Study of kinetics of epithelial cell populations in normal tissues of the rat's intestines and in carcinogenesis. III. Changes in kinetics of enterocyte populations in the course of experimental intestinal tumour induction in rats.

A stage-by-stage study of disturbances in enterocyte proliferation in the ileum and descending colon in the course of tumour induction by treatment with 1,2-dimethylhydrazine was performed. Even at early stages, an expansion of the zone of epithelial cell proliferation in the crypts and migration of dividing cells as far as to the crypt mouth, which is a manifestation of enterocyte differentiation disturbances, were observed. Enterocytes of the crypts chiefly proliferated through a short cycle, the mean duration of which was slightly greater than in normal intestinal tissue. The reduced cell loss in the epithelium and resultant disturbances of its steady state led to the accumulation of great numbers of atypical cells in the superficial layers of the crypts and formation of carcinomas in situ in the descending colon. The microscopically unaltered sections of the mucosa, prior to development of overt neoplastic changes carcinomas in situ, superficial cancers and small-size adenocarcinomas revealed a simplified structure of enterocyte population, as compared with normal epithelium. As tumours progressed, the heterogeneity of its component cell subpopulations increased, and several subpopulations, differing in mean duration of the mitotic cycle, were formed. Pathologic mitoses made up a greater portion (50-60 per cent) of the dividing cells of the descending colon, as compared with ordinary 4 per cent at all stages of experimental tumour induction.

Study of kinetics of epithelial cell populations in normal tissues of the rat's intestines and in carcinogenesis. I. A comparison of enterocyte population kinetics in different segments of the small intestine and colon.

The peculiarities of enterocyte proliferation in the duodenum, jejunum, ileum, caecum, ascending, transverse and descending colon in the rat were studied by different methods of analysis of cell population kinetics (percentage-labelled mitosis curves, cumulative labelling curves, distribution of labelling index curves, etc.). The majority of proliferating cells in the small intestine are homogenous, as far as mitotic cycle mean duration (11-12 hrs) is concerned. All proliferating cells in all the zones of the colonic crypts and the bottom of the small intestine crypts are divided into subpopulations, having different mean durations of the mitotic cycle. It is suggested that, in the crypt bottom in all intestines as well as the crypt's maximum proliferation zones in most of the colonic segments, a considerable fraction of cells has a very long mitotic cycle or enters resting phase R1. The average value of the mean durations of the mitotic cycle of all colonic enterocyte subpopulations is 18-22 hours. On the basis of the authors' findings and literature data, a model for the enterocyte life cycle is proposed, according to which the cell flux is branched during the mitotic cycle and the crypt develops from a stem enterocyte population located at its bottom.

Study of kinetics of epithelial cell populations in normal tissues of the rat's intestines and in carcinogenesis. II. Peculiarities of kinetics of enterocyte populations in experimental tumours of the colon.

Cell proliferation in adenocarcinomas induced in the rat's colon by parenteral injection of 1,2-dimethylhydrazine was compared with that in normal colonic epithelium by means of autoradiographs. The distinct zone of proliferation, typical of the intestines, was not observed in the tumours, and cells replicated nearly in all segments of neoplasms. Tumour enterocytes were found to have a longer short mitotic cycle (16 instead of 11 hrs), due, chiefly, to an extension of G1-period duration. They were also characterized by a more pronounced heterogeneity as far as the values of ts and tG2 are concerned, and, probably, by the formation of an R2-population. Both the index of S-phase (29%) and labelled cell fraction (87%) after 6 injections of 3H-thymidine spaced at six-hour intervals, were lower in adenocarcinomas than in the zone of maximum proliferation in the descending colon (45 and 100%, respectively) and yet higher than the same parameters calculated for the whole population of the intestinal epithelium (17 and 60%, respectively). As far as proliferation parameters go, adenocarcinoma cells highly resemble those of the crypt bottom population in control animals, which was found to consist of several subpopulations with a varying mean duration of the mitotic cycle, and where stem enterocytes are likely to occur. When enterocytes become malignant, disturbances in their differentiation decrease cell shedding into the intestinal lumen and, thus, cause tumours to arise and develop.