Mouse models for the study of colon carcinogenesis

Abstract

The study of experimental colon carcinogenesis in rodents has a long history, dating back almost 80 years. There are many advantages to studying the pathogenesis of carcinogen-induced colon cancer in mouse models, including rapid and reproducible tumor induction and the recapitulation of the adenoma-carcinoma sequence that occurs in humans. The availability of recombinant inbred mouse panels and the existence of transgenic, knock-out and knock-in genetic models further increase the value of these studies. In this review, we discuss the general mechanisms of tumor initiation elicited by commonly used chemical carcinogens and how genetic background influences the extent of disease. We will also describe the general features of lesions formed in response to carcinogen treatment, including the underlying molecular aberrations and how these changes may relate to the pathogenesis of human colorectal cancer.

Fig. 1.

Metabolism of AOM involves multiple transcriptionally regulated xenobiotic-metabolizing enzymes.

Fig. 2.

Metabolic pathway for PhIP activation and induced mutations.

Fig. 3.

(A) Protocol for AOM/DSS-induced colon carcinogenesis. Animals received a single i.p. injection (10 mg/kg body wt for AOM and 10 or 20 mg/kg body wt for DMH), or intragastric intubation (PhIP, 200 mg/kg body wt), followed by a 1 week exposure of DSS (1–2%) in drinking water to induce colonic neoplasms. Between 15 and 20 weeks, colon tumors in mice (B) and rats (C) develop. (D) Dysplastic crypts induced by the combination of AOM/DSS in mice. (E) Tubular adenoma induced by AOM/DSS in mice. (F) A representative tubular adenocarcinoma induced by AOM/DSS in mice. Scale bar = 60 μm.