| Metabolic changes during carcinogenesis: potential impact on invasiveness. | |
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MedLine Citation:
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PMID: 17055536 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Successful adaptation to varying microenvironmental constraints plays a crucial role during carcinogenesis. We develop a hybrid cellular automation approach to investigate the cell-microenvironmental interactions that mediate somatic evolution of cancer cells. This allows investigation of the hypothesis that regions of premalignant lesions develop a substrate-limited environment as proliferation carries cells away from blood vessels which remain separated by the intact basement membrane. We find that selective forces in tumoural regions furthest from the blood supply act to favour cells whose metabolism is best suited to respond to local changes in oxygen, glucose and pH levels. The model predicts three phases of somatic evolution. Initially, cell survival and proliferation is limited due to diminished oxygen levels. This promotes adaptation to a second phase of growth dominated by cells with constitutively up-regulated glycolysis, less reliant on oxygen for ATP production. Increased glycolysis induces acidification of the local environment, limiting proliferation and inducing cell death through necrosis and apoptosis. This promotes a third phase of cellular evolution, with emergence of phenotypes resistant to acid-induced toxicity. This emergent cellular phenotype has a significant proliferative advantage because it will consistently acidify the local environment in a way that is toxic to its competitors but harmless to itself. The model's results suggest this sequence is essential in the transition from self-limited premalignant growth to invasive cancer, and, therefore, that this transition may be delayed or prevented through novel strategies directed towards interrupting the hypoxia-glycolysis-acidosis cycle. |
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Authors:
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Kieran Smallbone; Robert A Gatenby; Robert J Gillies; Philip K Maini; David J Gavaghan |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2006-09-16 |
Journal Detail:
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Title: Journal of theoretical biology Volume: 244 ISSN: 0022-5193 ISO Abbreviation: J. Theor. Biol. Publication Date: 2007 Feb |
Date Detail:
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Created Date: 2007-01-30 Completed Date: 2007-06-11 Revised Date: 2007-12-03 |
Medline Journal Info:
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Nlm Unique ID: 0376342 Medline TA: J Theor Biol Country: Netherlands |
Other Details:
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Languages: eng Pagination: 703-13 Citation Subset: IM |
Affiliation:
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Centre for Mathematical Biology, Mathematical Institute, 24-29 St Giles', Oxford, OX1 3LB, UK. kieran.smallbone@manchester.ac.uk |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Adenosine Triphosphate
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biosynthesis Cell Communication / physiology Cell Death / physiology Cell Division / physiology Cell Survival / physiology Cell Transformation, Neoplastic / metabolism Glucose / metabolism Glycolysis / physiology Humans Hydrogen-Ion Concentration Mathematics Models, Biological Neoplasm Invasiveness Neoplasms / metabolism* Oxygen / metabolism Precancerous Conditions / metabolism Up-Regulation / physiology |
| Grant Support | |
ID/Acronym/Agency:
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U56CA113004/CA/NCI NIH HHS |
| Chemical | |
Reg. No./Substance:
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50-99-7/Glucose; 56-65-5/Adenosine Triphosphate; 7782-44-7/Oxygen |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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