W. Boersma-van Ek

Dysplasia in fundic gland polyps is associated with nuclear beta-catenin expression and relatively high cell turnover rates

Background: Fundic gland polyps (FGPs) occur in both syndromic and sporadic form. Syndromic FGPs arise through mutations in the adenomatous polyposis coli (APC) gene, whereas sporadic FGPs are caused by

Changes in Bile Acid Composition and Effect on Cytolytic Activity of Fecal Water by Ursodeoxycholic Acid Administration: a Placebo-Controlled Cross-over Intervention Trial in Healthy Volunteers

-catenin gene mutations. Dysplasia in sporadic FGPs, found less often than in syndromic FGPs, was recently associated with APC rather than

Independent induction of caspase-8 and cFLIP expression during colorectal carcinogenesis in sporadic and HNPCC adenomas and carcinomas

-catenin mutations. These data suggest different functional consequences of APC and

Calcium affects biomarkers of colon carcinogenesis after right hemicolectomy

-catenin mutations. To investigate this hypothesis, we examined proliferative activity, degree of apoptosis, # -catenin expression and p53 expression in syndromic and sporadic FGPs. Methods: Syndromic FGPs ( n r = r 9) from familial adenomatous polyposis (FAP) patients and sporadic FGPs ( n r = r 18) were studied. Proliferative activity, apoptotic cell death and expression of # -catenin and p53 were examined by immunohistochemistry. In FGPs containing dysplasia, areas with and without dysplasia were compared. Results: Syndromic and sporadic FGPs without dysplasia exhibited similar proliferative activity, degree of apoptosis, # -catenin and p53 expression. Dysplasia was observed more often in syndromic (4/9) than in sporadic FGPs (1/18). Within FGPs containing dysplasia, dysplastic areas showed abnormal nuclear # -catenin staining in 3/5 cases and higher rates of cell proliferation and apoptosis than non-dysplastic areas. Overexpression of p53 was not observed. Conclusion: The finding of similar rates of proliferation and apoptosis in syndromic and sporadic FGPs does not support the hypothesis that APC and

Regulation of TRAIL receptor expression by β-catenin in colorectal tumours

-catenin gene mutations have different functional consequences in FGPs. The association of dysplasia with relatively high cell turnover rates and nuclear expression of

Cell cycle regulators and apoptosis-associated proteins in relation to proliferative activity and degree of apoptosis in HNPCC versus sporadic endometrial carcinoma

- catenin indicates activation of the Wnt-APC- # -catenin pathway in dysplasia. The finding of dysplasia in some but not all syndromic FGPs suggests the involvement of other genes in addition to the APC gene in the development of dysplasia in FGPs.BACKGROUND Fundic gland polyps (FGPs) occur in both syndromic and sporadic form. Syndromic FGPs arise through mutations in the adenomatous polyposis coli (APC) gene, whereas sporadic FGPs are caused by beta-catenin gene mutations. Dysplasia in sporadic FGPs, found less often than in syndromic FGPs, was recently associated with APC rather than beta-catenin mutations. These data suggest different functional consequences of APC and beta-catenin mutations. To investigate this hypothesis, we examined proliferative activity, degree of apoptosis, beta-catenin expression and p53 expression in syndromic and sporadic FGPs. METHODS Syndromic FGPs (n = 9) from familial adenomatous polyposis (FAP) patients and sporadic FGPs (n = 18) were studied. Proliferative activity, apoptotic cell death and expression of beta-catenin and p53 were examined by immunohistochemistry. In FGPs containing dysplasia, areas with and without dysplasia were compared. RESULTS Syndromic and sporadic FGPs without dysplasia exhibited similar proliferative activity, degree of apoptosis, beta-catenin and p53 expression. Dysplasia was observed more often in syndromic (4/9) than in sporadic FGPs (1/18). Within FGPs containing dysplasia, dysplastic areas showed abnormal nuclear beta-catenin staining in 3/5 cases and higher rates of cell proliferation and apoptosis than non-dysplastic areas. Overexpression of p53 was not observed. CONCLUSION The finding of similar rates of proliferation and apoptosis in syndromic and sporadic FGPs does not support the hypothesis that APC and beta-catenin gene mutations have different functional consequences in FGPs. The association of dysplasia with relatively high cell turnover rates and nuclear expression of beta-catenin indicates activation of the Wnt-APC-beta-catenin pathway in dysplasia. The finding of dysplasia in some but not all syndromic FGPs suggests the involvement of other genes in addition to the APC gene in the development of dysplasia in FGPs.

Sulindac increases epithelial cell proliferative activity in the proximal colon of HNPCC-patients.

