The mitotic machinery as a source of genetic instability in cancer

Development and growth of all organisms involves the faithful reproduction of cells and requires that the genome be accurately replicated and equally partitioned between two cellular progeny. In human cells, faithful segregation of the genome is accomplished by an elaborate macromolecular machine, the mitotic spindle. It is not difficult to envision how defects in components of this complex machine-molecules that control ifs organization and function and regulators that temporally couple spindle operation to other cell cycle events-could lead to chromosome missegregation. Recent evidence indicates that the persistent missegregation of chromosomes result in gains and losses of chromosomes and may be an important cause of aneuploidy. This form of chromosome instability may contribute to tumor development and progression by facilitating loss of heterozygocity (LOH) and the phenotypic expression of mutated tumor suppressor genes, and by favoring polysomy of chromosomes that harbor oncogenes. In this review, we will discuss mitotic defects that cause chromosome missegregation, examine components and regulatory mechanisms of the mitotic machine implicated in cancer, and explore mechanisms by which chromosome missegregation could bad to cancer.