Colonic epithelial cell proliferation in hereditary non-polyposis colorectal cancer

Abstract

Background-Despite the recent discovery of four genes responsible for up to 90% of all cases of hereditary non-polyposis colorectal cancer (HNPCC), there will still be families in whom predictive testing is not possible. A phenotypic biomarker would therefore be useful. An upwards shift of the proliferative compartment in colonic crypts is reported to be one of the earliest changes in premalignant mucosa. Aims-To assess the role of crypt cell proliferation as a phenotypic biomarker in HNPCC. Patients-Thirty five patients at 50% risk of carrying the HNPCC gene (21 of whom subsequently underwent predictive testing and hence gene carrier status was known) and 18 controls. Methods-Crypt cell proliferation was measured at five sites in the colon using two diVerent techniques. Labelling index was determined using the monoclonal antibody MIB1 and whole crypt mitotic index was measured using the microdissection and crypt squash technique. The distribution of proliferating cells within the crypts was also assessed. Results-There were no significant diVerences in the total labelling index or mean number of mitoses per crypt, nor in the distribution of proliferating cells within the crypt, between the study and control groups at any site. When the 21 patients in whom gene carrier status was known were analysed separately there were no significant diVerences in the measured indices of proliferation between the HNPCC gene carriers and non-gene carriers. Conclusion-Crypt cell proliferation is not a discriminative marker of gene carriage in HNPCC. (Gut 1998;43:85-92)

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

“…The cause of this regional difference is not clear but may be a result of the specific intraluminal microenvironment of this segment of the colon (microflora, concentration, quality of bile acids, etc). The significance of proliferation within crypt compartment 3 is a matter of some controversy6 34 35 but we and other investigators6 34 feel that this finding represents an expansion of the “normal” proliferative compartment at the base of the crypt (compartments 1 and 2). Even if this expansion does not extend to the mouth of the crypt (compartments 4–5), the non-differentiated cells in this intermediate compartment are probably more exposed to various intraluminal factors than those situated in compartments 1 and 2.…”

“…39 Some investigators maintain that such changes are a non-specific finding reflecting the influence of factors such as diet, drugs, age, or methodological flaws. In support of this, Green and colleagues35 have shown that there is no increase in the somatic mutation rate in the normal mucosa of patients with HNPCC 40. However, increased stem cell somatic mutation in the non-neoplastic colorectal mucosa has been described in both familial adenomatous polyposis and Crohn's disease 41.…”

“…Terpstra and colleagues23 found intraregional differences in the TLIs of patients with adenomas <1 cm but not in those with a history of large adenomas (>1 cm). Green and colleagues35 reported a significant linear trend across the colon with the highest TLIs in the ascending colon and the lowest in the rectum in patients at 50% risk of carrying mutations for HNPCC. These findings suggest that different colon cancer risk factors (for example, small or large adenoma, familial predisposition) may be associated with different cell proliferation patterns in the colonic mucosa.…”

“…In the model proposed by Fearon and Vogelstein,2 a state of hyperproliferation is thought to precede neoplastic initiation but this concept has recently been questioned 3539 Some investigators maintain that such changes are a non-specific finding reflecting the influence of factors such as diet, drugs, age, or methodological flaws.…”

Epithelial cell proliferation of the colonic mucosa in diverticular disease: a case–control study

“…Such observation indicates that an upward shifting of the proliferation process does occur in the sigmoid tract of diverticular disease patients. This would appear as a relevant finding, as an upward expansion of the proliferating compartment towards the luminal surface of the crypt has been regarded as a meaningful event, non‐differentiated cells being dangerously exposed to possible carcinogenetic intraluminal factors 22, 23 . Intriguingly, such upward shifting has been also shown in the colonic mucosa of patients at high risk of colon cancer as those with large adenomas 24 .…”