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Boveri revisited: chromosomal instability, aneuploidy and tumorigenesis

Key Points

  • The mitotic checkpoint is a major cell cycle control mechanism that acts to guard against chromosome missegregation and the subsequent production of aneuploid daughter cells. Aneuploidy is a remarkably common feature of human tumours and was proposed more than 100 years ago to promote cancer.

  • Aneuploidy is often caused as a result of an underlying chromosomal instability, characterized by the frequent gains and losses of chromosomes during division. Increased kinetochore malorientation is a primary cause of the chromosomal instability that is found in cancer cells.

  • Mice with overexpressed or reduced levels of mitotic checkpoint components display elevated aneuploidy. In many cases, this elevated aneuploidy correlates with an increased susceptibility to spontaneous and/or carcinogen-induced tumours.

  • Although aneuploidy has been implicated in driving cancer, recent evidence has revealed that in vitro, aneuploidy hampers the growth of cells. Aneuploidy has also been found to antagonize tumorigenesis in certain genetic contexts and cell types.

  • The effect of aneuploidy on tumorigenesis is context dependent and is not driven by a particular combination of chromosomes per se, but rather by the specific interaction of the karyotype with the genetic context and microenvironment of the cell.

Abstract

The mitotic checkpoint is a major cell cycle control mechanism that guards against chromosome missegregation and the subsequent production of aneuploid daughter cells. Most cancer cells are aneuploid and frequently missegregate chromosomes during mitosis. Indeed, aneuploidy is a common characteristic of tumours, and, for over 100 years, it has been proposed to drive tumour progression. However, recent evidence has revealed that although aneuploidy can increase the potential for cellular transformation, it also acts to antagonize tumorigenesis in certain genetic contexts. A clearer understanding of the tumour suppressive function of aneuploidy might reveal new avenues for anticancer therapy.

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Figure 1: Pathways to the generation of aneuploidy.
Figure 2: Pathways to the acquisition of extra centrosomes.

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Acknowledgements

The authors thank W. Silkworth, D. Cimini, N. Ganem and D. Pellman for sharing results before publication. We apologize to all those whose work could not be cited owing to space limitations. D.W.C. receives salary support from the Ludwig Institute for Cancer Research and A.J.H. is supported by a European Molecular Biology Organization (EMBO) Long-Term Fellowship.

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Correspondence to Don W. Cleveland.

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Glossary

Transformation

The change that a normal cell undergoes when it becomes immortalized and acquires the potential to grow in an uncontrolled manner.

Microtubule spindle

A dynamic array of microtubules that forms during mitosis and serves to partition the duplicated chromosomes into the daughter cells.

Kinetochore

A complicated protein assembly that links the chromosomes to the microtubule-based mitotic spindle.

Separase

A Cys protease that triggers anaphase by cleaving the cohesin complex that holds sister chromatids together.

Securin

A chaperone that binds and inhibits the catalytic activity of separase.

Centrosome

The major microtubule-organizing centre of animal cells that forms the poles of the mitotic spindle.

Centriole

A short, barrel-shaped array of microtubules localized in the centrosome.

Down's syndrome

A chromosomal disorder caused by trisomy of chromosome 21.

Centromere

A specialized chromatin structure on which the kinetochore assembles. This occurs at the constricted point at which the two chromatids that form the chromosome are joined together.

Hypomorphic

A mutant that produces less than the normal amount of a gene product.

Benign

A tumour that does not grow in an uncontrolled manner, invade surrounding tissues or metastasize to other parts of the body.

RAE1

A protein initially charcterized as an mRNA export factor that shares sequence and structural similarity with BUB3.

NUP98

A nuclear pore complex component that interacts with RAE1.

Splenocyte

A type of white blood cell that is a precursor of splenic tissue.

Apc Min

A truncating mutation in the adenomatous polyposis coli tumour suppressor gene. Mice that are heterozygous for this mutation develop a large number of benign colon and intestinal tumours at an early age.

Loss of heterozygosity

Represents the loss of function of the remaining copy of a tumour suppressor gene in which the other allele has previously been inactivated.

p53

A tumour suppressor gene that is frequently mutated in human cancer. It has an important role in cell cycle regulation and apoptosis.

Retinoblastoma

A tumour suppressor gene that has an important function in the regulation of the cell cycle.

Tetraploid

Possessing four times the haploid number of chromosomes.

Endoreduplication

The duplication of the genome without subsequent cell division.

Aurora B

A member of the Aurora kinase family that localizes to the centromere during metaphase and to the spindle midzone during anaphase. Aurora B has a role in the correction of incorrect kinetochore microtubule attachments and cytokinesis.

Abscission

The separation of the two daughter cells at the end of cytokinesis.

NoCut pathway

A signalling pathway identified in yeast that delays the completion of cytokinesis when chromatin is present in the spindle midzone.

Aurora A

A member of the Aurora kinase family that is enriched at the poles of the spindle and has a role in bipolar spindle formation. Aurora A is frequently overexpressed in human cancers.

BRCA2

(Breast cancer 2, early onset). Mutations in this protein correlate with an increased risk of breast and/or ovarian cancer.

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Holland, A., Cleveland, D. Boveri revisited: chromosomal instability, aneuploidy and tumorigenesis. Nat Rev Mol Cell Biol 10, 478–487 (2009). https://doi.org/10.1038/nrm2718

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