Document Detail

Initiation of genetic instability and tumour formation: a review and hypothesis of a nongenotoxic mechanism.
MedLine Citation:
PMID:  12861379     Owner:  NLM     Status:  MEDLINE    
Genetic instability in tumours results in cell-to-cell variability of genome which parallels the cell-to-cell variability of microscopic morphology and of behaviour (tumour cell heterogeneity) of these lesions. Genetic instability is therefore strongly supported as the fundamental process by which normal tissue cells become neoplastic. The commonest current suggestion for the mechanism of initiation of carcinogenesis is a 'direct hit' mutation of a 'cancer critical' gene in a somatic cell by carcinogenic agents. However, this mechanism does not account for the activity of carcinogens which are not mutagens, and does not explain why many mutagens are not carcinogens. This paper proposes a nonmutational (nongenotoxic) mechanism of initiation of genetic instability in previously normal cells as follows: 1) During S phase of local tissue stem cells, carcinogen binds to and disables the proofreading enzyme for a new DNA strand. 2) While it is disabled, the proofreading enzyme fails to correct illicit changes in the nucleotide sequence(s) for one or more genes for proofreading fidelity or repair of DNA in the new strand of DNA, which passes to one daughter cell. 3) When this daughter cell is a continuing stem cell, the resulting cell line remains immortal, and retains its prior differentiation commitment to produce daughter cells of a particular type. However, the acquired genetic instability in this cell line causes secondary mutations which lead to uncontrolled growth, and the heterogeneous morphologic and behavioural features of a tumour resembling the parent cell type.
L P Bignold
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Publication Detail:
Type:  Journal Article; Review    
Journal Detail:
Title:  Cellular and molecular life sciences : CMLS     Volume:  60     ISSN:  1420-682X     ISO Abbreviation:  Cell. Mol. Life Sci.     Publication Date:  2003 Jun 
Date Detail:
Created Date:  2003-07-15     Completed Date:  2003-08-05     Revised Date:  2004-11-17    
Medline Journal Info:
Nlm Unique ID:  9705402     Medline TA:  Cell Mol Life Sci     Country:  Switzerland    
Other Details:
Languages:  eng     Pagination:  1107-17     Citation Subset:  IM    
Department of Pathology, University of Adelaide, SA 5005, Australia.
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MeSH Terms
Carcinogens / toxicity
Cell Division / drug effects,  genetics
Mitosis / drug effects
Models, Biological
Mutagens / toxicity
Neoplasms / etiology*,  genetics*,  pathology
Stem Cells / drug effects
Reg. No./Substance:
0/Carcinogens; 0/Mutagens

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