The consequences of tetraploidy and aneuploidy

Abstract

Polyploidy, an increased number of chromosome sets, is a surprisingly common phenomenon in nature, particularly in plants and fungi. In humans, polyploidy often occurs in specific tissues as part of terminal differentiation. Changes in ploidy can also result from pathophysiological events that are caused by viral-induced cell fusion or erroneous cell division. Tetraploidization can initiate chromosomal instability (CIN), probably owing to supernumerary centrosomes and the doubled chromosome mass. CIN, in turn, might persist or soon give way to a stably propagating but aneuploid karyotype. Both CIN and stable aneuploidy are commonly observed in cancers. Recently, it has been proposed that an increased number of chromosome sets can promote cell transformation and give rise to an aneuploid tumor. Here, we review how tetraploidy can occur and describe the cellular responses to increased ploidy. Furthermore, we discuss how the specific physiological changes that are triggered by polyploidization might be used as novel targets for cancer therapy. Tetraploid cells can also be created after an aberrant cell division. During mitosis, the chromosomes attach via proteinaceous structures called kinetochores to spindle microtubules that emanate from MTOCs (Box 1). This enables cells to segregate their chromosomes evenly into two daughter cells. Spindle-assembly checkpoint (SAC) activity holds back the onset of anaphase until all kinetochores are properly attached (Musacchio and Salmon, 2007). If there is a persistent error, the cell can escape SAC arrest (Brito and Rieder, 2006) and exit from mitosis without undergoing anaphase or cytokinesis, thereby producing a tetraploid cell with a single nucleus and two centrosomes (Azeddine et al., 1998;Lanni and Jacks, 1998). This so-called 'mitotic slippage' also occurs in cells that have an altered SAC, such as mouse embryonic fibroblasts (MEFs), which overexpress the SAC gene Mad2 (mitotic-arrest deficient 2) (Sotillo et al., 2007).In addition, cells that have entered anaphase might fail to finalize cell division. Cytokinesis might fail owing to a disturbance of cleavage-furrow formation, which occurs when bulk chromatin (Mullins and Biesele, 1977), or even a single lagging chromosome, is trapped in the cleavage furrow (Shi and King, 2005). The result is a single binucleated cell with two centrosomes. Abnormal spindle positioning and movements might also interfere with cytokinesis and lead to the accumulation of tetraploid cells, as has been observed, for example, in cells with deregulated integrin functions that inhibited spindle assembly (Reverte et al., 2006).The list of mechanisms that lead to tetraploidy is growing, and raises the issue of how frequently unscheduled tetraploidization occurs in normal tissues. Although difficult to estimate, tetraploid cells can be found with variable frequencies (0.5-20%) in nearly every human tissue (Biesterfeld et al., 1994), suggesting that tetraploidization is a more common process than was previously thought. In fact, spontaneous unsched...

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