Chronic irritation due to cholelithiasis may be associated with neoplastic transformation of gallbladder epithelium.10,11
Two types of metaplasia (antral and intestinal) are frequently observed with ageing in gallbladder epithelium.10,11
Several investigators have demonstrated that intestinal metaplasia is observed more frequently in patients with cholelithiasis than in those without, and furthermore, intestinal metaplasia is accompanied by dysplasia and carcinoma.10,11
Such histological evidence suggests a stepwise progression of gallbladder carcinoma through a path comprising intestinal metaplasia, dysplasia, and carcinoma.10,11
Although aberrant maspin expression did not significantly correlate with the presence of cholelithiasis, a tendency for higher maspin positivity was observed in patients with cholelithiasis compared with those without. Moreover, strong immunoreactivity for maspin protein was significantly correlated with the presence of intestinal metaplasia. Our previous (gallbladder carcinomas)8
and present (intestinal metaplasia) observations of aberrant maspin expression support the assumption that intestinal metaplasia of the gallbladder epithelium might increase susceptibility to the development of gallbladder carcinoma.
In hepatolithiasis, it is well established that aberrant expression of certain proteins is associated with the presence of gastric and/or intestinal metaplasia. Ishikawa et al12
demonstrated that aberrant expression of CDX2 was closely related to intestinal metaplasia and MUC2 overexpression in patients with mucinous intrahepatic cholangicarcinoma (ICC) and intraductal papillary neoplasm of the liver. Furthermore, their group also demonstrated aberrant expression of trefoil factor family (TFF)‐1, which has tumour suppressor properties, in biliary epithelial dysplasia and non‐invasive ICC, associated with overexpression of gastric‐type apomucin (MUC5AC).13
Interestingly, TFF‐1 protein was negative in normal biliary epithelium and gain of TFF‐1 expression was observed in biliary dysplasia and non‐invasive ICC. Moreover, loss of maspin expression was observed in invasive ICC. DNA methylation status in the TFF‐1 promoter region was inversely correlated with protein expression at each stage.13
This switchback phenomenon in both epigenetic status and protein expression suggests the existence of epigenetic instability in the sequence that extends through normal epithelium, metaplasia, and cancer.
In gallbladder carcinogenesis, Wu et al14
recently demonstrated aberrant CDX2 expression in intestinal metaplasia and dysplasia of the gallbladder epithelium and in tubular‐type gallbladder carcinoma. The possibility that CDX2 gene expression in gastric cancer is regulated by an epigenetic mechanism has been reported.15
These facts led us to speculate that epigenetic instability might contribute to metaplastic and/or neoplastic transformation of gallbladder epithelium. Although we attempted to investigate the DNA methylation status of the maspin promoter by use of a methylation specific PCR method combined with microdissection,5
we were unable to obtain sufficient DNA for bisulphite treatment because of the extremely small size of maspin positive areas.
Recently, the issue of whether the maspin gene has tumour suppressor or tumour promoting activity has been highlighted. Although tumour suppressive functions have been confirmed in vitro, several investigators have demonstrated that cancer patients with gain of maspin expression have a poor prognosis.2,3
Therefore, we propose an explanation for this apparently paradoxical expression of maspin protein. Maspin plays an important role in the establishment and/or maintenance of normal cells in a cell specific manner (breast and prostate).6
In tumours arising from these organs, maspin has tumour suppressive activity, such as inhibition of cell motility, invasion, and metastasis. Conversely, in gallbladder, pancreatic, and ovarian carcinomas, maspin shows aberrant expression.2,3,8
In these tissues, maspin is usually repressed in a cell type restricted manner, and the maspin gene is expressed aberrantly when differentiated normal epithelial cells transform to metaplastic or dysplastic cells. Tumour cells derived from these tissues are disrupted in a cell type restricted manner. In addition, Sood et al2
have reported that nuclear subcellular localisation of maspin protein was frequently observed in tumours with low malignant potential, such as ovarian tumours, and that invasive tumours also showed cytoplasmic staining for maspin.2
The authors hypothesised that the maspin protein might act as β‐catenin in the Wnt signalling pathway.
Definitive conclusions about the relationship between morphological transformation of cells and the subcellular localisation of maspin, and that between aberrant protein expression and epigenetic instability in areas of the gallbladder showing metaplastic formation, will require a more functional investigation of the maspin gene.
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- Aberrant expression of maspin protein is frequently observed in gallbladder carcinomas, but not in non‐cancerous gallbladder epithelium.
- Using immunohistochemistry on samples from 69 patients with cholelithiasis and 30 patients with gastric cancer without cholelithiasis, immunoreactivity for maspin was observed in regions of the gallbladder epithelium.
- Positive immunoreactivity for maspin was significantly associated with the presence of intestinal metaplasia in patients with cholelithiasis (p<0.05)
- This study supports the assumption that intestinal metaplasia of the gallbladder may predispose to gallbladder carcinoma.