Mitotic chromosomal instability and cancer: mouse modelling of the human disease

Abstract

The stepwise progression from an early dysplastic lesion to full-blown metastatic malignancy is associated with increases in genomic instability. Mitotic chromosomal instability - the inability to faithfully segregate equal chromosome complements to two daughter cells during mitosis - is a widespread phenomenon in solid tumours that is thought to serve as the fuel for tumorigenic progression. How chromosome instability (CIN) arises in tumours and what consequences it has are still, however, hotly debated issues. Here we review the recent literature with an emphasis on models that recapitulate observations from human disease.

Figure 1. The mitotic checkpoint

a | Outline of the mitotic checkpoint. An unattached kinetochore is shown on the left with the inner complex in purple, MAD1 in grey and MAD2 in its open and closed forms in purple. The mitotic checkpoint complex (MCC) is shown to inhibit the anaphase promoting complex/cyclosome (APC/C), which after attachment of the last kinetochore is activated and ubiquitylates securin and cyclin B1. More details of this pathway are described in the main text. b | The amplification of the unoccupied kinetochore signal is thought to depend on the conversion of MAD2 open complexes (MAD2(O)) to closed complexes (MAD2(C)) that bind to cell division cycle 20 (CDC20) and deliver it to the APC/C for ubiquitylation (Ub). The nature of the MCC is still debated, as indicated by question marks. A separate APC/C is shown to indicate its role in timing, independent of the kinetochore-derived signal. CDK1, cyclin-dependent kinase 1.

Figure 2. Multiple mechanisms leading to aneuploidy

The normal mitotic checkpoint (MC) events from prometaphase to anaphase are shown in the centre. An absent checkpoint leads to mitotic cell death. A weak checkpoint (left) leads to premature sister chromatid separation and near-diploid aneuploidy. An overactive checkpoint (right) can lead either to mitotic cell death or lagging chromosomes and subsequent near-diploid aneuploidy or tetraploidy. Multiple centrosomes can have similar consequences to an overactive checkpoint. A multipolar mitosis leads to cell death unless centrosomes cluster, in which case the likelihood of lagging chromosomes is high.