Evidence for a role of delayed death and genomic instability in radiation-induced neoplastic transformation of human hybrid cells

HeLa x skin fibroblast human hybrid cells have been developed into a model of radiation-induced neoplastic transformation. The authors' studies indica te that the loss of putative tumour suppressor loci on fibroblast chromosom es 11 and 14 is evident after radiation-induced neoplastic transformation. How these fibroblast chromosomes/putative tumour suppressor loci are lost a fter radiation exposure is currently being investigated. It has been shown that the appearance of transformed foci correlates with the onset of the de layed reduction in plating efficiency or delayed death. This delayed death appears to be the result of the onset of a nobel delayed apoptosis in the i rradiated progeny beginning around day 8 post-irradiation. It was proposed that the reduction in plating efficiency and subsequent neoplastic transfor mation are all the result of a radiation-induced genomic instability. The i nstability process has two relevant outcomes: (1) cell death due to the ind uction of a delayed apoptosis in cells; and (2) neoplastic transformation o f a small subset of survivors that have lost fibroblast chromosomes 11 and 14 (tumour suppressor loci) but either have not acquired enough genetic dam age to induce the apoptotic response or have undergone molecular changes al lowing them to bypass apoptosis. Data from the genomic instability and dela yed death literature will be reviewed in terms of relevance to radiation-in duced neoplastic transformation. New data are presented which demonstrate t hat use of growth media supplemented with a specific lot of calf serum was found to increase the number of cells undergoing radiation-induced neoplast ic transformation, compared with standard serum after a fixed dose of radia tion. This correlates with an increase in delayed death in the irradiated p rogeny which the authors propose is the result of increased genomic instabi lity postirradiation of cells grown in this serum. Preliminary data are pre sented indicating that a delayed apoptosis is also seen after high-energy H e- particle exposure in this system.