Maximizing mouse cancer models

The laboratory mouse (Mus musculus) is one of the best model systems for investigations of cancer biology in vivo, ranging from basic models such as xenograft tumours derived from tumour cell lines or explants, to highly complex genetically engineered mice (GEM).We suggest that xenografts should no longer be referred to as mouse cancer models. Xenografts represent an intermediate step between cell culture and mouse cancer models, and could be more accurately termed 'animal culture'.GEM can be classified as either transgenic or endogenous. This distinction is not merely semantic but is highly relevant, because the type of GEM can determine the experimental outcome in certain situations.Transgenic GEM are mutant mice that express oncogenes or dominant-negative tumour-suppressor genes (TSGs) in a non-physiological manner owing to ectopic promoter and enhancer elements. Advantages of transgenic GEM include the ability to reversibly control target-gene expression with exogenous ligands. One disadvantage is that it might be difficult to elicit the exquisite control necessary to express oncogenes at physiological levels.Endogenous GEM represent mutant mice that lose the expression of TSGs or express dominant-negative TSGs or oncogenes from their native promoters through the use of knockout and knockin technology. Conditional GEM models rely on the use of site-specific recombinases, such as Cre, to control the spatiotemporal mutation of the mouse genome. The use of these conditional models will prove to be key in addressing important molecular and therapeutic questions.Modern GEM are poised to explore facets of cancer biology and medicine that are difficult or impossible to pursue clinically. However, all GEM described so far have certain shortcomings in mimicking human malignancy. Several issues (such as humanizing mice) and practical considerations concerning GEM will need to be addressed in order to meet our objectives.