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. 2013 Jun 10;10:39.
doi: 10.1186/1742-4682-10-39.

An Integrated Multidisciplinary Model Describing Initiation of Cancer and the Warburg Hypothesis

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Free PMC article

An Integrated Multidisciplinary Model Describing Initiation of Cancer and the Warburg Hypothesis

Edward A Rietman et al. Theor Biol Med Model. .
Free PMC article

Abstract

Background: In this paper we propose a chemical physics mechanism for the initiation of the glycolytic switch commonly known as the Warburg hypothesis, whereby glycolytic activity terminating in lactate continues even in well-oxygenated cells. We show that this may result in cancer via mitotic failure, recasting the current conception of the Warburg effect as a metabolic dysregulation consequent to cancer, to a biophysical defect that may contribute to cancer initiation.

Model: Our model is based on analogs of thermodynamic concepts that tie non-equilibrium fluid dynamics ultimately to metabolic imbalance, disrupted microtubule dynamics, and finally, genomic instability, from which cancers can arise. Specifically, we discuss how an analog of non-equilibrium Rayleigh-Benard convection can result in glycolytic oscillations and cause a cell to become locked into a higher-entropy state characteristic of cancer.

Conclusions: A quantitative model is presented that attributes the well-known Warburg effect to a biophysical mechanism driven by a convective disturbance in the cell. Contrary to current understanding, this effect may precipitate cancer development, rather than follow from it, providing new insights into carcinogenesis, cancer treatment, and prevention.

Figures

Figure 1
Figure 1
Diagram of proposed transition from healthy to aneuploidy cell. An excess of external glucose causes a series of phase transitions starting with glycolytic oscillators which induce a pH imbalance precipitating in mitochondrial membrane breakage followed by microtubule depolymerization and mitotic failure.
Figure 2
Figure 2
Example of Rayleigh-Benard convection rolls. (Based on GNU Matlab code of Parmigiani et al. [24]).
Figure 3
Figure 3
Data from Table "Range of Glycolytic Oscillations in Yeast Extract" in Hess et al.[29]with ~10% error bars. Curves showing oscillation time as a function of external concentration using Eq [4] and setting α = 10-4.
Figure 4
Figure 4
Intracellular localization of GAPDH in HMEC cells on glass slides with and without glucose.
Figure 5
Figure 5
Intracellular localization of GAPDH in HMEC cells on Cytoo Chips with and without glucose.
Figure 6
Figure 6
Bifurcation diagram for sine-circle map. Computed after 10,000 iterations.
Figure 7
Figure 7
Phase diagram for a coupled-map. Numbers indicate cycle of oscillator. White regions are either undefined or represent a fixed point.
Figure 8
Figure 8
Example of dynamics for coupled system similar to glucose and pH oscillations in a cell a = 0.3, b = 0.4, c = 0.2, d = 0.2.

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