Browsing All Paterson Institute for Cancer Research by Authors
Endopolyploidy in irradiated p53-deficient tumour cell lines: persistence of cell division activity in giant cells expressing Aurora-B kinase.Erenpreisa, Jekaterina; Ivanov, Andrei; Wheatley, Sally P; Kosmacek, Elizabeth A; Ianzini, Fiorenza; Anisimov, Alim P; Mackey, Mike; Davis, Paul J; Plakhins, Gregory; Illidge, Timothy M; et al. (2008-09)Recent findings including computerised live imaging suggest that polyploidy cells transiently emerging after severe genotoxic stress (and named 'endopolyploid cells') may have a role in tumour regrowth after anti-cancer treatment. Until now, mostly the factors enabling metaphase were studied in them. Here we investigate the mitotic activities and the role of Aurora-B, in view of potential depolyploidisation of these cells, because Aurora-B kinase is responsible for coordination and completion of mitosis. We observed that endopolyploid giant cells are formed via different means in irradiated p53 tumours, by: (1) division/fusion of daughter cells creating early multi-nucleated cells; (2) asynchronous division/fusion of sub-nuclei of these multi-nucleated cells; (3) a series of polyploidising mitoses reverting replicative interphase from aborted metaphase and forming giant cells with a single nucleus; (4) micronucleation of arrested metaphases enclosing genome fragments; or (5) incomplete division in the multi-polar mitoses forming late multi-nucleated giant cells. We also observed that these activities can release para-diploid cells, although infrequently. While apoptosis typically occurs after a substantial delay in these cells, we also found that approximately 2% of the endopolyploid cells evade apoptosis and senescence arrest and continue some form of mitotic activity. We describe here that catalytically active Aurora-B kinase is expressed in the nuclei of many endopolyploid cells in interphase, as well as being present at the centromeres, mitotic spindle and cleavage furrow during their attempted mitotes. The totally micronucleated giant cells (containing sub-genomic fragments in multiple micronuclei) represented only the minor fraction which failed to undergo mitosis, and Aurora-B was absent from it. These observations suggest that most endopolyploid tumour cells are not reproductively inert and that Aurora-B may contribute to the establishment of resistant tumours post-irradiation.
Segregation of genomes in polyploid tumour cells following mitotic catastrophe.Erenpreisa, Jekaterina; Kalejs, Martins; Ianzini, Fiorenza; Kosmacek, Elizabeth A; Mackey, Mike; Emzinsh, Dzintars; Cragg, Mark S; Ivanov, Andrei; Illidge, Timothy M; Biomedicine Centre of the Latvia University, Ratsupites 1, Riga LV-1067, Latvia. email@example.com (2005-12)Following irradiation p53-function-deficient tumour cells undergo mitotic catastrophe and form endopolyploid cells. A small proportion of these segregates nuclei, and give rise to viable descendants. Here we studied this process in five tumour cell lines. After mitotic failure, tumour cells enter the endocycle and form mono-nucleated or multi-nucleated giant cells (MOGC and MNGC). MNGC arise from arrested anaphases, MOGC, from arrested metaphases. In both cases the individual genomes establish a radial pattern by links to a single microtubule organizing centre. Segregation of genomes is also ordered. MNGC present features of mitosis being resumed from late anaphase. In MOGC the sub-nuclei retain arrangement of stacked metaphase plates and are separated by folds of the nuclear envelope. Mitosis then resumes in sub-nuclei directly from metaphase. The data presented indicate that endopolyploid tumour cells preserve the integrity of individual genomes and can potentially re-initiate mitosis from the point at which it was interrupted.