Deep Insight Section

Many human malignant tumours exhibit abnormal chromosomal segregation at cell division. It is believed that these anomalies play a role in tumorigenesis by increasing the rate of chromosome mutations, including deletion and amplification of genes involved in cellular proliferation and/or survival. In vitro experiments have also shown that mitotic instability may be a mechanism for developing resistance to cytotoxic drugs. Abnormal mitotic mechanisms may result in numerical or structural aberrations in the daughter cells. Numerical aberrations can be caused either by the loss of chromosomes at metaphase/anaphase or by multipolar divisions associated with abnormal number or structure of centrosomes. Structural rearrangements have been associated with chromosomal breakage-fusion-bridge (BFB) cycles that can be initiated by telomeric dysfunction, giving rise to unstable dicentric or ring chromosomes. In most tumours exhibiting chromosomal instability, including high-grade malignant pancreatic, ovarian, and headand neck carcinomas, as well as osteoand soft tissue sarcomas, the two types of instability occur together. However, in some low-grade mesenchymal and neuroglial tumours, rarely showing numerical changes, BFB events involving telomeric associations and ring chromosomes dominate the mitotic process. At progression towards higher malignancy in these tumours, complex structural and numerical aberrations become more frequent. This may be explained by a process initiated by telomeric dysfunction and anaphase bridging, which, in turn, may give rise to an increased frequency of multinucleated cells through failure of cytokinesis. These cells will contain an abnormal number of centrosomes leading to multipolar mitotic figures at the next cell division. Further understanding of these events may lead to novel strategies for detection and treatment of malignancy.