Severe imbalance of cell proliferation and apoptosis in the left colon and in the rectosigmoid tract in subjects with a history of large adenomas

Abstract

Background-Alterations in epithelial proliferation and apoptosis in colonic mucosa are associated with an increased risk of colon cancer. It is unclear if these alterations represent a generalised "field defect". Aims-To analyse segmental patterns of cell proliferation and apoptosis in the colon of subjects with a high and no apparent risk of colon cancer. Methods-Pancolonoscopywas performed in 15 patients with resected adenomas (>1.5 cm) and in nine subjects without an apparent risk of colorectal cancer. Mucosal biopsies were taken from the right colon, left colon, and sigmoid rectum. Crypt cell proliferation and apoptosis were evaluated, respectively, with bromodeoxyuridine immunohistochemistry and terminal deoxyuridine nucleotidyl nick end labelling of DNA strand breaks. Results are expressed as total labelling index (TLI) and labelling index (LI) for each of the five compartments in which colonic crypts were divided (fourth and fifth compartments were evaluated together) for cell proliferation and as apoptotic index (AI) for apoptosis assessment. Results-No significant segmental variations in proliferation were found in either group. Compared with controls, adenoma patients had higher TLIs for the right (p>0.05), left (p<0.005), and sigmoid rectum (p<0.05) segments, and higher left colon LIs for crypt compartments (compartment 1, p<0.01; compartment 2, p<0.005; compartment 3, p<0.001; compartments 4-5, p<0.01). Control AIs were similar in all segments but in the adenoma patients left colon and sigmoid rectum AIs were lower than their right colon indexes (p<0.05, p<0.05) and corresponding values for controls (p<0.01, p<0.05). Conclusions-The colonic mucosa of patients with past adenomas presents diVuse hyperproliferation and, distally, abnormally distributed proliferating cells and markedly reduced apoptosis. These changes represent a significant risk for malignancies and could account for the high prevalence of left colon tumours. (Gut 2001;48:238-246)

Apoptosis in Normal Rectal Mucosa, Baseline Adenoma Characteristics, and Risk of Future Adenomas

“…Neoplasms can arise when decreased apoptosis leads to the accumulation of genetically aberrant cells (9)(10)(11)(12). Thus, apoptosis may serve a protective role in the colorectal mucosa by preventing the development of adenomas and colorectal cancer (13)(14)(15). Observation of low apoptosis in the normal rectal mucosa supports the concept of a field effect, namely, that characteristics of the mucosa provide a substrate for the development of adenomas.…”

Evidence for colorectal cancer cell specificity of aspirin effects on NFκB signalling and apoptosis

“…Nonetheless, comparisons between cell culture concentrations and plasma levels are somewhat artificial, because of the inability to accurately mimic in vivo metabolism and tissue concentration of the agent in epithelial or tumour cells. Decreased basal levels of apoptosis and hyperproliferative mucosa have been observed in patients with adenomas, suggesting the existence of a 'field defect' in the colonic mucosa (Anti et al, 2001). Although we observed proportionally less apoptosis at lower concentrations of aspirin, there is evidence that low levels of apoptosis translate into significant tumour regression over time in cell kinetics studies (Pritchard and Watson, 1996).…”

Are there two sides to colorectal cancer?

“…20 Some studies have suggested the existence of a proximal to distal proliferative gradient in the normal colon, 21 although others have reported the opposite result 22 or no segmental variation. 23 The apoptotic index is lower in the right colon, possibly due to lower expression of the pro-apoptotic Bcl-2 homologue Bak compared to the left colonic mucosa. 24 Fermentation reactions leading to short-chain fatty acid production are up to 8-fold higher in the proximal compared to distal colon.…”