ß-Catenin, Cox-2 and p53 immunostaining in colorectal adenomas to predict recurrence after endoscopic polypectomy.

BACKGROUND: Endoscopic polypectomy significantly reduces the incidence of colorectal cancer, but recurrence rates are high, especially for adenomas with advanced histology. The present guidelines recommend re-colonoscopy 3 to 5 years later. Due to limited resources, more precise predictions of adenoma recurrence are required. DESIGN: Lesions from 109 patients with colorectal adenomas recruited into a randomized, placebo-controlled chemoprevention trial with mesalazine were included. Formalin-fixed paraffin-embedded tissue sections were stained for ß-catenin, cyclooxygenase-2 (Cox-2), and p53 and scored. Adenoma recurrence rates were recorded after 3 years and associated with clinical and immunohistochemical parameters by contingency table analysis. RESULTS: After 3 years, adenomas recurred in 51.4% of patients. Out of 109 adenomas, 95 met at least one criterion of advanced adenoma (size >1 cm, villous histology, high-grade intraepithelial neoplasia). There was no influence of age, sex, size or villous histology on adenoma reappearance, whilst the number of adenomas at baseline was positively associated with recurrence (p = 0.003). In contrast, ß-catenin nuclear localisation, Cox-2 expression and p53 nuclear expression were significantly associated with adenoma recurrence after 3 years (ß-catenin: p = 0.002; Cox-2: p = 0.001; p53: p = 0.001). Combining these three markers led to a negative predictive value of 88.5% and a sensitivity of 94.6%. (OR = 13.54) CONCLUSIONS: Scoring each single parameter and, more strongly, the combination of all three parameters of the expression of ß-catenin, Cox-2 and p53 in colorectal adenoma tissue may be a useful negative predictor for adenoma recurrence in patients with advanced colorectal adenomas.

The influence of 5-aminosalicylic acid on the progression of colorectal adenomas via the ß-catenin signaling pathway.

Surveillance colonoscopy is an important strategy for prevention of colorectal cancer. 5-aminosalicylate (ASA) (mesalazine) is discussed as a chemopreventive agent as it reduces the cancer risk in ulcerative colitis patients. The current study analyses the effect of 5-ASA on Wnt/ß-catenin signaling in vitro and in vivo in colon epithelial cells. The effect of 5-ASA was determined using a ß-catenin/T-cell factor (TCF)-reporter assay and by western blotting in cultured colon cancer cells. Formalin fixed paraffin embedded material from 227 polyps removed from a subgroup of 56 patients, who participated in a randomized placebo-controlled 3-year prevention trial with 5-ASA was evaluated according to histomorphological characteristics and expression of ß-catenin and target genes Cox2, cyclin D1 and E-cadherin as well as ornithine decarboxylase (ODC). Patients were grouped into a low-risk and a high-risk group according to the number of adenomas at initial colonoscopy. ß-catenin/TCF signaling activity was significantly reduced by 5-ASA treatment possibly through a reduction in ß-catenin levels. Moreover, 5-ASA significantly reduced ß-catenin levels and nuclear localization in patients' adenomas. In addition, 5-ASA also significantly changed expression of the downstream targets Cox2, cyclin D1 and E-cadherin, correlating with ß-catenin status. Moreover, 5-ASA significantly reduced levels of ODC in vivo. Expression of p53 was unaltered by the 5-ASA treatment. Our study shows a significant in vitro and long-term in vivo effect of 5-ASA on ß-catenin signaling as a key signaling pathway in the development of colorectal adenoma. Therefore, we suggest the use of 5-ASA as a promising drug for prevention of sporadic colorectal carcinoma.