Title

Characterization of the differential susceptibility of inbred mouse strains to azoxymethane-induced colon carcinogenesis

Date of Completion

January 1999

Keywords

Health Sciences, Toxicology|Health Sciences, Oncology

Degree

Ph.D.

Abstract

Rodent carcinogen models provide a means for identifying factors involved in tumor development. Genetic background of laboratory animals is a significant component of organ-specific carcinogenesis. Inbred mouse lines were shown to vary in susceptibility to tumor induction by azoxymethane (AOM), a colon-specific carcinogen. A/J mice were highly susceptible, SWR/J mice were moderately susceptible and AKR/J mice were completely resistant. Potential mechanisms that may play a role in differential tumor susceptibility were examined. ^ AOM is metabolized to a highly electrophilic species capable of forming DNA adducts. The role of DNA methyl adduct formation in conferring differential cancer risk was therefore investigated. Specific susceptibilities to AOM-induced carcinogenesis did not correlate with the extent of initial DNA methyl adduct formation within target tissue colonic mucosa. This data indicates that differences in later stages of carcinogenesis may be more important. ^ Aberrant crypt foci (ACF) are preneoplastic lesions induced by a variety of colon carcinogens. ACF developed in both resistant and sensitive mouse strains after AOM treatment. Furthermore, the total number of ACF was comparable in sensitive and resistant mice at various time points following AOM treatment. There was, however, a correlation between the formation of larger, more dysplastic ACF and strain sensitivity. These data suggest that AOM produces comparable preneoplastic changes in resistant and susceptible mice, but progression of lesions in resistant mice is somehow prevented. ^ Tumor modifier genes may possibly block progression of precursor lesions. The relation of group IIA secretory phospholipase A2 (sPLA 2), an intestinal tumor modifier, to AOM susceptibility was therefore examined. Constitutive expression of sPLA2 mRNA and protein was inversely correlated with tumor susceptibility in young mice. The effect of AOM on colonic sPLA2 expression was also examined. There was a significant increase in mRNA in normal-appearing epithelium and tumor tissue from AOM-treated mice relative to controls. ^ These data suggest that AOM produces comparable biochemical and morphological changes in resistant and susceptible mice. Differential susceptibility to AOM may have its basis in the failure of ACF to progress in the resistant AKR/J mice. The role of the tumor modifier gene, sPLA2, within this model is not clear. ^