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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

Qualitative behaviour of the single-cell and of the donor-acceptor system for the coarse-grained model.(a) In the cell-autonomous model, lactate overflow occurs when the glucose intake overcomes a threshold. Correspondingly, the flux through oxidative metabolism increases until the threshold before slowly decreasing once the crowding constraint is saturated and fermentation sets in. (b) In the donor/acceptor system, the donor behaves essentially as an autonomous cell and the acceptor adapts to it. For low glucose intakes, it operates oxidative pathways at small rate. When the donor saturates the crowding constraint excreting lactate, the acceptor imports it and uses it at a substrate to increase the flux through oxidative metabolism.
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f2: Qualitative behaviour of the single-cell and of the donor-acceptor system for the coarse-grained model.(a) In the cell-autonomous model, lactate overflow occurs when the glucose intake overcomes a threshold. Correspondingly, the flux through oxidative metabolism increases until the threshold before slowly decreasing once the crowding constraint is saturated and fermentation sets in. (b) In the donor/acceptor system, the donor behaves essentially as an autonomous cell and the acceptor adapts to it. For low glucose intakes, it operates oxidative pathways at small rate. When the donor saturates the crowding constraint excreting lactate, the acceptor imports it and uses it at a substrate to increase the flux through oxidative metabolism.

Mentions: The solution to this model is described pictorially in Fig. 2 and discussed in Fig. 3, where we also show the feasible range of values of the fluxes of the acceptor cell. In essence, this coarse-grained model suggests that an imbalance in the energetic demands of two cells can induce a metabolic coupling driven by a lactate shuttle from the high- to the low-demand cell, and provides a qualitative scenario for how carbon utilization in both cells changes by tuning the overall glucose supply. We shall now see that such a picture is fully recovered within a large-scale model of human metabolism.


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)

Qualitative behaviour of the single-cell and of the donor-acceptor system for the coarse-grained model.(a) In the cell-autonomous model, lactate overflow occurs when the glucose intake overcomes a threshold. Correspondingly, the flux through oxidative metabolism increases until the threshold before slowly decreasing once the crowding constraint is saturated and fermentation sets in. (b) In the donor/acceptor system, the donor behaves essentially as an autonomous cell and the acceptor adapts to it. For low glucose intakes, it operates oxidative pathways at small rate. When the donor saturates the crowding constraint excreting lactate, the acceptor imports it and uses it at a substrate to increase the flux through oxidative metabolism.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f2: Qualitative behaviour of the single-cell and of the donor-acceptor system for the coarse-grained model.(a) In the cell-autonomous model, lactate overflow occurs when the glucose intake overcomes a threshold. Correspondingly, the flux through oxidative metabolism increases until the threshold before slowly decreasing once the crowding constraint is saturated and fermentation sets in. (b) In the donor/acceptor system, the donor behaves essentially as an autonomous cell and the acceptor adapts to it. For low glucose intakes, it operates oxidative pathways at small rate. When the donor saturates the crowding constraint excreting lactate, the acceptor imports it and uses it at a substrate to increase the flux through oxidative metabolism.
Mentions: The solution to this model is described pictorially in Fig. 2 and discussed in Fig. 3, where we also show the feasible range of values of the fluxes of the acceptor cell. In essence, this coarse-grained model suggests that an imbalance in the energetic demands of two cells can induce a metabolic coupling driven by a lactate shuttle from the high- to the low-demand cell, and provides a qualitative scenario for how carbon utilization in both cells changes by tuning the overall glucose supply. We shall now see that such a picture is fully recovered within a large-scale model of human metabolism.

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