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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

Donor’s biomass flux and lactate overflow, and acceptor’s lactate intake for two coupled HCCNs with a biomass-maximizing donor.The qualitative behavior obtained when the donor is maximizing the ATP flux is reproduced in a more realistic case in which a biomass objective function is considered. See Table S9 for the biomass coefficients.
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f7: Donor’s biomass flux and lactate overflow, and acceptor’s lactate intake for two coupled HCCNs with a biomass-maximizing donor.The qualitative behavior obtained when the donor is maximizing the ATP flux is reproduced in a more realistic case in which a biomass objective function is considered. See Table S9 for the biomass coefficients.

Mentions: In order to assess the robustness of the occurrence of lactate overflow metabolism under the imposed constraints, we have further analyzed the flux configurations in a dono/acceptor system in which the donor maximizes the production of biomass precursors. We show here (see Fig. 7) results obtained by maximizing the biomass defined as in Table S9, which essentially reproduce those described above. Such a robustness becomes less surprising in the light of the fact that the qualitative features of the switch from oxidative to non-oxidative metabolism are obtained even in an unbiased sampling of the steady states. This observation suggets that such a scenario is to a large degree embedded in the stoichiometry and in the main topological features of the underlying reaction network.


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)

Donor’s biomass flux and lactate overflow, and acceptor’s lactate intake for two coupled HCCNs with a biomass-maximizing donor.The qualitative behavior obtained when the donor is maximizing the ATP flux is reproduced in a more realistic case in which a biomass objective function is considered. See Table S9 for the biomass coefficients.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f7: Donor’s biomass flux and lactate overflow, and acceptor’s lactate intake for two coupled HCCNs with a biomass-maximizing donor.The qualitative behavior obtained when the donor is maximizing the ATP flux is reproduced in a more realistic case in which a biomass objective function is considered. See Table S9 for the biomass coefficients.
Mentions: In order to assess the robustness of the occurrence of lactate overflow metabolism under the imposed constraints, we have further analyzed the flux configurations in a dono/acceptor system in which the donor maximizes the production of biomass precursors. We show here (see Fig. 7) results obtained by maximizing the biomass defined as in Table S9, which essentially reproduce those described above. Such a robustness becomes less surprising in the light of the fact that the qualitative features of the switch from oxidative to non-oxidative metabolism are obtained even in an unbiased sampling of the steady states. This observation suggets that such a scenario is to a large degree embedded in the stoichiometry and in the main topological features of the underlying reaction network.

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