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Quantitative constraint-based computational model of tumor-to-stroma coupling via lactate shuttle.

Capuani F, De Martino D, Marinari E, De Martino A - Sci Rep (2015)

Bottom Line: This suggests that mechanisms for recycling the fermentation products (e.g. a lactate shuttle) may be active, effectively inducing a mutually beneficial metabolic coupling between aberrant and non-aberrant cells.Here we analyze this scenario through a large-scale in silico metabolic model of interacting human cells.By going beyond the cell-autonomous description, we show that elementary physico-chemical constraints indeed favor the establishment of such a coupling under very broad conditions.

View Article: PubMed Central - PubMed

Affiliation: Dipartimento di Fisica, Sapienza Università di Roma, Piazzale A. Moro 5, Rome (Italy).

ABSTRACT
Cancer cells utilize large amounts of ATP to sustain growth, relying primarily on non-oxidative, fermentative pathways for its production. In many types of cancers this leads, even in the presence of oxygen, to the secretion of carbon equivalents (usually in the form of lactate) in the cell's surroundings, a feature known as the Warburg effect. While the molecular basis of this phenomenon are still to be elucidated, it is clear that the spilling of energy resources contributes to creating a peculiar microenvironment for tumors, possibly characterized by a degree of toxicity. This suggests that mechanisms for recycling the fermentation products (e.g. a lactate shuttle) may be active, effectively inducing a mutually beneficial metabolic coupling between aberrant and non-aberrant cells. Here we analyze this scenario through a large-scale in silico metabolic model of interacting human cells. By going beyond the cell-autonomous description, we show that elementary physico-chemical constraints indeed favor the establishment of such a coupling under very broad conditions. The characterization we obtained by tuning the aberrant cell's demand for ATP, amino-acids and fatty acids and/or the imbalance in nutrient partitioning provides quantitative support to the idea that synergistic multi-cell effects play a central role in cancer sustainment.

No MeSH data available.


Related in: MedlinePlus

Restricted matrices of Pearson correlation coefficients for two coupled HCCN cells when the lactate donor maximizes the ATP production and the overall glucose supply is large shows that the two cells are not correlated.The intensity of the color represents the magnitude of the correlation coefficient (see scale on the right hand side). The two cells can independently access glucose and internal fluxes of the lactate acceptor and donor are essentially uncorrelated. The four representative reactions displayed for each cell are the glucose influx (Glc, a proxy for glycolytic activity), LDH (a proxy for lactate overflow and exchange), PDH (a proxy for oxidative metabolism) and the ATP production flux (ATP).
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f8: Restricted matrices of Pearson correlation coefficients for two coupled HCCN cells when the lactate donor maximizes the ATP production and the overall glucose supply is large shows that the two cells are not correlated.The intensity of the color represents the magnitude of the correlation coefficient (see scale on the right hand side). The two cells can independently access glucose and internal fluxes of the lactate acceptor and donor are essentially uncorrelated. The four representative reactions displayed for each cell are the glucose influx (Glc, a proxy for glycolytic activity), LDH (a proxy for lactate overflow and exchange), PDH (a proxy for oxidative metabolism) and the ATP production flux (ATP).

Mentions: To formally assess the extent of metabolic coupling between an ATP-maximizing lactate donor and a lactate acceptor, we computed the matrix of normalized Pearson correlation coefficients of each pair of fluxes in the solutions sampled for different levels UG of the glucose supplied to the system. The Pearson coefficient between random variables X and Y is defined as r = cov(X,Y)/(σXσY), where cov(X,Y) denotes their covariance and σX and σY stand for their respective standard deviations. r ranges from −1 to 1 and quantifies the linear dependence of the two variables. More precisely, the linear correlation between variables X and Y is more positive the closer r is to 1, and more negative the closer r is to −1, while X and Y can be considered uncorrelated if . For sakes of clarity, we have considered the correlations arising in a system formed by an ATP-maximizing lactate donor (large β) and a lactate acceptor. For smaller values of β correlations get weaker while maintaing the same qualitative structure. Fig. 8 displays three reduced correlation matrices (obtained for three different values of the overall glucose supply) where only a small subset of fluxes (each presentative of a different biologically relevant pathway) appears. Full matrices for three choices of UG are instead shown in Figs. S3–S5.


