Aberrant crypts correlate with tumor incidence in F344 rats treated with azoxymethane and phytate

Abstract

Aberrant crypts are putative preneoplastic lesions that have been proposed as intermediate biomarkers for colon cancer. The goals of these studies were to determine (i) if the colon cancer chemopreventive agent, sodium phytate, when started 1 week after a single dose of carcinogen, has any effect on the development of aberrant crypt foci (ACF) in treated rats; and (ii) if ACF at an early time period under these conditions correlate with the later formation of tumors in similarly treated animals. The number of ACF with four or more crypts was greater (P = 0.02, Mann-Whitney test) in rats with tumors compared with rats without tumors killed at 36 weeks after the injection of azoxymethane (AOM); the total number of ACF was not significantly different in these two groups. The incidence of tumors in F344 rats treated with AOM without phytate was 83% (10/12) compared to 25% (3/12) in rats treated with AOM plus phytate (P = 0.0045, two-tail Fisher's exact test). The finding of more (P = 0.005, Mann-Whitney test) ACF with four or more crypts in rats without phytate than in rats with phytate at 12 weeks after the injection of AOM is consistent with the hypothesis that the development of larger ACF (with four or more crypts) is predictive of the tumor incidence. These results validate the use of this parameter, i.e. ACF with four or more crypts, as an intermediate biomarker for tumor incidence in this system.

A Mucinous Histochemical Study on Malignancy of Aberrant Crypt Foci(ACF) in Rat Colon.

“…These findings implied that some of the SuM-dominant ACF with 3 crypts or less are normalized with time. In ACF with 4-5 crypts [10,17] or in SiM-dominant ACF [28], which show similarities to colon cancer, the lesions with mucous types other than class I mucin were few. Our observation in normal fetal rats with paradoxical Con A-staining revealed that class I mucin is the type expressed in 18-day fetal rats, while class II mucin was detected in goblet cells of the small intestine from adult rats (unpublished data).…”

“…We reported that goblet cell mucin was produced by ACF, whose mucous nature is quite similar to that of adenocarcinomas, especially in ACF with more than 4 crypts [28]. Pretlow et al [17] and Kristiansen [10] pointed out that the presence of ACF with more than 4 crypts was an important risk factor for colon cancer. Moreover, a role of ACF in colon tumorigenesis has been indicated, by the observation that showed carcinomas in lesions histologically and macroscopically diagnosed as ACF [23] and by the results of proliferating cell nuclear antigen-labeling index [22], carcinoembryonic antigen [18] and K-ras mutation molecular analysis [8,16,21,24,25,30].…”

Colon tumor promotion: is it a selection process? Effects of cholate, phytate, and food restriction in rats on proliferation and apoptosis in normal and aberrant crypts

“…The growth of ACF correlates with the adenocarcinoma yield (8,15 Bile salts are putative cancer promoters (12), and dietary cholate can promote colon tumors in rats (8,11). In contrast, dietary phytate (inositol hexaphosphate) consistently decreases colon carcinogenesis (15,18,21). Food (or caloric) restriction also decreases liver and colon carcinogenesis (3,6,7).…”

Characterisation of aberrant crypt foci in carcinogen-treated rats: association with intestinal carcinogenesis

“…In some studies the total number of ACFs or ACF crypt multiplicity have been used; in some others the numbers of 'large' ACFs were considered (Corpet et al, 1990;Pretlow et al, 1992;Zhang et al, 1992;Magnuson et al, 1993). Although in most studies large ACFs are considered an indication of rapid growth, no consensus has thus far been reached on the most appropriate method of relating ACFs to carcinogenesis.…”