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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

When a lactate donor maximizes its ATP production it intakes most of the glucose supplied to the two-cell system.The ATP production by the acceptor cell increases in correspondence to a decrease in efficiency of the donor’s metabolism. (a) Glucose intakes for two coupled cells as a function of the total glucose available to the donor-acceptor pair. (b) ATP produced by the donor. Curves describe the behaviour obtained for two coupled HCCN cells with an ATP-maximizing donor (black lines, β = 50), a loosely maximizing donor (red lines, β = 5) or for an unbiased sampling of the two-cell solution space (blue lines, β = 0). Error bars for the s.e.m. are smaller than symbols.
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f5: When a lactate donor maximizes its ATP production it intakes most of the glucose supplied to the two-cell system.The ATP production by the acceptor cell increases in correspondence to a decrease in efficiency of the donor’s metabolism. (a) Glucose intakes for two coupled cells as a function of the total glucose available to the donor-acceptor pair. (b) ATP produced by the donor. Curves describe the behaviour obtained for two coupled HCCN cells with an ATP-maximizing donor (black lines, β = 50), a loosely maximizing donor (red lines, β = 5) or for an unbiased sampling of the two-cell solution space (blue lines, β = 0). Error bars for the s.e.m. are smaller than symbols.

Mentions: We now consider two replicas of the HCCN and again distinguish between a lactate acceptor and a donor cell. We also impose that there is no external lactate source, and explore the scenario where the donor optimizes ATP production to a degree tuned by the parameter β. Fig. 5a shows that, as expected, an ATP-maximizing donor cell sequesters all of the available glucose except for the small amount required for the acceptor’s survival. This is reflected by the ATP production curves as a function of the total glucose supply displayed in Fig. 5b. In such conditions, the acceptor’s ATP production fluxes matches the minimum required for survival, i.e. (which is set to be equal to 1 uG for simplicity) until the donor switches to aerobic glycolysis, thereby excreting lactate. The donor, on the other hand, goes through an initial phase of exclusive OXPHOS use, followed by a switch to aerobic glycolysis when the crowding constraint does not allow for a further increment of the mitochondrial flux. In Fig. 6a one indeed sees that glucose is mainly channeled to OXPHOS as long as the crowding constraint allows for it. As soon as the latter is saturated, the donor diverts pyruvate to LDH, usefully regenerating NAD from NADH and thus avoiding glycolysis halt. LDH generates lactate, which is then expelled and intaken by the acceptor. As shown in Fig. 6b, this is accompanied by a reversal of LDH in the acceptor: lactate is transformed into pyruvate that is then channeled to OXPHOS through PDHm. The acceptor can thus spare some cellular resources to produce pyruvate, at the cost of becoming strongly dependent on the donor for ATP production.


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)

When a lactate donor maximizes its ATP production it intakes most of the glucose supplied to the two-cell system.The ATP production by the acceptor cell increases in correspondence to a decrease in efficiency of the donor’s metabolism. (a) Glucose intakes for two coupled cells as a function of the total glucose available to the donor-acceptor pair. (b) ATP produced by the donor. Curves describe the behaviour obtained for two coupled HCCN cells with an ATP-maximizing donor (black lines, β = 50), a loosely maximizing donor (red lines, β = 5) or for an unbiased sampling of the two-cell solution space (blue lines, β = 0). Error bars for the s.e.m. are smaller than symbols.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f5: When a lactate donor maximizes its ATP production it intakes most of the glucose supplied to the two-cell system.The ATP production by the acceptor cell increases in correspondence to a decrease in efficiency of the donor’s metabolism. (a) Glucose intakes for two coupled cells as a function of the total glucose available to the donor-acceptor pair. (b) ATP produced by the donor. Curves describe the behaviour obtained for two coupled HCCN cells with an ATP-maximizing donor (black lines, β = 50), a loosely maximizing donor (red lines, β = 5) or for an unbiased sampling of the two-cell solution space (blue lines, β = 0). Error bars for the s.e.m. are smaller than symbols.
Mentions: We now consider two replicas of the HCCN and again distinguish between a lactate acceptor and a donor cell. We also impose that there is no external lactate source, and explore the scenario where the donor optimizes ATP production to a degree tuned by the parameter β. Fig. 5a shows that, as expected, an ATP-maximizing donor cell sequesters all of the available glucose except for the small amount required for the acceptor’s survival. This is reflected by the ATP production curves as a function of the total glucose supply displayed in Fig. 5b. In such conditions, the acceptor’s ATP production fluxes matches the minimum required for survival, i.e. (which is set to be equal to 1 uG for simplicity) until the donor switches to aerobic glycolysis, thereby excreting lactate. The donor, on the other hand, goes through an initial phase of exclusive OXPHOS use, followed by a switch to aerobic glycolysis when the crowding constraint does not allow for a further increment of the mitochondrial flux. In Fig. 6a one indeed sees that glucose is mainly channeled to OXPHOS as long as the crowding constraint allows for it. As soon as the latter is saturated, the donor diverts pyruvate to LDH, usefully regenerating NAD from NADH and thus avoiding glycolysis halt. LDH generates lactate, which is then expelled and intaken by the acceptor. As shown in Fig. 6b, this is accompanied by a reversal of LDH in the acceptor: lactate is transformed into pyruvate that is then channeled to OXPHOS through PDHm. The acceptor can thus spare some cellular resources to produce pyruvate, at the cost of becoming strongly dependent on the donor for ATP production.

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