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Int J Cancer. 2015 May 1;136(9):2001-11. doi: 10.1002/ijc.28975. Epub 2014 May 27.

Cancer may be a pathway to cell survival under persistent hypoxia and elevated ROS: a model for solid-cancer initiation and early development.

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Computational Systems Biology Laboratory, Department of Biochemistry and Molecular Biology and Institute of Bioinformatics, University of Georgia, Athens, GA.


A number of proposals have been made in the past century regarding what may drive sporadic cancers to initiate and develop. Yet the problem remains largely unsolved as none of the proposals have been widely accepted as cancer-initiation drivers. We propose here a driver model for the initiation and early development of solid cancers associated with inflammation-induced chronic hypoxia and reactive oxygen species (ROS) accumulation. The model consists of five key elements: (i)human cells tend to have a substantial gap between ATP demand and supply during chronic hypoxia, which would inevitably lead to increased uptake of glucose and accumulation of its metabolites; (ii) the accumulation of these metabolites will cast mounting pressure on the cells and ultimately result in the production and export of hyaluronic acid; (iii) the exported hyaluronic acid will be degraded into fragments of various sizes, serving as tissue-repair signals, including signals for cell proliferation, cell survival and angiogenesis, which lead to the initial proliferation of the underlying cells; (iv) cell division provides an exit for the accumulated glucose metabolites using them towards macromolecular synthesis for the new cell, and hence alleviate the pressure from the metabolite accumulation; and (v) this process continues as long as the hypoxic condition persists. In tandem, genetic mutations may be selected to make cell divisions and hence survival more sustainable and efficient, also increasingly more uncontrollable. This model also applies to some hereditary cancers as their key mutations, such as BRCA for breast cancer, generally lead to increased ROS and ultimately to repression of mitochondrial activities and up-regulation of glycolysis, as well as hypoxia; hence the energy gap, glucose-metabolite accumulation, hyaluronic acid production and continuous cell division for survival.


Warburg effect; cancer resistance species; carcinogenesis; hyaluronic acid; hypoxia; reactive oxygen species

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