According to the American Cancer Association, more than 1.5 million new cases of cancer were diagnosed in 2010 in the United States alone. More than half a million people succumbed to the disease last year, making it the nation’s second deadliest disease.

It isn’t necessary to know the exact statistics to understand that cancer is a major concern for both the medical community and lay population. For this reason, the pharmaceutical industry continues to focus resources on discovering compounds for creating effective treatments for this prevalent and still mysterious disease. One of the industry’s most valuable in vivo tools in that quest is the rodent model.

Mouse models in oncology research
The rodent model has been used in oncology research for several decades. Historically, the mouse has been a model of choice for the battery of tests that compounds must undergo to determine efficacy and safety of cancer therapy candidates. Mice, above all other mammalian species, have proven useful in oncology research because of their small size, ease of rearing, and ability to be produced commercially with specific research-valuable traits.

The biomedical research community offers a wide variety of immunodeficient mouse models—models whose immune systems are compromised and allow acceptance and growth of a wide range of xenografts. Each immunodeficient mouse model has its own unique characteristics that have developed either through spontaneously arising mutation or genetic engineering.

Among mice with spontaneous mutation-derived immunodeficiencies—in which an immunodeficiency occurred naturally and then was carefully bred to create a permanent line—the most popular model is the athymic “nude” mouse (genotype Foxn1^nu). Nude mice fail to develop thymus-derived T cells, and consequently will accept a wide range of murine and xenogenic tumor transplants. Because the nude mutation blocks normal epithelial development, the mutation also presents with a characteristic hairless phenotype.  The lack of hair also makes for a more efficient model since researchers do not have to shave the animal in order to accurately measure subcutaneous tumor growth.

Another commonly-used mouse model carrying a spontaneous mutation is the SCID mouse (severe combined immune deficiency).  The SCID mouse (genotype Prkdc^scid) lacks both T and B cell lineages. Like the nude mouse, the model is useful in solid tumor biology and related therapeutic development. 

click to enlarge Table 1. Examples of Immunodeficient Mouse and Rat Models (Source: Charles River)

In addition to these two classic single-mutation models, numerous additional immunodeficient models have been produced through backcrossing (e.g., transferring a specific trait between two established mouse models). Common examples of immunodeficient mouse models are provided in table 1, including several models carrying the Beige (genotype Lyst^bg) mutation and the X-linked Immune Defect (genotype Btk^xid) mutations, which when paired with the nude or SCID mutations result in pan-lymphocyte impairment (e.g., lack of T, B, and natural killer cells). Also highlighted is the nonobese diabetic (NOD) mouse, which possesses deficits in T cell regulation and natural killer cells, and when crossed with the SCID mouse results in a deficiency in T, B and natural killer cells. Recently, the SCID mutation was crossed with a naturally hairless mouse to produce a hairless SCID model.  This model is available from Charles River as both outbred and congenic (inbred) lines—the SCID Hairless Outbred (SHO) and SCID hairless congenic (SHC) respectively.

In recent years, advances in genetic engineering have allowed the research community to customize mice with specific immunologic deficits that are useful in cancer research without waiting for spontaneous mutations to arise. Two genetically engineered mouse models that share a similar phenotype to the SCID mouse are the RAG1 and RAG2 (recombinant activating genes 1 and 2) deficient mice, both of which lack T and B cells.

Rat models in oncology research
Recently, rat models have found themselves in the conversation with regard to in vivo rodent cancer research. Theoretically, rats may provide benefits over the mouse in oncology research because they are larger and, as a result, they allow for prolonged dosing and increased tumor size development compared to mice. Currently, the use of rats in oncology has been hampered by the relative paucity of available models, particularly immunodeficient rat models for use with xenographs. The most common commercially available immunodeficient rat model is the nude rat (genotype Foxn1^rnu). Similar to the nude mouse, the rat model is deficient in thymus-derived T cells and its use is similar to the mouse model.

If rats are to play a larger role in the future of oncology research, it will more than likely result from advances in genetic engineering and the ability to create rat knockout models lacking specific genes associated with immune deficiency or tumor development. This activity has already begun, with researchers utilizing genetic engineering to create rat knockout models deficient in several tumor suppressor genes, including Apc, Bcra2 and Msh6.

Another good example of this type of rat model is the p53 model that is currently on the market. Tumor protein 53 is a well-characterized tumor suppressor that is involved in cell cycle control, apoptosis, angiogenesis, carcinogenesis, senescence, DNA repair, and changes in metabolism. The p53 rat develops a wide variety of malignant tumors, including sarcomas and lymphomas, making it useful for oncology research.

Conclusion
Of course, the type of model chosen for cancer research—rat, mouse, spontaneous mutation, genetically engineered, T cell deficient, or B cell deficient—completely depends on the nature of the research. Like every other facet of drug discovery and development, model choice and utilization is a complicated process that must be tailored to the goals, needs, and limits of the research.

Whether the future of oncology research lies with classic mice or genetically engineered rats, we can anticipate an increase in the number of available models for cancer research, with every refinement further increasing our understanding of the disease and, hopefully, an eventual cure.

About the Author
Guy Mulder is the attending veterinarian and Director of Professional Services with Research Models and Services at Charles River.