RELIABILITY OF RECTAL EPITHELIAL KINETIC PATTERNS AS AN INTERMEDIATE BIOMARKER OF COLON-CANCER

The use of biomarkers to assess cancer risk is based on the model of c ancer as a multistep process; such markers are assumed to reflect an e arly stage in this process. A valid biomarker of risk must therefore s how differential expression in normal and high-risk subjects, as well as quantitative correlation with the stage of carcinogenesis. It shoul d also be easy to detect in small tissue specimens and responsive to m odulation by chemopreventive agents. Cell proliferation is one of the most widely investigated markers of cancer risk. Case-control studies have shown that epithelial cell proliferation parameters, assessed in rectal mucosal biopsies by means of in vitro autoradiographic or immun ohistochemical techniques, can discriminate between populations with n ormal and high risks for colon cancer. However, we recently reviewed r ectal biopsies from 152 subjects (43 controls, 84 with adenomas, 25 re sected for colon cancer) processed for in vitro H-3-thymidine autoradi ography, and attempted to correlate various proliferative parameters w ith clinical and pathological variables by means of multiple regressio n analysis. Elevations of total crypt labeling indices (LIs), particul arly upper crypt LIs, were significantly associated with the presence of adenomatous polyps, although subsequent linear discriminant analysi s revealed that the accuracy of LIs in discriminating between polyp pa tients and controls was actually quite low. However, we have also foun d that upper crypt LIs are reliable predictors of adenomatous polyp re currence. Repeated evaluations of rectal proliferative indices over a 2-year post-polypectomy follow-up of 40 patients with colonic adenomas revealed substantial stability. We have also shown that, although cir cadian variation occurs, it is confined to the normal proliferative zo ne in the lower crypt, with upper crypt proliferation remaining quite stable. These proliferative indices have been shown to respond to chem opreventive agents (dietary and chemical), and we have recently shown that the improvements obtained with omega-3 fatty-acid supplementation persist during long-term treatment. Although definitive validation of the rectal epithelial cell proliferation biomarker has not yet been a chieved, recent prospective studies have shown parallel effects by put ative chemopreventive agents on cell proliferation and precursor lesio ns of colorectal cancer. (C) 1994 Wiley-Liss, Inc.