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Polyploid giant cells provide a survival mechanism for p53 mutant cells after DNA damage
T M Illidge1, M S Cragg, B Fringes
1CRC Department of Oncology, Southampton General Hospital, Southampton University, Southampton, SO16 6YD, UK. tmi@soton.ac.uk
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.
Insights
p53-mutated lymphoma cells form polyploid giant cells after DNA damage, with a small fraction surviving. These giant cells, not reproductively dead, may offer tumor resistance to genotoxic treatments.
Area of Science:
- Cell Biology
- Cancer Research
- Genetics
Background:
- DNA damage in p53-mutated lymphoma cells can lead to cell cycle arrest.
- Polyploid giant cells are observed following genotoxic insults like irradiation or chemotherapy.
- The fate and role of these giant cells in tumor survival are not fully understood.
Purpose of the Study:
- To investigate the relationship between delayed apoptosis, polyploid giant cells, and reproductive survivors in p53-mutated lymphoma cells.
- To determine if giant cells contribute to tumor resistance after DNA damage.
- To explore the potential repair mechanisms offered by giant cell formation.
Main Methods:
- Studying p53-mutated lymphoma cells subjected to genotoxic stress (irradiation, chemotherapy).
- Observing cell cycle arrest at G(2)-M checkpoint and subsequent endoreduplication.
- Kinetic analyses and cell isolation experiments to track giant cell fate and survival.
Main Results:
- Cells arrested at G(2)-M for up to 5 days, forming polyploid giant cells via endoreduplication.
- Majority of giant cells underwent delayed apoptosis, but a small proportion survived as clonogenic cells.
- A reciprocal relationship was observed between polyploid and diploid cell populations, with restitution after giant cell disintegration.
Conclusions:
- Giant cells in p53-mutated tumors are not always reproductively dead and can be a source of survivors.
- Giant cell formation, breakdown, and reorganization may represent a tumor repair and resistance mechanism against DNA damaging agents.
- Findings suggest a potential therapeutic target in understanding and overcoming tumor resistance.