Tetraploidy, aneuploidy and cancer

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Aneuploidy is one of the most obvious differences between normal and cancer cells. However, there remains debate over how aneuploid cells arise and whether or not they are a cause or consequence of tumorigenesis. One proposed route to aneuploid cancer cells is through an unstable tetraploid intermediate. Supporting this idea, recent studies demonstrate that tetraploidy promotes chromosomal aberrations and tumorigenesis in vivo. These tetraploid cells can arise by a variety of mechanisms, including mitotic slippage, cytokinesis failure, and viral-induced cell fusion. Furthermore, new studies suggest that there might not be a ploidy-sensing checkpoint that permanently blocks the proliferation of tetraploid cells. Therefore, abnormal division of tetraploid cells might facilitate genetic changes that lead to aneuploid cancers.

Introduction

Polyploidy, a state in which cells possess more than two sets of homologous chromosomes, occurs frequently in nature. Polyploid cells arise after cellular stress, ageing, and in various diseases, perhaps because polyploidy confers a metabolic benefit [1, 2]. Polyploidy also appears to be frequent during evolution; genome sequencing suggests that many contemporary genomes, including genomes of higher vertebrates, evolved from ancient genome duplications [3]. However, polyploidy also has its costs. Mounting evidence suggests that polyploid cells are genetically unstable and can act as intermediates on the road to aneuploidy and, ultimately, cancer. This hypothesis is appealing because it can explain simply why many cancers contain large-scale changes in chromosome numbers but rarely have simple gains or losses of individual chromosomes. In this review, we describe recent work that sheds new light on the mechanisms through which tetraploid cells arise, become aneuploid, and ultimately promote tumorigenesis.

Section snippets

Mechanisms generating tetraploid cells

Several mechanisms exist to promote the genesis of tetraploid cells in otherwise euploid tissues. Endoreplication, the process by which DNA replication occurs without cell division, is a normal, programmed cellular process that leads to the creation of terminally differentiated non-dividing polyploid cells (i.e. megakaryocytes [4]). However, polyploid, usually tetraploid, cells can also arise by accident (Figure 1). One common mechanism of tetraploid formation is through cytokinesis failure,

Tetraploidy: a transient intermediate on the road to aneuploidy and tumorigenesis

The idea that tetraploid cells are transient intermediates during tumorigenesis is a specific iteration of Theodor Boveri's nearly 100-year-old hypothesis about centrosomes and cancer [16]. Various lines of evidence currently support this early idea: first, tetraploid or near-tetraploid cells have been described in early-stage cancers, most recently cancers of the cervix [17]. One careful study revealed that tetraploid cells accumulate in the premalignant condition Barrett's oesophagus, in

Propagation of tetraploid cells and the role of p53

Given the apparent dangers, it is logical that cells have evolved mechanisms to prevent either the proliferation or survival of tetraploid cells. Indeed, it has long been observed that tetraploid cells often undergo a p53-dependent cell cycle arrest in the G1 phase following cytokinesis failure [30]. Andreassen et al. [31], after demonstrating that inhibition of cytokinesis with DCB in primary rat fibroblasts results in a p53-dependent G1 cell cycle arrest, proposed that a ‘tetraploidy

Mechanisms through which tetraploidy leads to aneuploidy

One consequence of tetraploidy, at least in certain cells, is the accumulation of both numerical and structural chromosome aberrations [26••]. However, although it is known that tetraploid cells with extra centrosomes can undergo abnormal mitoses and missegregate whole chromosomes, it is less clear how tetraploid cells can accumulate chromosome breaks and rearrangements. One possibility is that chaotic multipolar mitoses might break chromosomes directly. For instance, if cohesion or catenation

Conclusions

Understanding how aneuploid cells arise and whether or not they promote tumorigenesis is a central question in cancer research. Evidence is mounting that aneuploid cells can arise from inherently unstable tetraploid intermediates through a variety of mechanisms. The fate of tetraploid cells probably depends on the cell type and genetic context. In many cells, tetraploidy, especially if accompanied by genetic instability, is expected to be a disadvantage that could trigger growth arrest or cell

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

N Ganem and D Pellman are supported by grants from The National Institutes of Health (5T32GM008704 to NG and R01CA98537 to DP). Z Storchova is supported by The Claudia Adams-Barr Foundation.

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