The relationship between ionizing radiation-induced apoptosis and stem cells in the small and large intestine

Abstract

Summary Apoptosis is observed in the crypts of the small intestine of healthy animals and man (spontaneous apoptosis). The levels can be dramatically elevated 3-6 h following ionizing radiation exposure. Both the spontaneous and radiation-induced apoptosis in the small intestine crypts are most frequently observed at the positions in the crypt associated with stem cells (about four cell positions from the base of the crypt). The number of apoptotic deaths can be counted in routine histological preparations, but interpretation of the counts is complicated by numerous factors. However, recording the number of cells containing one or more apoptotic fragments in crypt sections provides a good estimate for the absolute number of cell deaths in crypts. Similarities are noted in the frequency and cell positional relationship of radiationinduced apoptosis in the small intestine of various strains of mice and one strain of rat. Apoptosis in the large intestine is generalty lower in frequency than in the small intestine and, for the mid-colonic and rectal regions, has a different cell positional frequency distribution, with the highest apoptotic yield at the crypt base. The caecal colon has a pattem of apoptotic distribution more similar to that in the small intestine. After exposure to 1 Gy ionizing radiation, the maximum apoptotic yield occurs over a period of 3-6 h in the small intestine. There is some unexplained variability in the values between groups of mice and between different mouse strains. After 8 Gy, the yield remains elevated for several days, however a similar maximum yield is still observed at the eariy times. In mouse large intestine and rat small intestine, the yield continues to rise until about 6 Gy in mouse large intestine and until at least 10 Gy in rat small intestine. Spontaneous apoptosis is interpreted as part of the homeostatic mechanism regulating stem cell numbers. About 1.6 cells per crypt are dying at any one time. Following irradiation, there is an apparent relationship between mitotic and apoptotic levels, suggesting that these processes are linked. The dose-response relationship suggests that there are about six apoptosis-susceptible cells in crypts of the small intestine, with about 2-4 of these occurring at cell positions in which there are other more resistant clonogenic cells. In the large intestine, the position of these apoptosis-susceptible cells varies with region, but the numbers are similar.

Opposing effects of butyrate and bile acids on apoptosis of human colon adenoma cells: differential activation of PKC and MAP kinases

“…Disruption of this balance underlies the development of cancer (Williams, 1991). In the colonic crypt, stem cells are located at the base and as they differentiate they progress up the crypt, eventually dying by apoptosis and are sloughed off into the colonic lumen (Potten and Grant, 1998). The high incidence of colorectal cancer in Western society has been attributed to a diet high in saturated fat and low in dietary fibre (Sandler et al, 1993).…”

Absence of acute apoptotic response to genotoxic carcinogens in p53‐deficient mice is associated with increased susceptibility to azoxymethane‐induced colon tumours

“…9 Inadequate apoptotic deletion could thus allow development of mutated clones with the potential to progress to cancer. 13,14 Proapoptotic chemopreventive agents might have the opposite effect and, thus, reduce the mutational load resulting from carcinogen exposure.Apart from AARGC, apoptosis occurs in several other contexts of relevance to CRC, including occasional ''spontaneous'' apoptosis in the proliferative zone of normal colonic crypts 15,16 and quite frequent apoptosis occurring in many cancers. 17 The role of p53 in triggering apoptosis in each of these contexts is unclear.…”

“…9 Inadequate apoptotic deletion could thus allow development of mutated clones with the potential to progress to cancer. 13,14 Proapoptotic chemopreventive agents might have the opposite effect and, thus, reduce the mutational load resulting from carcinogen exposure.…”

The relationship between intestinal histology and function as shown by compensatory enlargement of remnant villi after midgut resection in chickens

“…Epithelial cells are derived from mitotic cells situated in the crypt base (Cheng and Leblond, 1974;Potten, 1998;Potten and Grant, 1998;Wilson et al, 1998); these cells migrate upward to the villi and reach to the top of the villi, where they are extruded into the intestinal lumen within 48-96 hr (Imondi and Bird, 1966;Potten, 1998). This cell turn over seems to induce many types of cell morphologies on the villus apical surface depending upon intestinal function.…”