Elsevier

Human Pathology

Volume 40, Issue 6, June 2009, Pages 872-880
Human Pathology

Original contribution
Paneth cell differentiation in colonic epithelial neoplasms: evidence for the role of the Apc/β-catenin/Tcf pathway

https://doi.org/10.1016/j.humpath.2008.12.003Get rights and content

Summary

Paneth cell differentiation may occur in colonic epithelial neoplasms. However, its significance and mechanism of development remains unclear. Human defensin 5 is a specific marker of Paneth cells and has been shown to represent one of the target genes of the Apc/β-catenin/Tcf pathway. The aim of this study was to evaluate the frequency of Paneth cell differentiation in a variety of colonic neoplasms, and to investigate the role of human defensin 5 and β-catenin in this process. The clinical and pathologic findings, including histologic evidence of Paneth cell differentiation and immunostaining for human defensin 5 and β-catenin, were evaluated in 29 samples of nonneoplastic colonic mucosa, 18 hyperplastic polyps, 10 sessile serrated adenomas, 12 traditional serrated adenomas, 21 mixed polyps, 39 conventional adenomas, and 40 adenocarcinomas. Human defensin-5 and β-catenin expression were evaluated for the location and degree of staining in all cell types (dysplastic and nondysplastic) and correlated with histologic areas of Paneth cell differentiation in all types of polyps. Histologic evidence of Paneth cell differentiation was observed in 15 conventional adenomas (38.5%) and 1 adenocarcinoma (2.5%) but not in other types of polyps. Human defensin-5 immunostaining was positive in the cytoplasm of all nonneoplastic Paneth cells and all neoplastic cells with Paneth cell differentiation. Human defensin-5 expression was noted in 0% of hyperplastic polyps, 10% of sessile serrated adenomas, 25% of traditional serrated adenomas, 33.3% of mixed polyps, 82.1% of conventional adenomas, and 17.5% of adenocarcinomas: human defensin 5 expression was significantly higher in conventional adenomas compared to all other groups (P < .01). Seventeen (53.1%) of 32 human defensin 5 positive conventional adenomas, 6 (86%) of 7 of human defensin 5 positive adenocarcinomas, and all human defensin 5–positive sessile serrated adenomas, traditional serrated adenomas, and mixed polyps did not show histologic evidence of Paneth cell differentiation. All mixed polyps (100%) that revealed human defensin 5 expression (7; 33.3%) revealed conventional dysplasia. In the positive mixed polyp cases, human defensin 5 was only positive in areas of conventional dysplasia. Of the 31 conventional adenomas with nuclear β-catenin staining, 15 (48.4%) revealed histologic evidence of Paneth cell differentiation, and all of the neoplastic cells with Paneth cell differentiation showed nuclear β-catenin staining, whereas nonneoplastic Paneth cells consistently showed a normal pattern of membranous β-catenin staining. A strong topographical correlation was noted between human defensin 5 expression and nuclear β-catenin expression in conventional adenomas and in conventional dysplastic epithelium of mixed polyps. Paneth cell differentiation is common in early colonic neoplasms that develop via the conventional adenoma-carcinoma carcinogenic pathway. Activation of Apc/β-catenin/Tcf pathway may play a role in Paneth cell differentiation in human colonic neoplasms.

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)

  • NakagamaH. et al.

    Modeling human colon cancer in rodents using a food-borne carcinogen, PhIP

    Cancer Sci

    (2005)
  • FujiwaraK. et al.

    Global gene expression analysis of rat colon cancers induced by a food-borne carcinogen, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine

    Carcinogenesis

    (2004)
  • HamiltonS.R.

    Molecular genetic alterations as potential prognostic indicators in colorectal carcinoma

    Cancer

    (1992)
  • GoldsteinN.S.

    Serrated pathway and APC (conventional)–type colorectal polyps: molecular-morphologic correlations, genetic pathways, and implications for classification

    Am J Clin Pathol

    (2006)
  • PeruchoM.

    Microsatellite instability: the mutator that mutates the other mutator

    Nat Med

    (1996)
  • KambaraT. et al.

    BRAF mutation is associated with DNA methylation in serrated polyps and cancers of the colorectum

    Gut

    (2004)
  • ChirieacL.R. et al.

    Phenotype of microsatellite-stable colorectal carcinomas with CpG island methylation

    Am J Surg Pathol

    (2005)
  • Cited by (0)

    View full text