POLYPLOID GIANT CELLS PROVIDE A SURVIVAL MECHANISM FOR p53 MUTANT CELLS AFTER DNA DAMAGE

Abstract

The relationships between delayed apoptosis, polyploid 'giant' cells and reproductive survivors were studied in p53-mutated lymphoma cells after DNA damage. Following severe genotoxic insult with irradiation or chemotherapy, cells arrest at the G(2)-M cell cycle check-point for up to 5 days before undergoing a few rounds of aberrant mitoses. The cells then enter endoreduplication cycles resulting in the formation of polyploid giant cells. Subsequently the majority of the giant cells die, providing the main source of delayed apoptosis; however, a small proportion survives. Kinetic analyses show a reciprocal relationship between the polyploid cells and the diploid stem line, with the stem line suppressed during polyploid cell formation and restituted after giant cell disintegration. The restituted cell-line behaves with identical kinetics to the parent line, once re-irradiated. When giant cells are isolated and followed in labelling experiments, the clonogenic survivors appear to arise from these cells. These findings imply that an exchange exists between the endocyclic (polyploid) and mitotic (diploid or tetraploid) populations during the restitution period and that giant cells are not always reproductively dead as previously supposed. We propose that the formation of giant cells and their subsequent complex breakdown and subnuclear reorganization may represent an important response of p53-mutated tumours to DNA damaging agents and provide tumours with a mechanism of repair and resistance to such treatments.

Combination of nutlin-3 and VX-680 selectively targets p53 mutant cells with reversible effects on cells expressing wild-type p53

“…Indeed, some tetraploidy cells are more resistant to DNA-damaging agents, 27 providing selective survival advantage for p53 mutant cells. 28 Alternatively, a small number of cells may have escaped the effects of VX-680 and remained diploid throughout the drug treatment and recovery period. In the latter case, it is possible that repeated drug exposure could further eliminate the 'survivors'.…”

MOS, aneuploidy and the ploidy cycle of cancer cells

“…The evidence that endopolyploid tumor cells (ETC) induced by genotoxic treatment are capable of returning to para-diploidy and have access to additional means of survival, resulting in increased resistance to DNAdamaging agents is growing (de la Hoz and Baroja, 1993;Illidge et al, 2000;Ianzini and MacKey, 2002;Prieur-Carrillo et al, 2003;Chu et al, 2004;Sundaram et al, 2004;Puig et al, 2008), resulting in greater attention from the wider scientific community (Storchova and Pellman, 2004;Vakifahmetoglu et al, 2008;Wheatley, 2008;Martin et al, 2009;Forer, 2009;Lee et al, 2009). Lee et al (2009) recently provided an excellent summary of the 'purpose' of endopolyploidy in ontogenesis and adaptation to various stresses.…”

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

“…As a consequence of mitosis being disturbed in p53-deficient tumours cells, they may alternatively reset in interphase to recycle as tetraploid cells (Castedo et al, 2004), further rounds of which producing cells of higher ploidy (up to 64 C; Illidge et al, 2000). Noteworthy in the context of tumour cells was the finding by Baroja et al (1996) that giant cells could become highly resistant to genotoxic agents previously used on them.…”