Endopolyploidy in irradiated p53‐deficient tumour cell lines: Persistence of cell division activity in giant cells expressing Aurora‐B kinase

Abstract

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.

MOS, aneuploidy and the ploidy cycle of cancer cells

“…Furthermore, overexpression in somatic cells of v-Mos causes an oocyte phenotype (Fukasawa et al, 1994). Moreover, in our experiments with two lymphoma cell lines, we could identify a proportion of endopolyploids that entered cell division having omitted the preceding S-phase (Erenpreisa et al, 2008this is yet further evidence of meiosis-like behavior and somatic reduction division.…”

A nuclear budding mechanism in transiently arrested cells generates drug-sensitive and drug-resistant cells

“…Some of those cells may escape cell death and undergo further polyploidization [26]. DNA damage may provide the molecular background to trigger entry into an endocycle instead of mitosis [27], which also explains the presence of large multinucleated cells. These cells may facilitate cell survival [28], and their presence has thus been linked to a poor response to chemotherapy.…”

Growing evidence of the repopulation of regressed tumours by the division of giant cells

“…However, it seems quite reasonable that these findings would be seen in the body. Within this issue of CBI, the papers by Erenpreisa et al (2008) and Puig et al (2008) which follow this editorial provide new evidence of considerable significance. In the former report, the prominence of anaphase bridges due to dicentric chromosomes forming in the majority of irradiated cells (w70%) compares with only 2e5% in control cells.…”

“…This increases the seriousness of the matter, which may only be fully appreciated when the emerging evidence is assimilated and properly understood. We first need to review briefly some of the crucial evidence that has accumulated, primarily because it helps to introduce three papers in this issue of Cell Biology International that further substantiates the role of giant cells in tumour repopulation, viz Erenpreisa et al (2008;pps. 1044), Puig et al (2008; pps.…”