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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

Schematic representation of the minimal model of two cells coupled via a lactate shuttle.Two cells (lactate donor and acceptor, respectively) share glucose as an energy source. Glucose is partitioned according to the fluxes fglyc,don and fglyc,acc, which convert one internal glucose molecules to two pyruvate molecules producing two ATP molecules. Pyruvate can then undergo oxidative phosphorylation (with the irreversible fluxes fox,don and fox,acc, giving 36 more ATP molecules) or LDH (with fluxes fLDH,don and fLDH,acc, by which lactate (L) is obtained). Lactate is for simplicity assumed to be secreted upon production. If both cells produce lactate, no coupling sets in, unless due to competition for nutrients under glucose limitation. If however the donor cell secretes lactate, the acceptor cell may intake it to replace glucose whenever its access to the latter is limited (e.g. because the donor cell’s glucose intake is large). In such cases a lactate shuttle will effectively couple the metabolisms of the two cells.
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f1: Schematic representation of the minimal model of two cells coupled via a lactate shuttle.Two cells (lactate donor and acceptor, respectively) share glucose as an energy source. Glucose is partitioned according to the fluxes fglyc,don and fglyc,acc, which convert one internal glucose molecules to two pyruvate molecules producing two ATP molecules. Pyruvate can then undergo oxidative phosphorylation (with the irreversible fluxes fox,don and fox,acc, giving 36 more ATP molecules) or LDH (with fluxes fLDH,don and fLDH,acc, by which lactate (L) is obtained). Lactate is for simplicity assumed to be secreted upon production. If both cells produce lactate, no coupling sets in, unless due to competition for nutrients under glucose limitation. If however the donor cell secretes lactate, the acceptor cell may intake it to replace glucose whenever its access to the latter is limited (e.g. because the donor cell’s glucose intake is large). In such cases a lactate shuttle will effectively couple the metabolisms of the two cells.

Mentions: Let us now consider two replicas of Vazquez et al.‘s cell and assume that the two cells can interact via the exchange of lactate, which, in particular, can be intaken and used as an alternative carbon source through reverse LDH (catalyzing the conversion of lactate back to pyruvate). For sakes of simplicity, we distinguish between a donor cell (‘don’, which can only excrete lactate) and an acceptor cell (‘acc’, which can both excrete and import lactate) (see Fig. 1). In order to avoid starvation, we furthermore impose that both cells generate a minimum flux of ATP, i.e.where the ATP production flux is given by (4), namely


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)

Schematic representation of the minimal model of two cells coupled via a lactate shuttle.Two cells (lactate donor and acceptor, respectively) share glucose as an energy source. Glucose is partitioned according to the fluxes fglyc,don and fglyc,acc, which convert one internal glucose molecules to two pyruvate molecules producing two ATP molecules. Pyruvate can then undergo oxidative phosphorylation (with the irreversible fluxes fox,don and fox,acc, giving 36 more ATP molecules) or LDH (with fluxes fLDH,don and fLDH,acc, by which lactate (L) is obtained). Lactate is for simplicity assumed to be secreted upon production. If both cells produce lactate, no coupling sets in, unless due to competition for nutrients under glucose limitation. If however the donor cell secretes lactate, the acceptor cell may intake it to replace glucose whenever its access to the latter is limited (e.g. because the donor cell’s glucose intake is large). In such cases a lactate shuttle will effectively couple the metabolisms of the two cells.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f1: Schematic representation of the minimal model of two cells coupled via a lactate shuttle.Two cells (lactate donor and acceptor, respectively) share glucose as an energy source. Glucose is partitioned according to the fluxes fglyc,don and fglyc,acc, which convert one internal glucose molecules to two pyruvate molecules producing two ATP molecules. Pyruvate can then undergo oxidative phosphorylation (with the irreversible fluxes fox,don and fox,acc, giving 36 more ATP molecules) or LDH (with fluxes fLDH,don and fLDH,acc, by which lactate (L) is obtained). Lactate is for simplicity assumed to be secreted upon production. If both cells produce lactate, no coupling sets in, unless due to competition for nutrients under glucose limitation. If however the donor cell secretes lactate, the acceptor cell may intake it to replace glucose whenever its access to the latter is limited (e.g. because the donor cell’s glucose intake is large). In such cases a lactate shuttle will effectively couple the metabolisms of the two cells.
Mentions: Let us now consider two replicas of Vazquez et al.‘s cell and assume that the two cells can interact via the exchange of lactate, which, in particular, can be intaken and used as an alternative carbon source through reverse LDH (catalyzing the conversion of lactate back to pyruvate). For sakes of simplicity, we distinguish between a donor cell (‘don’, which can only excrete lactate) and an acceptor cell (‘acc’, which can both excrete and import lactate) (see Fig. 1). In order to avoid starvation, we furthermore impose that both cells generate a minimum flux of ATP, i.e.where the ATP production flux is given by (4), namely

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