The AOM/DSS murine model for the study of colon carcinogenesis: From pathways to diagnosis and therapy studies

Abstract

Colorectal cancer (CRC) is a major health problem in industrialized countries. Although inflammation-linked carcinogenesis is a well accepted concept and is often observed within the gastrointestinal tract, the underlying mechanisms remain to be elucidated. Inflammation can indeed provide initiating and promoting stimuli and mediators, generating a tumour-prone microenvironment. Many murine models of sporadic and inflammation-related colon carcinogenesis have been developed in the last decade, including chemically induced CRC models, genetically engineered mouse models, and xenoplants. Among the chemically induced CRC models, the combination of a single hit of azoxymethane (AOM) with 1 week exposure to the inflammatory agent dextran sodium sulphate (DSS) in rodents has proven to dramatically shorten the latency time for induction of CRC and to rapidly recapitulate the aberrant crypt foci-adenoma-carcinoma sequence that occurs in human CRC. Because of its high reproducibility and potency, as well as the simple and affordable mode of application, the AOM/DSS has become an outstanding model for studying colon carcinogenesis and a powerful platform for chemopreventive intervention studies. In this article we highlight the histopathological and molecular features and describe the principal genetic and epigenetic alterations and inflammatory pathways involved in carcinogenesis in AOM/DSS-treated mice; we also present a general overview of recent experimental applications and preclinical testing of novel therapeutics in the AOM/DSS model.

Keywords: Animal model; chemical carcinogens; colorectal carcinogenesis; preclinical studies.

Figure 1

Comparison of different protocols based on DMH-AOM-DSS administration for induction of colorectal tumors in the murine model. Different protocols based on DMH or AOM, administered individually or in combination with DSS, are schematically represented. The time of tumor identification (T) has been indicated. Protocol number 6 shows a short latency time and a very simple procedure of tumor induction.

Figure 2

Schematic representation of multistep tumor progression in the AOM/DSS murine model. The multistep tumor progression observed in the AOM/DSS murine model of CRC, based on the ACF-adenoma-carcinoma sequence, is represented on the timeline, with the principal molecular alterations assessed in specific phases of the carcinogenic process.

Figure 3

Histopathology of early colonic neoplasms developed in AOM/DSS-treated mice. Single aberrant crypt (a, d); aberrant crypt focus - ACF (b, e); microadenoma (c, f). Methylene blue (a, b, c) and hematoxylin-eosin (d, e, f) stain. Original magnification, (a, b, c) ×10; (d, e, f) ×20. (Unpublished data).

Figure 4

Macroscopic observation and histopathology showing late colonic neoplasms developed in AOM/DSS-treated mice. Tubular adenoma (a, d); moderately differentiated adenocarcinoma (b, e); and moderately differentiated adenocarcinoma invading into the mucosa (c, f). Macroscopic analysis in necroscopy (a, b, c) and hematoxylin-eosin stain (d, e, f). Original magnification ×4. (Unpublished data).