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Conditional mouse models of sporadic cancer

Nature Reviews Cancer volume 2, pages 251–265 (2002)Cite this article

Key Points

  • Sporadic cancer development is triggered by initiating mutations in a single cell, which result in tumour growth in a genetically wild-type environment that might actively contribute to tumour progression.

  • Tumour models that use conventional transgenic or knockout mice do not allow modelling of sporadic cancer, because the initiating mutation is present in all cells of a specific tissue or throughout the body. These cells include those that constitute the tumour microenvironment.

  • Various methods for conditional tumour-suppressor gene mutation and oncogene activation allow modelling of sporadic cancer in genetically engineered mice.

  • Recombinase-mediated conditional gene mutation can be used successfully to circumvent embryonic lethality or unwanted tumorigenesis in conventional tumour-suppressor gene knockouts.

  • Tumour growth and maintenance in mice with regulatable oncogene expression depends, in most cases, on continuous oncogene expression, supporting the validity of these factors as therapeutic targets.

  • Combining mouse models of sporadic cancer with various genome-wide screens for genetic alterations allows a comparison, on a molecular level, of mouse tumours with their human counterparts, and facilitates the discovery of new cancer genes and pathways that are involved in multistep tumorigenesis.

  • Mouse imaging systems that enable the non-invasive monitoring of tumour development will render conditional mouse models of sporadic cancer particularly useful for preclinical testing of therapeutic intervention or chemoprevention strategies.

Abstract

First-generation mouse tumour models, which used transgenic mice or conventional knockouts, are now being superseded by models that are based on conditional knockouts and mice that carry regulatable oncogenes. In these mice, somatic mutations can be induced in a tissue-specific and time-controlled fashion, which more faithfully mimics sporadic tumour formation. These second-generation models provide exciting new opportunities to gain insight into the contribution of known and unknown genes in the initiation, progression and treatment of cancer, and mimic human cancer better than ever before.

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Figure 1: Conventional versus conditional mouse tumour models.
Figure 2: Systems that allow conditional gene mutation in mice.
Figure 3: Systems that allow controllable oncogene expression in mice.
Figure 4: In vivo imaging of spontaneous tumour development.

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Acknowledgements

We apologize to all colleagues whose relevant contributions to the field could not be cited owing to space constraints. We thank P. Krimpenfort, A. Loonstra, R. Meuwissen and K. Quon for critical reading of the manuscript. Our studies reviewed in this article were supported by the Dutch Cancer Society and the Netherlands Organization for Scientific Research.

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Authors and Affiliations

  1. Division of Molecular Genetics, and Centre of Biomedical Genetics, The Netherlands Cancer Institute, Plesmanlaan 121, CX, 1066, Amsterdam, The Netherlands

    Jos Jonkers & Anton Berns

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  1. Jos Jonkers
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  2. Anton Berns
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Correspondence to Anton Berns.

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DATABASES

Cancer.gov

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FURTHER READING

Anton Berns' lab

Biology of the mammary gland

Cre transgenic and floxed gene database

Mouse Models for Human Cancer Consortium (MMHCC) homepage

Mouse Tumor Biology (MTB) database

Online version of Lee Silver's 'Mouse Genetics'

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Glossary

PRISTANE

A carcinogenic saturated hydrocarbon (2,6,10,14-tetramethylpentadecane) that is purified from mineral oil.

PROVIRUS

The duplex DNA form of the retroviral genome. The provirus is produced by reverse transcription of the RNA genome and is subsequently integrated into the chromosomal DNA of the infected host cell.

HOMOLOGOUS RECOMBINATION

The process by which segments of DNA are exchanged between two DNA duplexes that share high sequence similarity.

K14–HPV16

A transgenic mouse strain that expresses the human papillomavirus type 16 (HPV16) early-region genes, including the E6 and E7 oncogenes, under the control of the human keratin-14 promoter (K14), in basal keratinocytes. Invasive squamous carcinomas of the epidermis develop through characteristic stages.

APICAL ECTODERMAL RIDGE

(AER). The layer of surface ectodermal cells that is at the apex of the embryonic limb bud. This layer exerts an inductive influence on the condensation of the underlying mesenchyme.

MESENCHYME

Embryonic tissue that is composed of loosely organized, unpolarized cells of both mesodermal and ectodermal (for example, neural crest) origin, with a proteoglycan-rich extracellular matrix.

HYPOMORPHIC ALLELE

An allele that results in a reduction, but not the elimination, of wild-type levels of gene product or activity, often causing a less severe phenotype than a loss-of-function (or null) allele.

MEDULLOBLASTOMA

A brain tumour that consists of cells resembling the undifferentiated cells of the primitive medullary tube. Medulloblastomas are often located in the vermis of the cerebellum.

EXTERNAL GRANULAR LAYER

The deepest of the three layers in the cerebellar cortex. It contains large numbers of granule cells, the dendrites of which form synapses with incoming mossy fibres in cerebellar glomeruli. The axons of the granule cells ascend into the molecular layer in which they bifurcate into fibres that form numerous synapses with the dendrites of Purkinje cells, basket cells and stellate cells.

TRANSCRIPTIONAL TERMINATOR

A specific DNA sequence, represented at the end of a gene, that causes RNA polymerase to terminate transcription.

ADENOVIRAL VECTOR

A gene-therapy vector that is derived from an adenovirus. Genes necessary for replication of the virus can be deleted to make replication-defective vectors.

HERPES SIMPLEX VIRUS VP16

A potent transcriptional activator protein of herpes simplex virus. Various chimeric sequence-specific transcriptional activators have been engineered by fusing the VP16 transcriptional activation domain to the sequence-specific DNA-binding domains of other proteins.

PAPILLOMATOSIS

Papillary projections of the epidermis that form a microscopically undulating surface.

FORWARD SCREENS

Genetic screens that employ genome-wide saturation mutagenesis to obtain specific mutant phenotypes. The causal mutations can be subsequently identified by genetic and/or molecular approaches.

ATAXIA-TELENGIECTASIA MUTATED

(ATM). Germ-line mutations in the ATM gene — involved in the DNA-damage response — are responsible for ataxia-telangiectasia/Louis–Bar syndrome, a familial recessive disease that is characterized by progressive cerebellar ataxia, oculocutaneous telangiectases and susceptibility to pulmonary infections.

PML–RARα AND RARα–PML

Protein fusions between the promyelocytic leukaemia tumour suppressor (PML) and the retinoic-acid receptor-α (RARα). The fusion genes are associated with human acute promyelocytic leukaemias and are generated by reciprocal translocations of chromosomes 15 and 17.

RIP-TAg

A transgenic mouse strain that expresses the simian virus 40 large T antigen (TAg) under the rat insulin II promoter (RIP) in the pancreatic islet cells. Carcinomas develop in the pancreatic islets and progress through characteristic stages.

TELOMERE CRISIS

State of cells in which the progressive shortening of telomeres during successive cell divisions has impaired their capacity to protect the ends of chromosomal DNA, leading to end-to-end fusions and genomic instability.

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Jonkers, J., Berns, A. Conditional mouse models of sporadic cancer. Nat Rev Cancer 2, 251–265 (2002). https://doi.org/10.1038/nrc777

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