific marker of Paneth cells in the gastrointestinal tract [4], [5], [6] and is also one of the target genes of the Apc/β-catenin/Tcf pathway of colon carcinogenesis [15]. Although Paneth cell differentiation in adenomas in Apc-mutant mice has been well described [21], the role of the Apc/β
References (34)
Alpha-defensins in the gastrointestinal tract
Mol Immunol
(2003)- et al.
Serrated adenomatous polyposis in humans
Gastroenterology
(1996) - et al.
Paneth cell antimicrobial peptides: topographical distribution and quantification in human gastrointestinal tissues
FEBS Lett
(2006) - et al.
Wnt control of stem cell and differentiation in the intestinal epithelium
Exp Cell Res
(2005) - et al.
Beta-catenin and TCF mediate cell positioning in the intestinal epithelium by controlling the expression of EphB/ephrinB
Cell
(2002) - et al.
Are metaplasias in colorectal adenomas truly metaplasias?
Am J Pathol
(1984) - et al.
Duodenal adenomas in familial adenomatous polyposis: relation of cell differentiation and mucin histochemical features to growth pattern
Mod Pathol
(1994) - et al.
The Paneth cell in the adenoma of familial polyposis coli
Bull Tokyo Med Dent Univ
(1975) - et al.
Human defensin 5 is stored in precursor form in normal Paneth cells and is expressed by some villous epithelial cells and by metaplastic Paneth cells in the colon in inflammatory bowel disease
Gut
(2001) - et al.
Human defensin 5 expression in intestinal metaplasia of the upper gastrointestinal tract
J Clin Pathol
(2005)