Quantitative constraint-based computational model of tumor-to-stroma coupling via lactate shuttle.

Capuani F, De Martino D, Marinari E, De Martino A - Sci Rep (2015)

Restricted matrices of Pearson correlation coefficients for two coupled HCCN cells when the lactate donor maximizes the ATP production and the overall glucose supply is large shows that the two cells are not correlated.The intensity of the color represents the magnitude of the correlation coefficient (see scale on the right hand side). The two cells can independently access glucose and internal fluxes of the lactate acceptor and donor are essentially uncorrelated. The four representative reactions displayed for each cell are the glucose influx (Glc, a proxy for glycolytic activity), LDH (a proxy for lactate overflow and exchange), PDH (a proxy for oxidative metabolism) and the ATP production flux (ATP).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4493718&req=5

f8: Restricted matrices of Pearson correlation coefficients for two coupled HCCN cells when the lactate donor maximizes the ATP production and the overall glucose supply is large shows that the two cells are not correlated.The intensity of the color represents the magnitude of the correlation coefficient (see scale on the right hand side). The two cells can independently access glucose and internal fluxes of the lactate acceptor and donor are essentially uncorrelated. The four representative reactions displayed for each cell are the glucose influx (Glc, a proxy for glycolytic activity), LDH (a proxy for lactate overflow and exchange), PDH (a proxy for oxidative metabolism) and the ATP production flux (ATP).
Mentions: To formally assess the extent of metabolic coupling between an ATP-maximizing lactate donor and a lactate acceptor, we computed the matrix of normalized Pearson correlation coefficients of each pair of fluxes in the solutions sampled for different levels UG of the glucose supplied to the system. The Pearson coefficient between random variables X and Y is defined as r = cov(X,Y)/(σXσY), where cov(X,Y) denotes their covariance and σX and σY stand for their respective standard deviations. r ranges from −1 to 1 and quantifies the linear dependence of the two variables. More precisely, the linear correlation between variables X and Y is more positive the closer r is to 1, and more negative the closer r is to −1, while X and Y can be considered uncorrelated if . For sakes of clarity, we have considered the correlations arising in a system formed by an ATP-maximizing lactate donor (large β) and a lactate acceptor. For smaller values of β correlations get weaker while maintaing the same qualitative structure. Fig. 8 displays three reduced correlation matrices (obtained for three different values of the overall glucose supply) where only a small subset of fluxes (each presentative of a different biologically relevant pathway) appears. Full matrices for three choices of UG are instead shown in Figs. S3–S5.

Bottom Line: This suggests that mechanisms for recycling the fermentation products (e.g. a lactate shuttle) may be active, effectively inducing a mutually beneficial metabolic coupling between aberrant and non-aberrant cells.Here we analyze this scenario through a large-scale in silico metabolic model of interacting human cells.By going beyond the cell-autonomous description, we show that elementary physico-chemical constraints indeed favor the establishment of such a coupling under very broad conditions.

View Article: PubMed Central - PubMed

Affiliation: Dipartimento di Fisica, Sapienza Università di Roma, Piazzale A. Moro 5, Rome (Italy).

ABSTRACT
Cancer cells utilize large amounts of ATP to sustain growth, relying primarily on non-oxidative, fermentative pathways for its production. In many types of cancers this leads, even in the presence of oxygen, to the secretion of carbon equivalents (usually in the form of lactate) in the cell's surroundings, a feature known as the Warburg effect. While the molecular basis of this phenomenon are still to be elucidated, it is clear that the spilling of energy resources contributes to creating a peculiar microenvironment for tumors, possibly characterized by a degree of toxicity. This suggests that mechanisms for recycling the fermentation products (e.g. a lactate shuttle) may be active, effectively inducing a mutually beneficial metabolic coupling between aberrant and non-aberrant cells. Here we analyze this scenario through a large-scale in silico metabolic model of interacting human cells. By going beyond the cell-autonomous description, we show that elementary physico-chemical constraints indeed favor the establishment of such a coupling under very broad conditions. The characterization we obtained by tuning the aberrant cell's demand for ATP, amino-acids and fatty acids and/or the imbalance in nutrient partitioning provides quantitative support to the idea that synergistic multi-cell effects play a central role in cancer sustainment.

No MeSH data available.


Related in: MedlinePlus