TY - JOUR
T1 - Destructive cycles
T2 - The role of genomic instability and adaptation in carcinogenesis
AU - Schneider, Brandt L.
AU - Kulesz-Martin, Molly
N1 - Funding Information:
We thank Colette Schneider, Jody Markwardt, Tim Bowden, Jim Hutson and Simon Williams for helpful discussions and comments. B.L.S. is supported by grants from the American Heart Association, The CH Foundation, the Wendy Will Cancer Fund, the Houston Endowment Incorporation, the South Plains Foundation and Texas Tech University Health Sciences Center. M.K.M. is supported by grants CA98577 and CA98893 and the OHSU Cancer Institute grant CA69533.
PY - 2004/11
Y1 - 2004/11
N2 - 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.
AB - 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.
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U2 - 10.1093/carcin/bgh204
DO - 10.1093/carcin/bgh204
M3 - Review article
C2 - 15180945
AN - SCOPUS:8844279091
SN - 0143-3334
VL - 25
SP - 2033
EP - 2044
JO - Carcinogenesis
JF - Carcinogenesis
IS - 11
ER -