Pathobiology of strain-specific responses to azoxymethane-induced colorectal cancer

Colorectal cancer (CRC) is the third leading cause of cancer in the United States. Ninety percent of colorectal cancers arise sporadically. Nonetheless, individuals with close relatives that have sporadic CRC are at an increased risk for developing this disease. Administration of the alkylating agent, azoxymethane (AOM), predominantly induces distal colon tumors in rodents that appear histopathologically similar to human sporadic colon tumors. Susceptibility to AOM is background-dependent and shows marked variability among inbred mouse strains. This dissertation investigates strain-specific responses to AOM exposure. We hypothesize that potential genetic modifiers of colorectal cancer susceptibility can be identified from studying strain- and susceptibility-specific responses to AOM. To investigate this hypothesis, studies were designed to (1) Establish a dosing regime to sensitively identify inter-strain variation in response to AOM; (2) Establish a tumor profile using a variety of inbred strains; (3) Determine whether strain-specific susceptibilities to AOM-induced CRC translates to differences in tumor histopathology and pathway disruption; and (4) Correlate acute changes in AOM-induced gene expression profiles with CRC susceptibility. The tumor profile study included 39 inbred strains and extensive strain variation in tumor incidence was demonstrated. Further studies to analyze tumor morphology and molecular pathways altered in AOM tumorigenesis identified strain-specific differences in morphological characteristics. Immunohistochemical studies showed strain-specific differences in beta-catenin and transforming growth factor beta receptor type II staining patterns. Cyclooxygenase II immunohistochemical analysis identified localization patterns indicative of tumor shape. The examination of early changes in colonic gene expression profiles in response to AOM identified genes significantly altered with respect to susceptibility and time after AOM treatment using significance of microarray analysis (SAM). Gene ontology analysis of the genes identified time and susceptibility specific differences related to immune response. Our studies should lead to clues to the mechanism responsible for AOM-induced colon cancer. Additionally, this project will help to identify new, morphology-specific mouse models for human CRC.