Chromosome segregation errors: a double-edged sword

Abstract

Unequal separation of the mother cells’ DNA over its two daughter cells upon cell division is a prevalent phenotype found in cancer cells. This imbalanced nuclear division manifests itself as chromosome segregation errors in the final phases of Mitosis. Chromosome unstable (CIN) cancer cells continuously display chromosome segregation errors, which leads to an abnormal chromosome number, termed aneuploidy, in the cancer cells’ progeny. Research described in this thesis suggests that CIN is a ‘double-edged sword’. Although single gains and losses of certain chromosomes could lead to tumor growth promoting effects, severely enhanced levels of CIN unequivocally kills all cells. It is generally hypothesized that single chromosome missegregations can induce gain of certain oncogenes or loss of tumor suppressor genes and thereby stimulate tumorigenesis. One of the chapters of this thesis describes another mechanism by which chromosome segregation errors could enhance tumorigenesis. Cell division in the presence of chromosome segregation errors can lead to DNA damage on the chromosomes that lag behind. These double strand breaks were found to result in structural chromosomal changes in the progeny of the missegregating cells, suggesting that CIN not only enhances tumorigenesis by inducing aneuploidy, but also by introducing breaks in the chromatin. The second part of the thesis describes the possibilities of exploiting CIN in anti-cancer strategies. Although severe levels of CIN eventually leads to cell death in any cell type, data in several chapters of this thesis demonstrate that tumor cells could be more sensitive to an increase in chromosome segregation errors when compared to ‘healthy’ cells. These data fuel the idea of exploiting CIN in future anti-cancer therapies.