Destructive cycles: The role of genomic instability and adaptation in carcinogenesis

Brandt L. Schneider, Molly Kulesz-Martin

Research output: Contribution to journalArticle

49 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2033-2044
Number of pages12
JournalCarcinogenesis
Volume25
Issue number11
DOIs
StatePublished - Nov 2004

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Genomic Instability
Carcinogenesis
Neoplasms
Nonlinear Dynamics
Tumor Microenvironment
Genetic Heterogeneity
Aneuploidy
Mutation Rate
Cell Cycle Checkpoints
Epigenomics
Carcinogens
Homeostasis
Phenotype
Mutation
Population

ASJC Scopus subject areas

  • Cancer Research

Cite this

Destructive cycles : The role of genomic instability and adaptation in carcinogenesis. / Schneider, Brandt L.; Kulesz-Martin, Molly.

In: Carcinogenesis, Vol. 25, No. 11, 11.2004, p. 2033-2044.

Research output: Contribution to journalArticle

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