Background: Ursodeoxycholic acid (UDCA) has been shown to affect membrane-damaging effects of bile acids in vitro and fecal bile acid composition in rats. This study evaluates the effect of UDCA on fecal bile acid composition and on cytolytic activity of fecal water in man to clarify the potential chemopreventive role of UDCA for colorectal cancer. Methods: In this placebo-controlled crossover intervention trial, the effect of 900 mg/day UDCA orally in 15 healthy volunteers was studied. At the end of each 4-week period, 72 h feces were collected. Total and individual bile acids in feces were determined by gas chromatography and soluble bile acids were analyzed by high-performance liquid chromatography. Cytolytic activity of fecal water was measured using an erythrocyte lysis assay. Results: In feces, the percentages of primary bile acids--cholic acid (CA) and chenodeoxycholic acid (CDCA)--and of secondary bile acid--deoxycholic acid (DCA)--decreased after supplementation with UDCA, whereas those of UDCA and LCA increased from 2.7 ± 0.4% to 23.7 ± 2.6%, P < 0.0001 and from 26.2 ± 1.2% to 49.4 ± 1.8%, P < 0.0001 respectively. The concentrations of these two bile acids in fecal water also increased after UDCA administration from 7.8 ± 1.9 μmol/l to 47.0 ± 6.7 μmol/l (UDCA), P < 0.0001 and from 2.5 ± 0.6 μmol/l to 18.3 ± 4.1 μmol/l (LCA), P < 0.002, respectively. Cytolytic activity of fecal water was not affected by UDCA. Conclusion: These results do not support a protective effect of UDCA supplementation against colorectal cancer in man.

Induction of caspase-8 and competitor cellular flice-like inhibitory protein expression during colorectal carcinogenesis in sporadic and hereditary nonpolyposis colorectal cancer adenomas and carcinomas

Background: TNF-Related Apoptosis Inducing Ligand (TRAIL) is a promising agent for the induction of apoptosis in neoplastic tissues. Important determinants of TRAIL sensitivity are two intracellular proteins of the TRAIL pathway, caspase-8 and its anti-apoptotic competitor cellular Flice-Like Inhibitory Protein (cFLIP). Methods: The aim of this study was to investigate basic expression of caspase-8 and cFLIP in normal colorectal epithelium (n = 20), colorectal adenomas (n = 66) and colorectal carcinomas (n = 44) using immunohistochemistry performed on both sporadic and Hereditary Non-Polyposis Colorectal Cancer (HNPCC or Lynch syndrome)-associated adenomas and carcinomas. Results: Expression of both caspase-8 and cFLIP was similar in cases with sporadic and hereditary origin. Expression of caspase-8 in colorectal adenomas and carcinomas was increased when compared to normal colon tissue (P = 0.02). Nuclear, paranuclear as well as cytoplasmic localizations of caspase-8 were detected. Immunohistochemistry revealed an upregulation of cFLIP in colorectal carcinomas in comparison to normal epithelium and colorectal adenomas (P < 0.001). A large variation in the caspase-8/cFLIP ratio was observed between the individual adenomas and carcinomas. Conclusion: Caspase-8 and cFLIP are upregulated during colorectal carcinogenesis. Upregulation of caspase-8 and/or downregulation of cFLIP may be interesting approaches to maximize TRAIL sensitivity in colorectal neoplasms.

Colorectal neoplasia after liver transplantation is associated with higher proliferative activity, lower apoptosis and increased beta-catenin expression compared with controls

Background In Western societies colonic cancer most frequently develops in the distal colon, largely as a result of the composition of the diet. Modulation of dietary factors is therefore an attractive modality to reduce colorectal cancer risk. This study aims to evaluate the potentially protective effects of calcium in right hemicolectomy patients.

TRAIL induces apoptosis in human colorectal adenomas and human colorectal adenoma cell lines

Tumour-necrosis-factor-related apoptosis-inducing ligand (TRAIL) is being investigated as a targeted cancer therapeutic and the expression of its pro-apoptotic receptors, DR4 and DR5, increases during colorectal carcinogenesis. This study investigated the role of β-catenin in the regulation of these receptors. In human colorectal adenoma and carcinoma cell lines, downregulation of β-catenin resulted in lower total DR4 and DR5 protein levels. Similarly, cell membrane expression of DR4 and DR5 was reduced after downregulation of β-catenin in colon carcinoma cells, whereas induction of β-catenin in HeLa cells led to increased cell membrane expression of DR4 and DR5. Downregulation of β-catenin decreased the recombinant human TRAIL sensitivity of human colon carcinoma cells. Activation of the transcription factor T-cell factor-4 (TCF-4) is an important function of β-catenin. Dominant-negative TCF-4 overexpression, however, did not significantly affect TRAIL receptor expression or recombinant human TRAIL sensitivity. Human colorectal adenomas (N = 158) with aberrant (cytoplasmic and nuclear) β-catenin expression had a higher percentage of immunohistochemical DR4 and DR5 staining per tumour (mean: 73 and 88%, respectively) than those with membranous β-catenin staining only (mean: 50 and 70%, respectively, P < 0.01 for both). Furthermore, aberrant β-catenin staining co-localized with DR4 and DR5 expression in 92% of adenomas. In 53 human colorectal carcinomas, aberrant β-catenin expression was present in most cases and DR4/5 expression was largely homogenous. Similarly, in adenomas from APC(min) mice, cytoplasmic β-catenin staining co-localized with staining for the murine TRAIL death receptor. In conclusion, the gradual increase in TRAIL receptor expression during colorectal carcinogenesis is at least partially mediated through increased β-catenin expression, independently of TCF-4-signalling.