Abstract
Prior to the advent of genetic engineering in the mouse, the rat was the model of choice for investigating the etiology of cancer. Now, recent advances in the manipulation of the rat genome, combined with a growing recognition of the physiological differences between mice and rats, have reignited interest in the rat as a model of human cancer. Two recently developed rat models, the polyposis in the rat colon (Pirc) and Kyoto Apc Delta (KAD) strains, each carry mutations in the intestinal-cancer-associated adenomatous polyposis coli (Apc) gene. In contrast to mouse models carrying Apc mutations, in which cancers develop mainly in the small intestine rather than in the colon and there is no gender bias, these rat models exhibit colonic predisposition and gender-specific susceptibility, as seen in human colon cancer. The rat also provides other experimental resources as a model organism that are not provided by the mouse: the structure of its chromosomes facilitates the analysis of genomic events, the size of its colon permits longitudinal analysis of tumor growth, and the size of biological samples from the animal facilitates multiplexed molecular analyses of the tumor and its host. Thus, the underlying biology and experimental resources of these rat models provide important avenues for investigation. We anticipate that advances in disease modeling in the rat will synergize with resources that are being developed in the mouse to provide a deeper understanding of human colon cancer.
Highlights
Colon cancer is a leading cause of cancer-related death worldwide
Many animal models of colorectal cancer are based on mutations in the adenomatous polyposis coli (Apc) gene, which is mutated in over 80% of colon cancers in humans (Fearnhead et al, 2001)
Conclusions and future developments In this Review, we have identified ways in which the understanding of the etiology, early detection, chemoprevention and treatment of colon cancer can be developed further using rat models
Summary
Colon cancer is a leading cause of cancer-related death worldwide. Globally, ~1.4 million new cases of colorectal cancer were diagnosed in 2012, making up nearly 10% of all cancers (Ferlay et al, 2014). A rat model isolated in Kyoto, Japan that was created by germline ENU-induced mutagenesis that generates a nonsense mutation in the Apc gene leading to tumors only when exposed to AOM and DSS. Studies of chemoprevention must consider many different issues: primary prevention versus recurrence, prevention versus treatment, the molecular pathway along which the tumor developed, and the dose and duration of treatment needed to be effective This last point is especially important in considering tests in animal models, because colon cancer has a long latent period (Jones et al, 2008) and a successful preventive agent might need to be in place far in advance of carcinoma establishment. New genome-editing technologies such as ZFNs (Cui et al, 2011; Geurts et al, 2009; Mashimo et al, 2010), TALENs (Mashimo et al, 2013; Ponce de León et al, 2014) and CRISPR/Cas
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