Sequential Changes in Colonic Mucosal Morphology and Epithelial Proliferation during Chemically Induced Carcinogenesis in Rats

Abstract

The rat model of azoxymethane (AOM) induced colonic carcinogenesis was evaluated for preneoplastic changes in epithelial DNA synthesis and histopathologic characteristics analogous to those observed in human beings at high risk for colonic carcinoma. 10-week-old male Fischer 344 rats were given 10 weekly subcutaneous injections of AOM at a dose of 15 mg/kg. Every 2 weeks after the first carcinogen dose, 5 animals were sacrificed 1 h after an intraperitoneal injection of methyl-³thymidine, 0.5 mCi/kg body weight. The experiment was terminated 25 weeks after the first AOM injection. By autoradiography, the labelling index (LI) of the ascending colon (AC) was 8.6 ± 0.5 % for AOM-treated animals and 4.7 ± 0.94% for controls (p < 0.05). In the descending colon (DLC) the LI was 10.3 ± 0.9% for AOM-treated animals as compared to 6.8 ± 1.4% for controls (p < 0.01). In the AC the main zone of DNA synthesis shifted from the lower third to the middle third of the crypt in AOM-treated rats, while in the DLC the zone remained in the basal third. No crypt epithelial hyperplasia was found with carcinogen treatment. Crypt elongation, crypt dilatation, and mucosal edema formation were associated with the course of AOM administration and appeared to be toxic effects. In contrast, the mucus content of the crypt epithelium showed a biphasic decrease over the entire time course of the study. Dysplastic crypts appeared earlier in the AC, however, and the early appearance was associated with persistently elevated labelling indices and shift in the main zone of DNA synthesis. We conclude that in experimental colonic carcinogenesis, preneoplastic changes in cell proliferation (‘stage I’ and ‘stage IF abnormalities) similar to those in human beings at high risk can be observed. Thus, despite the absence of an adenoma-carcinoma sequence, experimental colonic carcinogenesis provides an important model to study modulators of preneoplastic changes and their impact on malignant transformation of colonic mucosa.

Effects of androgen manipulations on chemically induced colonic tumours and on macroscopically normal colonic mucosa in male Sprague-Dawley rats

“…Thus the colonic segments showed a variable susceptability to the colonic carcinogen, as reported previously (Izbicki et al, 1988 (Naito, 1982) is also indicated by the results of crypt length measurements. In the right colon, all hormonal manipulations led to significantly decreased crypt lengths, whereas the left colon did not reveal significant changes in crypt length after hormonal manipulations.…”

“…Chemical induction of colonic carcinomas in rats has been found to provide a reliable model of colonic carcinogenesis in humans. Although an adenoma-carcinoma sequence cannot be identified as clearly as in humans (Maskens & DujardinLoits, 1981;Izbicki et al, 1985), proliferative abnormalities similar to those observed in human individuals at high risk for colonic cancer are demonstrable (Izbicki et al, 1988;Deschner, 1983). In recent years these experimental carcinogenesis models were used to evaluate the effects of steroid hormones, including androgens, and of hormonal manipulations on chemically induced tumours.…”

“…Proliferative abnormalities in colonic crypt epithelium are considered to be precursors to the malignant transformation of colonic mucosa in humans (Deschner, 1983) as well as in experimental animals (Deschner, 1983;Izbicki et al, 1988). The postulated carcinogen-induced hypersensitivity of colonic mucosal cells to androgens (Jacobson, 1984) should therefore be reflected in alterations of proliferation as a consequence of hormonal manipulations.…”

“…The prevalence of dysplastic crypts is generally thought to be influenced by the degree of proliferative abnormalities (Izbicki et al, 1988;Deschner, 1983). In this study, severe proliferative abnormalities of the ascending colon, which were especially pronounced after chemical castration, were not followed by increased occurence of dysplastic crypts (groups II and IV).…”

Activity Patterns of Proteolytic Enzymes – Relationship to Neoplastic Events during Experimental Carcinogenesis and Preliminary Results from Colorectal Tumor Patients

“…The animals received subcutaneous injections of 15 mg AOM (Ash staging of Stevens, Detroit, Mich., USA) once weekly starting at 10 weeks of age. The carcinogen was prepared as described previously [15,16], Ani mals were randomly allocated to groups of 5. The experiment was designed as a serial kill study.…”