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Cytokinesis defects and cancer

Nature Reviews Cancer volume 19, pages 32–45 (2019)Cite this article

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Abstract

Whole-genome and centrosome duplication as a consequence of cytokinesis failure can drive tumorigenesis in experimental model systems. However, whether cytokinesis failure is in fact an important cause of human cancers has remained unclear. In this Review, we summarize evidence that whole-genome-doubling events are frequently observed in human cancers and discuss the contribution that cytokinesis defects can make to tumorigenesis. We provide an overview of the potential causes of cytokinesis failure and discuss how tetraploid cells that are generated through cytokinesis defects are used in cancer as a transitory state on the route to aneuploidy. Finally, we discuss how cytokinesis defects can facilitate genetic diversification within the tumour to promote cancer development and could constitute the path of least resistance in tumour evolution.

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Fig. 1: The stages of cytokinesis.
Fig. 2: From tetraploidy to aneuploidy.
Fig. 3: Causes of cytokinesis failure.
Fig. 4: The different fates of a tetraploid G1 cell.

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Acknowledgements

The authors thank the reviewers for their constructive suggestions for improvement. The authors apologize to all of their colleagues whose work could not be cited in this Review because of space limitations. This work is part of Oncode Institute, which is partly financed by the Dutch Cancer Society.

Reviewer information

Nature Reviews Cancer thanks M. Burkard, A. Holland and the other anonymous reviewer for their contribution to the peer review of this work.

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Authors and Affiliations

  1. Oncode Institute, Utrecht, Netherlands

    Susanne M. A. Lens & René H. Medema

  2. Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands

    Susanne M. A. Lens

  3. Division of Cell Biology and Cancer Genomics Center, The Netherlands Cancer Institute, Amsterdam, Netherlands

    René H. Medema

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S.M.A.L. and R.H.M. contributed equally to writing the article and to review and editing of the manuscript before submission.

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Correspondence to Susanne M. A. Lens or René H. Medema.

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Related links

cBioPortal: http://www.cbioportal.org/

NCI Cancer Genome Anatomy Project: https://cgap.nci.nih.gov/Chromosomes/Mitelman

Supplementary information

Glossary

Ploidy

The number of chromosomes in the nucleus of a cell.

Tetraploid cell

A cell that has four copies of each chromosome (4N).

Aneuploid cells

Cells with an abnormal chromosome content (a number that deviates from a multiple of the haploid (N) set). It encompasses both numerical aneuploidies (gains and/or losses of whole chromosomes) and structural aneuploidies (gains or losses of chromosome segments, including imbalanced translocations).

Chromosomal instability

(CIN). An elevated frequency of chromosome segregation errors during mitosis.

Centrosomes

Organelles consisting of two centrioles and surrounding pericentriolar material that serves as the main microtubule-nucleating and organizing centre of mammalian cells.

Chromosomal passenger complex

(CPC). A protein complex consisting of the mitotic kinase Aurora B, and three non-enzymatic subunits: INCENP, borealin and survivin. It has a dynamic localization in the dividing cell, localizing to the inner centromere region in late prophase and (pro)metaphase, the central spindle and equatorial cortex in anaphase and the midbody in telophase. The complex is essential for the acquisition of proper chromosome–spindle connections and for proper execution of cytokinesis.

Buccal micronucleus cytome assay

A non-invasive assay using exfoliated buccal cells to quantify the mean frequencies of cells containing aberrant nuclei, such as micronuclei (pieces of DNA that reside outside of the nucleus caused by chromosome breakage or missegregation), binucleation and abnormal chromatin condensation.

Chromatin bridge

A DNA structure that is observed in anaphase when the centromeres of the two sister chromatids are pulled towards opposite spindle poles but the sisters remain connected through, for instance, telomere fusion or regions of incompletely replicated DNA.

Cohesion fatigue

Loss of sister chromatid cohesion before anaphase onset that can occur as a consequence of a prolonged metaphase arrest or as a consequence of defects in the machinery that controls timely establishment and loss of cohesin.

Sister chromatids

The two identical copies of a single replicated chromosome that are kept together by DNA catenation and the cohesin complex from S phase until anaphase.

Mutator phenotype

An increase in mutation rate in cancer cells.

Dicentric chromosomes

Abnormal chromosomes with two centromeres, which are usually formed through the fusion of two chromosome segments.

Centromeres

Specialized regions of the chromosome where the kinetochore is assembled, thereby directing the segregation of the chromosomes.

DNA catenanes

Structures generated from the intertwining of replicated sister strands, which occurs when two converging replication forks meet. DNA catenanes are a normal consequence of DNA replication and are resolved during mitosis.

Kinetochore

A multi-protein complex that assembles on centromeres and serves as the main microtubule binding site of the chromosome. It also acts as a signalling platform for the mitotic checkpoint, which is a surveillance mechanism that prevents anaphase onset until all chromosomes are properly connected to the mitotic spindle.

Non-reciprocal translocations

Transfer of a chromosomal fragment of one chromosome to another non-homologous chromosome.

Replication stress

The slowing or stalling of replication fork progression owing to replication barriers formed by difficult to replicate regions, shortage of ribonucleotides or collisions between active translation and replication.

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Lens, S.M.A., Medema, R.H. Cytokinesis defects and cancer. Nat Rev Cancer 19, 32–45 (2019). https://doi.org/10.1038/s41568-018-0084-6

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