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 segregat ion of the genome is accomplished by an elaborate macromolecular machine, t he mitotic spindle. It is not difficult to envision how defects in componen ts of this complex machine-molecules that control ifs organization and func tion and regulators that temporally couple spindle operation to other cell cycle events-could lead to chromosome missegregation. Recent evidence indic ates that the persistent missegregation of chromosomes result in gains and losses of chromosomes and may be an important cause of aneuploidy. This for m of chromosome instability may contribute to tumor development and progres sion by facilitating loss of heterozygocity (LOH) and the phenotypic expres sion of mutated tumor suppressor genes, and by favoring polysomy of chromos omes that harbor oncogenes. In this review, we will discuss mitotic defects that cause chromosome missegregation, examine components and regulatory me chanisms of the mitotic machine implicated in cancer, and explore mechanism s by which chromosome missegregation could bad to cancer.