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From polyploidy to aneuploidy, genome instability and cancer

Nature Reviews Molecular Cell Biology volume 5, pages 45–54 (2004)Cite this article

Key Points

  • Polyploidy is a relatively common event in eukaryotic organisms. Polyploid cells can arise during development by cell fusion, endoreplication or an abortive cell cycle. There is also evidence that polyploid cells might form more frequently during ageing or stress.

  • The physiology of polyploids is altered relative to diploids: there are alterations in gene expression and genetic stability, and certain genes that are not essential for viability in diploid yeasts become essential in polyploid yeast, a phenomenon known as ploidy-specific lethality.

  • Increased ploidy in animal cells usually results in a proportional increase in the number of centrosomes. The presence of supernumerary centrosomes can lead to: i) cell-cycle arrest by a recently described tetraploidy checkpoint; ii) apoptosis; iii) a return to a diploid state through a poorly characterized process that is known as a reduction mitosis; or iv) successful propagation after an adaptation that allows the clustering of extra centrosomes.

  • Tumour cells frequently have an increased number of aberrant chromosomes (aneuploidy) and extra centrosomes.

  • It is generally assumed that aneuploidy develops from diploid cells by ongoing chromosomal instability. In light of recent studies on the tetraploidy checkpoint, and because of the need to explain why tumours often have extra centrosomes, we reconsider an old hypothesis about the genesis of aneuploidy: that aneuploidy can develop in cells after an abortive cell cycle that forces cells through a tetraploid intermediate. Furthermore, we consider the possibility that the altered physiology of cells with extra chromosomes, particularly the phenomenon of ploidy-specific lethality, could be exploited to develop new drugs that selectively kill cancer cells but not normal cells.

Abstract

Polyploidy is a frequent phenomenon in the eukaryotic world, but the biological properties of polyploid cells are not well understood. During evolution, polyploidy is thought to be an important mechanism that contributes to speciation. Polyploid, usually non-dividing, cells are formed during development in otherwise diploid organisms. A growing amount of evidence indicates that polyploid cells also arise during a variety of pathological conditions. Genetic instability in these cells might provide a route to aneuploidy and thereby contribute to the development of cancer.

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Figure 1: Several routes to polyploidy.
Figure 2: The fate of tetraploid cells.
Figure 3: Potential mechanisms to generate aneuploid cells.

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Acknowledgements

The authors are grateful to J. Cande, M. Gupta, T. Fujiwara and other members of the Pellman lab for helpful discussions. We thank G. Fink, R. DePinho, A. DiAndrea, M. McLaughlin and M. Raschle for critical reading of the manuscript.

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Authors and Affiliations

  1. Department of Pediatric Oncology of The Dana-Farber Cancer Institute, Department of Pediatric Hematology/Oncology of the Children's Hospital and Harvard Medical School, Room M621A, 44 Binney Street, Boston, 02115, Massachusetts, USA

    Zuzana Storchova & David Pellman

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  1. Zuzana Storchova
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  2. David Pellman
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Correspondence to David Pellman.

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DATABASES

OMIM

Barrett's oesophagus

Saccharomyces genome database

Bik1

CLN1

CLN2

Cln3

FLO11

Swiss-Prot

Akt1

CLIP-170

cyclin D1

p21

p53

Rb

S6 ribosomal protein

TOR

Glossary

POLYPLOIDY

An increase in DNA content by whole-number multiples of the entire set of chromosomes.

ANEUPLOIDY

Deviation from the normal 2N complement of chromosomes that is usually accompanied by structural rearrangements of chromosomes.

POLYTENE CHROMOSOME

A type of chromosome in some polyploid cells that is formed when several copies of a homologous chromosome are aligned side by side to give a giant chromosome, in which distinct chromosome bands are visible.

MEGAKARYOCYTE

The bone-marrow precursor cell that gives rise to blood platelets. During differentiation, megakaryocytes become polyploid by endoreplication.

ANAPHASE

The stage of mitosis that begins with the separation of sister chromatids towards the poles of the spindle (anaphase A), followed by spindle elongation (anaphase B).

SENESCENCE

Passage-dependent death of tissue-culture cells.

TOR-FAMILY KINASES

(TOR, target of rapamycin). A family of kinases conserved in all eukaryotes that are sensitive to rapamycin and function in nutrient-sensing signal transduction, regulate translation and promote cell-cycle progression.

CYCLINS

A family of proteins, the classic members of which fluctuate in concentration throughout the cell cycle, and which regulate processes such as cell-cycle progression by binding to cell-cycle-dependent kinases.

KINETOCHORE

A large multiprotein complex that assembles onto the centromere of the chromosome and links the chromosome to the microtubules of the mitotic spindle.

CENTROSOME

A structure that occurs close to the nucleus in eukaryotic cells during interphase; it comprises a pair of centrioles, satellite bodies and a cytoplasmic zone and, in animal cells, serves as the main microtubule-organizing centre.

MICROTUBULE-ORGANIZING CENTRE (MTOC)

The MTOC contains γ-tubulin and other proteins that are required to nucleate microtubules. In animals, the centrosome is usually the dominant MTOC. In addition to the microtubule-nucleating material, the centrosome also contains the centriole. The spindle pole body is the equivalent of the centrosome in yeast.

TELOMERE

A segment at the end of each chromosome arm that consists of a series of repeated DNA sequences.

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Storchova, Z., Pellman, D. From polyploidy to aneuploidy, genome instability and cancer. Nat Rev Mol Cell Biol 5, 45–54 (2004). https://doi.org/10.1038/nrm1276

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