Thomas, Michael Graham; (1994) Luminal and humoral influences on colorectal epithelial cytokinetics. Masters thesis (M.S), UCL (University College London).

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Abstract

Colorectal cancer may occur in individuals with a recognised high risk of developing the disease, or as sporadic cases in people with an apparently normal chance. Multiple genetic steps and environmental factors, such as diet, may be responsible for the development of colorectal neoplasia, and experimental evidence suggests that promoters of colorectal cancer also induce colorectal epithelial hyperplasia. As a corollary, dietary intervention can reduce large bowel epithelial cell proliferation. I have used the crypt cell production rate (CCPR) as my standard cytokinetic parameter to determine the effect of dietary and humoral factors on colorectal mucosal proliferation in both animals and man. In Experiment 1, the use of a digestible fibre caused an elevation in faecal bile acids and ameliorated the hypoplasia induced by enteral feeding in rats. Neutral steroid analysis suggested this effect may be linked to bacterial degradation of bile acids. The double-blind trial reported in Experiment 2, showed that oral supplementation with calcium reduces human rectal CCPR in patients with familial adenomatous polyposis (PAP) but it had no effect on established neoplasia. In addition, vitamin D3 metabolites were elevated in serum from the control patients. In Experiments 3, 4 and 5, I have used organ and cell culture to demonstrate, for the first time, that vitamin D3 and its synthetic (less toxic) analogues reduce cell proliferation in normal, premalignant and malignant human colorectal epithelial cells. I have also demonstrated that epidermal growth factor (EGF) increases CCPR in FAP tissue that expresses the EGF receptor. In addition, I have combined static and dynamic measurements of cell proliferation to determine the various phases of the cell cycle in FAP. Dietary and therapeutic manipulations may, in the future help, decrease the incidence of colorectal cancer, and synthetic vitamin D3 analogues with limited effects on calcium metabolism could possibly help treat established disease.

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