On the road to cancer: aneuploidy and the mitotic checkpoint

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Abstract
Aneuploidy, or abnormal chromosome content, is the most common characteristic of human solid tumours. Aneuploidy might contribute to tumour formation and is associated with acquired resistance to some chemotherapeutics. Tumour cells become aneuploid as a result of aberrant mitotic divisions. These aberrant divisions are caused by divisions with a multipolar spindle as a result of previous defects in cytokinesis or centrosome amplification, by defects in chromosome cohesion, by spindle attachment defects, or by impairment of the mitotic checkpoint response. The mitotic checkpoint is a signalling cascade that arrests the cell cycle in mitosis when even a single chromosome is not properly attached to the mitotic spindle. This arrest is achieved by inhibiting the anaphase-promoting complex/cyclosome (APC/C), an E3 ubiquitin ligase that is essential for mitotic progression. Many tumour cells have a diminished, but not absent, mitotic checkpoint response. Mouse models in which mitotic checkpoint signalling is decreased show an increase in spontaneous or carcinogen-induced tumour formation. Mutations in mitotic checkpoint genes themselves are not a common mechanism of checkpoint impairment in human tumour cells. Mitotic checkpoint impairment and aneuploidy in human tumour cells are often associated with changes in the protein levels of mitotic checkpoint proteins. In some tumour cells, these changes occur through altered transcriptional regulation by tumour suppressors or oncogene products. Complete inactivation of mitotic checkpoint signalling causes cell-autonomous lethality. Drugs that specifically and efficiently interfere with mitotic checkpoint signalling could therefore be useful as anticancer agents.