Analyses of clonality and genomic changes in the regeneration of gastric mucosa

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1. We analyzed clonality of regenerative gastric glands in cases of freeze-ulceration, catechol administration, and irradiation. Monoclonality of regenerating glands and a BALB/c-superior strain variation were demonstrated both histologically and genetically, but no sex difference was found.2.Isolation of regenerative glands by our crypt-isolation technique has not yet been successful because of strong attachment to the stroma and a fragile structure making them susceptible to destruction during isolation process. Radiation- induced intestinal metaplasia in the rat gastric glandular mucosa is frequently- associated with regenerative glands. In order to examine genetic changes, glands were isolated and histologically divided into several subtypes using gastric and intestinal cell differentiation markers. Analyses of changes in p53, K-ras, H-ras, and APC genes are now under way.3. We have also concentrated attention on the relationship between regeneration and carcinogenic steps in the MNU-initiated chimeric mouse glandular stomach exposed to catechol. Regenerative epithelia, hyperplastic epithelia, adenomas, and carcinomas are all observed in the mucosa in this model. Regenerative and hyperplastic epithelia were demonstrated to be monoclonal at the level of the unit gland in a polyclonal tissue background. Adenomas and the most of carcinomas were monoclonal, but a few large carcinomas proved to be polyclonal probably due to fusion of discrete tumors. Strain differences in carcinogenecity were also preserved in the chimera. With BrdU administration to mice, no proliferative differences were apparent in the normal glandular stomach mucosa. However, lesions growing into the submucosa, frequently observed in hyperplastic epithelium, exhibited a BALB/c-superiority, in this context suggesting strain differences in cellular responses. The interrelationships of the observed lesions are now under investigation.