Hypoxia and reoxygenation: a pressure for mutant p53 cell selection and tumour progression.
Recent findings indicate that in a hypoxic environment, oncogenically transformed cells with a mutant form of the tumour suppressor gene p53 may have a survival advantage over similar cells with wild-type p53. This is because the extent of hypoxia-induced apoptosis has been observed to diminish with the loss of wild-type p53 function in certain cell lines. Hypoxic conditions, common in most solid tumours, may thus provide a physiological pressure to select for cells with mutations in the p53 gene. A new model incorporating cell-specific parameters is proposed here to quantify the survival advantage of mutant or null p53 cells over their wild-type counterparts at any level of oxygen deprivation. Predictions are in good agreement with previous monolayer culture experiments comparing hypoxic survival of null and wild-type p53 cells. By extending the model we are able to investigate the effects of repeated rounds of hypoxia and reoxygenation on a mixture of wild-type and mutant or null p53 cells and determine how many rounds are required before a subpopulation of mutant or null p53 cells overtakes a given population of wild-type p53 cells.
Thompson
K E
KE
Institute of Cancer Studies, Sheffield University Medical School, Sheffield S10 2RX, UK. kevin_edward.thompson@virgin.net
Royds
J A
JA
D017209:Apoptosis; D015687:Cell Hypoxia / Q000235:genetics*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D016158:Genes, p53; D006801:Humans; D008433:Mathematics; D008954:Models, Biological; D009154:Mutation; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D010100:Oxygen / Q000378:metabolism; D012641:Selection, Genetic
D010100:Oxygen