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Mitotic chromosomal instability and cancer: mouse modelling of the human disease

Key Points

  • Chromosomal instability (CIN), the inability to correctly segregate sister chromatids during mitosis, provides the evolutionary fuel to initiate and propagate the transformed state of multiple forms of cancer.

  • The mitotic checkpoint is seldom lost or weakened in human tumours.

  • Mitotic checkpoint overactivation is a more frequent observation in human tumours and is sufficient to generate CIN in vivo and in vitro. Mitotic checkpoint overactivation results in a prolonged mitosis, abnormal stabilization of cyclin B1 and securin, and an increased incidence of merotelic attachments and lagging chromosomes.

  • Many of the key regulators of the mitotic checkpoint are downstream targets of the Rb tumour suppressor pathway and are therefore upregulated in most human tumours.

  • The consequences of CIN are manifold and context-dependent. Although CIN can initiate tumour formation in many mouse models, under some conditions it decreases cellular fitness, providing a potential tumour suppressor effect. This effect is nevertheless often overcome, giving rise to the karyotypic complexity observed in advanced tumours.

  • Mitotic checkpoint overactivation could prove effective as a novel therapeutic target as mitotic checkpoint loss is incompatible with cellular viability.

Abstract

The stepwise progression from an early dysplastic lesion to full-blown metastatic malignancy is associated with increases in genomic instability. Mitotic chromosomal instability — the inability to faithfully segregate equal chromosome complements to two daughter cells during mitosis — is a widespread phenomenon in solid tumours that is thought to serve as the fuel for tumorigenic progression. How chromosome instability (CIN) arises in tumours and what consequences it has are still, however, hotly debated issues. Here we review the recent literature with an emphasis on models that recapitulate observations from human disease.

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Figure 1: The mitotic checkpoint.
Figure 2: Multiple mechanisms leading to aneuploidy.

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Acknowledgements

We apologize to those authors whose work is not cited because of space limitations. We would like to thank A. Unni and W. Forrester for helpful discussions of the manuscript. J.M.S. is supported by a Breast Cancer Research Program Predoctoral Traineeship Award from the Department of Defense (Congressionally Directed Medical Research Program). R.S. was supported by the Charles H. Revson Foundation. R.B. is supported by the National Institutes of Health.

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DATABASES

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ataxia–telangiectasia

Li–Fraumeni

mosaic variegated aneuploidy

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Glossary

Chromosome instability

The inability to maintain a correct chromosome complement after cell division.

Aneuploidy

An abnormal chromosome number.

Mitotic checkpoint

A cell cycle checkpoint that arrests cell division at metaphase until all sister kinetochores are attached to microtubules from opposite spindle poles.

Breakage–fusion–bridge cycles

A process of amplification in which two centromeres of a dicentric chromosome are pulled to opposite poles during mitosis. If the chromosome breaks then the double-stranded breaks persist in the following S-phase and can contribute to translocations or form new dicentric chromosomes that continue the process of instability.

Whole chromosome instability

This describes CIN in terms of abnormal numbers of chromosomes.

Segmental chromosome instability

This describes CIN in terms of structural abnormalities, such as translocations, inversions, interstitial deletions and amplifications.

Kinetochore

The protein complex that assembles around centromeric chromosome regions and is the source of the signal that activates the mitotic checkpoint and the site of spindle fibre attachment.

Spindle pole

The site of origin of microtubule fibres in mitosis. In most cells this site is delineated by the presence of centrosomes that act as microtubule organizing centers.

Cohesin

A protein complex composed of structural maintenance of chromosomes 1A (SMC1A), SMC3, sister chromatid cohesion 1 (SSC1, also known as RAD21) and SSC3 (also known as stromal antigen 1), the function of which is to topologically link sister chromatids before metaphase.

Anaphase promoting complex/cyclosome

A large E3 ubiquitin ligase complex that degrades cyclin B1 and securin once the mitotic checkpoint is satisfied.

Spindle poison

A compound that affects microtubule function and therefore mitotic spindle formation by stabilizing (such as taxanes) or depolymerizing (such as vinka alkaloids or nocodazole) microtubules.

Transformation

A mechanistically defined process in which a primary cell acquires the ability togrow indefinitely in vitro (immortalization), form colonies in soft agar (anchorage-independent growth) and form tumour xenografts when implanted intradermally in nude mice.

Microcephaly

An abnormally small head circumference, which usually results from abnormal brain development.

Mosaic aneuploidy

A tissue in which groups of cells contain chromosome complements that differ from those of neighbouring cells.

Merotelic attachment

When a single kinetochore is attached to microtubules from two spindle poles rather than to one pole.

Mitotic slippage

The process by which a cell arrested in mitosis proceeds through anaphase despite an active mitotic checkpoint.

Monastrol

A small molecule inhibitor of the plus-end directed KIF11 kinesin motor, the function of which is required for chromosome segregation in mitosis.

Nocodazole

A chemical inhibitor of microtubule polymerization often used to activate the mitotic checkpoint and therefore arrest cells in the G2/M phase of the cell cycle.

Lagging chromosome

In anaphase, pairs of sister chromatids that remain at the metaphase plate, often as a consequence of merotelic attachment, can be the source of aneuploidy in the resulting daughter cells. This is distinct from a single chromatid that fails to segregate upon disjunction from its sister chromatid.

Chromosome bridge

In anaphase, a chromosome that bridges the two separating daughter nuclei as a result of abnormal attachments.

Robertsonian translocation

A non-reciprocal chromosomal translocation in which two distinct acrocentric chromosomes become fused and share a single centromere.

DMBA-induced tumour

An induced tumour model in mice in which the carcinogen DMBA (7,12-dimethylbenz(a)anthracene) is applied to the skin of 5–7 day old pups. This results in the appearance of skin and lung tumours once animals reach adulthood.

Array-comparative genomic hybridization

A genomic DNA hybridization technique that allows high-resolution analysis of copy number changes between two populations (such as normal versus tumour DNA).

Non-cell-autonomous effect

A phenotypic effect seen in a field of cells that are mediated by cells that are not part of that field, such as the clearance of tumour cells by bone marrow cells or cells of the tumour microenvironment.

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Schvartzman, JM., Sotillo, R. & Benezra, R. Mitotic chromosomal instability and cancer: mouse modelling of the human disease. Nat Rev Cancer 10, 102–115 (2010). https://doi.org/10.1038/nrc2781

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