Destructive cycles: the role of genomic instability and adaptation in carcinogenesis.
Classical theories of carcinogenesis postulate that the accumulation of several somatic mutations is responsible for oncogenesis. However, these models do not explain how non-mutagenic carcinogens cause cancer. In addition, known mutation rates appear to be insufficient to account for observed cancer rates. Moreover, the current theory doesn't easily account for the long latencies observed in human cancers. Proponents of an aneuploidy-driven theory of carcinogenesis suggest that genomic instability has a causative role in carcinogenesis. In support of this theory, pre-neoplastic cells frequently display genomic instability while normal cells do not. Data obtained from a variety of model organisms have revealed that disruption of the cell cycle controls required for homeostasis results in the acquisition of genomic instability. Subsequently, this genomic instability becomes self-propagating via 'destructive cycles' and provides a medium for cellular selection and adaptation. Genomic instability allows numerous genetic and epigenetic alterations to accumulate during carcinogenesis without markedly changing phenotype until they are qualitatively or quantitatively sufficient to be selectively advantageous in the tumor microenvironment. Observations of adaptation in tumor cell populations and application of chaos theory may help elucidate the mechanism that drives the enormous genetic heterogeneity observed in tumors and provide insights into the development of new therapeutic cancer interventions and treatments.
Schneider
Brandt L
BL
Department of Cell Biology and Biochemistry, Room 5C119, Texas Tech University Health Sciences Center, 3601 4th Street, Lubbock, TX 79430, USA. brandt.schneider@ttmc.ttuhsc.edu
Kulesz-Martin
Molly
M
D000818:Animals; D002273:Carcinogens; D002455:Cell Division; D005786:Gene Expression Regulation; D042822:Genomic Instability; D006706:Homeostasis; D006801:Humans; D009154:Mutation; D009369:Neoplasms / Q000139:chemically induced / Q000235:genetics*
D002273:Carcinogens