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  • Review Article
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Maximizing mouse cancer models

Nature Reviews Cancer volume 7, pages 654–658 (2007)Cite this article

Key Points

  • 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.

Abstract

Animal models of cancer provide an alternative means to determine the causes of and treatments for malignancy, thus representing a resource of immense potential for cancer medicine. The sophistication of modelling cancer in mice has increased to the extent that investigators can both observe and manipulate a complex disease process in a manner impossible to perform in patients. However, owing to limitations in model design and technology development, and the surprising underuse of existing models, only now are we realising the full potential of mouse models of cancer and what new approaches are needed to derive the maximum value for cancer patients from this investment.

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Figure 1: Transgenic GEM.
Figure 2: Endogenous GEM.
Figure 3: Sequential mutations in mouse cancer models.
Figure 4: Hallmarks of humanized mouse models.

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Acknowledgements

We thank members of the Tuveson lab for helpful comments on the manuscript. Work is supported by US National Institutes of Health grants 1F32CA123887-01 (K.K.F.), CA101973 (D.A.T.), CA111292 (D.A.T.), CA084291 (D.A.T.), CA105490 (D.A.T.) and the Lustgarten Foundation for Pancreatic Cancer Research (D.A.T.). D.A.T. is a group leader of Cancer Research UK.

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    Kristopher K. Frese & David A. Tuveson

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Glossary

Xenograft

Tumour tissue or cell lines from one species propagated in immunodeficient mice in ectopic or orthotopic sites.

Genetically engineered mice

(GEM). Mice harbouring genetic modifications designed to express either exogenous or endogenous mutated genes. In cancer modelling, these are frequently oncogenes or tumour-suppressor genes.

Cell autonomous

A trait engendered only in cells harbouring the mutation. In the case of a carcinoma, a cell autonomous function occurs only in the mutant tumour epithelial cells.

Non-cell autonomous

A trait engendered in cells that do not harbour the mutation. In the case of a carcinoma, a non-cell autonomous function occurs in stromal, immune and endothelial cells.

Autochthonous tumour

An endogenous or in situ tumour that evolves from normal cells of a tumour-bearing animal. This is in contrast to animal cultures in which exogenous tumour cells are implanted into a non-tumour-bearing animal.

Tumour microenvironment

The stroma and supporting milieu surrounding the tumour that consists of fibroblasts, immune cells and endothelial cells.

Oncogene addiction

The hypothesis that tumours arising as a result of a particular oncogenic lesion are exquisitely dependent on continued expression of that oncogene.

Loss of heterozygosity

Mutation or 'loss' of the remaining wild-type allele in a heterozygous GEM.

Haploinsufficiency

A phenotypic state that results from loss of one functional allele of any given gene in diploid cells. Sometimes also called allelic insufficiency.

Conditional models

GEM that rely on site-specific recombinase systems to engender gene expression in a spatially and/or temporally restricted manner.

Site-specific recombinase

(SSR). An enzyme, such as bacterial Cre, that catalyses recombination between two specific inverted repeat sequences (such as LoxP).

CreERT

A general term for a tamoxifen-inducible Cre recombinase in which the Cre cDNA is fused to the oestrogen receptor ligand-binding domain. This fusion protein is sequestered in the cytoplasm by heat shock proteins until exposure to Tamoxifen promotes nuclear translocation.

LoxStopLox

A LoxP-flanked sequence, often containing an antibiotic resistance marker, that prevents expression of a gene when placed between the promoter and coding exons.

Latent allele

An endogenous GEM strategy in which a stochastic recombination event is required to activate expression of the oncogenic allele. This is one of the few endogenous GEM that does not require a site-specific recombinase.

Hypomorphic allele

A mutation conveying decreased activity, either through reduced expression or partial loss of function.

Neomorphic allele

A mutation conveying a novel activity not present in the wild type protein.

Adeno-associated virus

(AAV) Small DNA viruses often used for gene therapy due to their broad host range and the ability to infect non-dividing cells.

Xenobiotic receptors

A family of enzymes involved in the metabolism of drugs by sensing the presence of a drug and initiating a response.

Cytochrome P450

A family of metabolic enzymes responsible for detoxifying and modifying drugs and other foreign compounds.

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Frese, K., Tuveson, D. Maximizing mouse cancer models. Nat Rev Cancer 7, 654–658 (2007). https://doi.org/10.1038/nrc2192

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