Chromosomal aberrations as a contributing factor for tumor promotion in the mouse skin.
Tumor promotion in mouse skin can be dissected in two stages: stage I (conversion) and stage II. Whereas for stage II clonal expansion of transformed cells is believed to play a major role, the mechanism(s) underlying conversion is still a matter of debate. Because conversion can be achieved upon treatment with phorbol ester tumor promoters prior to initiation, it is unlikely to represent simply proliferative stimulation of initiated cells (due to epigenetic changes induced). Since tumor promoters exert clastogenic activities and, on the other hand, the clastogen methyl methanesulfonate proved to be convertogenic, the possibility arises that chromosomal changes are involved in conversion. Based on this hypothesis, several findings concerning the action of tumor promoters and the process of tumor promotion in the mouse skin system are discussed and interpreted: the frequency, reversibility, and transient nature of conversion, dependence of tumor promotion on DNA synthesis, induction of DNA breaks by tumor promoters, and the protecting effect of scavengers of free radicals. A model is presented suggesting tumor formation in mouse skin (and other systems) to proceed in discrete, genetically determined steps. Initiation is considered to be due to the induction of point mutations in a dominant-acting oncogene that becomes thereupon activated, whereas the decisive event in the conversion stage of tumor promotion is the induction of numerical and/or structural chromosomal changes with the consequence of loss or inactivation of gene(s) involved in suppression of the tumor phenotype.
Kaina
B
B
Nuclear Research Center, Institute of Genetics and Toxicology, Karlsruhe, Federal Republic of Germany.
D000818:Animals; D002273:Carcinogens / Q000633:toxicity*; D002869:Chromosome Aberrations; D003043:Cocarcinogenesis; D004249:DNA Damage; D004261:DNA Replication / Q000187:drug effects; D005609:Free Radicals; D005786:Gene Expression Regulation / Q000187:drug effects; D051379:Mice; D008954:Models, Biological; D009857:Oncogenes; D012878:Skin Neoplasms / Q000139:chemically induced* / Q000235:genetics
D002273:Carcinogens; D005609:Free Radicals