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Preclinical mouse solid tumour models: status quo, challenges and perspectives

Nature Reviews Cancer volume 17, pages 751–765 (2017)Cite this article

Subjects

Key Points

  • A systematic survey of 949 studies published in 2016 was conducted to quantitatively review the status quo of mouse tumour model experimentation.

  • The vast majority of in vivo studies relied on reductionist cell line-based models. More advanced models such as patient-derived xenograft, genetically engineered mouse and environmentally induced models were not used in most studies, and their availability is dependent on the tumour type.

  • Primary tumours are still the major focus of preclinical oncology, and there is a lack of mouse models focusing on advanced stages of cancer progression such as metastasis, resistance and relapse.

  • The predictive value of therapeutic mouse tumour experiments would likely benefit from a better implementation of clinical-like study design and data representation.

  • Insufficient and non-standardized reporting of mouse tumour experiments calls into question the reproducibility and comparability of preclinical studies.

  • Concerted efforts to ensure a wide distribution of standardized mouse tumour models that faithfully recapitulate the dynamics of human cancer are urgently needed.

Abstract

Oncology research in humans is limited to analytical and observational studies for obvious ethical reasons, with therapy-focused clinical trials being the one exception to this rule. Preclinical mouse tumour models therefore serve as an indispensable intermediate experimental model system bridging more reductionist in vitro research with human studies. Based on a systematic survey of preclinical mouse tumour studies published in eight scientific journals in 2016, this Analysis provides an overview of how contemporary preclinical mouse tumour biology research is pursued. It thereby identifies some of the most important challenges in this field and discusses potential ways in which preclinical mouse tumour models could be improved for better relevance, reproducibility and translatability.

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Figure 1: Schematic representation of the frequency distribution of different categories of tumour models in preclinical studies published in 2016.
Figure 2: Modelling of different tumour types in mouse model studies.
Figure 3: Modelling tumour progression and metastatic disease in mouse tumour model studies.
Figure 4: Experimental approaches in mouse tumour model studies.
Figure 5: Examples of data representation in preclinical mouse tumour studies.

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Acknowledgements

The authors regret that, because of space limitations, they could not cite all original research articles and related references on this topic. Work in the authors' laboratory is supported by funds from the Deutsche Forschungsgemeinschaft, the Helmholtz Association and the European Union.

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Author notes

  1. Nicolas Gengenbacher and Mahak Singhal: These authors contributed equally to this work.

Authors and Affiliations

  1. Division of Vascular Oncology and Metastasis, German Cancer Research Center (DKFZ–ZMBH Alliance), Heidelberg, 69120, Germany

    Nicolas Gengenbacher, Mahak Singhal & Hellmut G. Augustin

  2. Department of Vascular Biology and Tumor Angiogenesis (CBTM), Medical Faculty Mannheim, Heidelberg University, Mannheim, 68167, Germany

    Mahak Singhal & Hellmut G. Augustin

  3. German Cancer Consortium, Heidelberg, 69120, Germany

    Hellmut G. Augustin

Authors
  1. Nicolas Gengenbacher
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  3. Hellmut G. Augustin
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All authors researched data for the article, substantially contributed to discussion of the content, and wrote, reviewed and edited the manuscript before submission.

Corresponding author

Correspondence to Hellmut G. Augustin.

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Related links

PowerPoint slides

Supplementary information

Supplementary information S1 (table)

List of all reviewed 2016 studies (PDF 782 kb)

Supplementary information S2 (table)

Drop-down list values (PDF 235 kb)

Supplementary information S3 (figure)

Venn diagram of mouse tumour model categories indicating absolute numbers as well as percentage of total mouse tumour model studies (n=618) (PDF 287 kb)

Supplementary information S4 (table)

Journal-wise model distribution (PDF 86 kb)

Glossary

Immune checkpoint blockade

A therapeutic approach aimed at restoring or enhancing antitumour immune response by blocking signalling pathways that naturally limit immune reactions to prevent autoimmunity.

Autochthonous

Arising in its natural site; refers to de novo tumours that evolve out of normal cells within a living organism, in contrast to transplanted tumours, which are referred to as non-autochthonous.

Allografts

Tumours transplanted from one individual to another of the same species.

Xenografts

Cells or tissues that are transplanted between two different species, such as human and mouse.

Orthotopically

The engraftment of tumours into the 'natural' anatomical site or organ in which they usually arise.

Co-clinical trials

Trials in which an ongoing human clinical trial is mirrored by simultaneous studies in mice.

Avatar mice

A mouse into which a patient's tumour tissue is grafted to generate a 'personalized' model that is then used to identify an optimal therapeutic strategy.

'One animal per model per treatment' trial design

Also known as '1 × 1 × 1' trial design; a type of trial design in which individual mice (instead of groups of mice) from large patient-derived xenograft collections are used to evaluate drug response in a heterogeneous study population.

Carcinogen bioassay

A standardized measurement of an animal response to an environmental exposure in order to estimate its cancer-causing potential.

Site-specific recombinase (SSR) systems

Enzymatic systems, such as Cre–loxP or Flp–FRT, that rearrange genomic target segments that have been marked by specific DNA recognition sites.

Tumour dormancy

Undetectable and asymptomatic tumour cells that remain in patients who have been clinically disease-free for a long period of time. Tumours can clinically recur from this population of cells.

Response Evaluation Criteria in Solid Tumours

(RECIST). A rule set aimed at defining whether a patient with a tumour improves (objective response), stays the same (stable disease) or worsens (progressive disease) under treatment.

3R principles

Guidelines aimed at improving animal welfare and the quality of in vivo experiments by developing alternative models (replacement), limiting the number of animals used (reduction) and minimizing the suffering of animals (refinement).

Animal Research: Reporting In Vivo Experiments (ARRIVE) guidelines

A framework for proper design, analysis and reporting of mouse studies.

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Gengenbacher, N., Singhal, M. & Augustin, H. Preclinical mouse solid tumour models: status quo, challenges and perspectives. Nat Rev Cancer 17, 751–765 (2017). https://doi.org/10.1038/nrc.2017.92

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