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On the road to cancer: aneuploidy and the mitotic checkpoint

Nature Reviews Cancer volume 5, pages 773–785 (2005)Cite this article

Key Points

  • Aneuploidy, or abnormal chromosome content, is the most common characteristic of human solid tumours. Aneuploidy might contribute to tumour formation and is associated with acquired resistance to some chemotherapeutics.

  • Tumour cells become aneuploid as a result of aberrant mitotic divisions. These aberrant divisions are caused by divisions with a multipolar spindle as a result of previous defects in cytokinesis or centrosome amplification, by defects in chromosome cohesion, by spindle attachment defects, or by impairment of the mitotic checkpoint response.

  • The mitotic checkpoint is a signalling cascade that arrests the cell cycle in mitosis when even a single chromosome is not properly attached to the mitotic spindle. This arrest is achieved by inhibiting the anaphase-promoting complex/cyclosome (APC/C), an E3 ubiquitin ligase that is essential for mitotic progression.

  • Many tumour cells have a diminished, but not absent, mitotic checkpoint response. Mouse models in which mitotic checkpoint signalling is decreased show an increase in spontaneous or carcinogen-induced tumour formation.

  • Mutations in mitotic checkpoint genes themselves are not a common mechanism of checkpoint impairment in human tumour cells.

  • Mitotic checkpoint impairment and aneuploidy in human tumour cells are often associated with changes in the protein levels of mitotic checkpoint proteins. In some tumour cells, these changes occur through altered transcriptional regulation by tumour suppressors or oncogene products.

  • Complete inactivation of mitotic checkpoint signalling causes cell-autonomous lethality. Drugs that specifically and efficiently interfere with mitotic checkpoint signalling could therefore be useful as anticancer agents.

Abstract

Abnormal chromosome content — also known as aneuploidy — is the most common characteristic of human solid tumours. It has therefore been proposed that aneuploidy contributes to, or even drives, tumour development. The mitotic checkpoint guards against chromosome mis-segregation by delaying cell-cycle progression through mitosis until all chromosomes have successfully made spindle-microtubule attachments. Defects in the mitotic checkpoint generate aneuploidy and might facilitate tumorigenesis, but more severe disabling of checkpoint signalling is a possible anticancer strategy.

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Figure 1: The roads to aneuploidy.
Figure 2: The mammalian mitotic checkpoint — signalling and silencing.
Figure 3: Mutations in mitotic checkpoint genes.
Figure 4: Mitotic checkpoint defects in cancer.
Figure 5: Induction of gross chromosome mis-segregations as an anticancer strategy.

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Author information

Authors and Affiliations

  1. Department of Medical Oncology, Laboratory of Experimental Oncology, University Medical Center, Utrecht, 3584 CG, The Netherlands

    Geert J. P. L. Kops

  2. Ludwig Institute for Cancer Research and Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, 92093-0670, California, USA

    Beth A. A. Weaver & Don W. Cleveland

Authors
  1. Geert J. P. L. Kops
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  2. Beth A. A. Weaver
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  3. Don W. Cleveland
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Corresponding authors

Correspondence to Geert J. P. L. Kops or Don W. Cleveland.

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DATABASES

Entrez Gene

APC

aurora kinase A

aurora kinase B

BRCA1

BRCA2

BUB3

BUBR1

CDC20

CENPE

CMT2

cyclin B1

E2F

MAD1

MAD2

MPS1

PTEN

RASSF1A

RB1

ROD

securin

separase

survivin

TP53

ZW10

zwilch

National Cancer Institute

breast cancer

colorectal cancer

OMIM

mosaic variegated aneuploidy

Glossary

ADENOMATOSIS POLYPOSIS COLI

Tumour-suppressor protein that, in a mutated, defective form, causes familial adenomatous polyposis (FAP), a rare hereditary disease in which patients have thousands of colorectal polyps that develop into tumours. Most sporadic colorectal tumours harbour mutations in both APC alleles.

LOSS OF HETEROZYGOSITY

Following acquisition of a deleterious mutation in one of the two copies of a specific gene, loss of heterozygosity occurs from subsequent loss of, or mutation in, the normal allele.

NUDE MICE

Strains of athymic mice bearing the recessive allele nu/nu, which are largely hairless and lack all, or most, of the T-cell population. Nude mice can accept either allografts or xenografts. nu/nu alleles on some backgrounds have near-normal numbers of T-cells.

KINETOCHORE

A multiprotein structure, positioned at the central constriction of each chromosome (centromere), which is responsible for chromosome attachment to the mitotic spindle, chromosome segregation during anaphase and mitotic checkpoint activity.

ANAPHASE PROMOTING COMPLEX/CYCLOSOME

Multisubunit E3 ubiquitin ligase required for mitotic progression by targeting key mitotic regulators such as cyclin B1 and securin for destruction through direct poly-ubiquitylation. Note that the nomenclature can be confusing here: the APC/C is completely distinct from the APC associated with β-catenin signalling and colorectal cancer.

MICROTUBULE CAPTURE

Process in prometaphase in which unattached kinetochores each interact with one or more microtubules that emanate from one spindle pole. The interaction is mediated by microtubule-binding proteins that stably associate with the kinetochore.

MEGAKARYOPOIESIS

Process that leads to the production of megakaryocytes, the polyploid precursor to platelets. These precursors develop from haematopoietic stem cells by executing several cell-cycles in which cytokinesis is skipped (known as endoreduplication).

DOMINANT-INTERFERING MUTANT

Non-functional mutant protein that inhibits the function of the endogenous wild-type protein. These mutants often work by occupying subcellular binding sites required for the activation or correct subcellular positioning of the wild-type protein.

NOCODAZOLE

Synthetic compound that binds tubulin dimers, thereby causing inibition of microtubule polymerization. Because of the highly dynamic nature of spindle microtubules in mitosis, this results in complete depolymerization of the cellular microtubule network.

CELL-AUTONOMOUS LETHAL

The situation in which a deleterious subcellular environment (such as a genetic lesion that inactivates the mitotic checkpoint) causes cell death from damage solely developed within that cell. Surrounding cells have no influence on this process.

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Kops, G., Weaver, B. & Cleveland, D. On the road to cancer: aneuploidy and the mitotic checkpoint. Nat Rev Cancer 5, 773–785 (2005). https://doi.org/10.1038/nrc1714

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