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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

An isolated HCCN maximizes the ATP yield by directing glucose to OXPHOS even in absence of an active ATP maximization.(a) Average ATP production as a function of the re-scaled average glucose supply. (b) Average flux through LDH (crosses) and PDHm (circles) as a function of the re-scaled average glucose supply. (c) Fraction of ATP produced via glycolysis (crosses) or via OXPHOS (circles) as a function of the re-scaled total ATP produced. The flux through each pathway is re-scaled by half the amount of glucose intaken by the cell (because with one molecule of glucose cells produce two molecules of pyruvate). Curves describe the behaviour of an ATP-maximizing HCCN (black lines, β = 50), a loosely maximizing donor (red lines, β = 5) or the result of a uniform sampling of the allowed flux states for a HCCN (blue lines, β = 0). Error bars for the s.e.m. are smaller than symbols.
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f4: An isolated HCCN maximizes the ATP yield by directing glucose to OXPHOS even in absence of an active ATP maximization.(a) Average ATP production as a function of the re-scaled average glucose supply. (b) Average flux through LDH (crosses) and PDHm (circles) as a function of the re-scaled average glucose supply. (c) Fraction of ATP produced via glycolysis (crosses) or via OXPHOS (circles) as a function of the re-scaled total ATP produced. The flux through each pathway is re-scaled by half the amount of glucose intaken by the cell (because with one molecule of glucose cells produce two molecules of pyruvate). Curves describe the behaviour of an ATP-maximizing HCCN (black lines, β = 50), a loosely maximizing donor (red lines, β = 5) or the result of a uniform sampling of the allowed flux states for a HCCN (blue lines, β = 0). Error bars for the s.e.m. are smaller than symbols.

Mentions: In Fig. 4a we show the ATP production of a single HCCN cell as a function of the available glucose. If ATP production is maximized (large β), one first encounters a regime with a yield of roughly 30 ATPs per glucose molecule (to be compared with the theoretical value of 38) and then a regime where the yield is about 1.7 ATPs per glucose. ATP is produced by OXPHOS in the former case, and by fermentation in the latter (see also Fig. 4b and Fig. 4c). As expected, networks maximizing ATP shift their metabolic strategy at the glucose intake for which the resources available for ATP production by oxidation is exhausted. Note that for β = 5 one obtains an ATP efficiency very close to optimal. Quite importantly and surprisingly, however, for β = 0 (i.e. when no ATP maximization is performed) the emerging picture is qualitatively preserved, albeit with lower ATP yields. Indeed solutions sampled at β = 0 appear to employ a mixture of OXPHOS and fermentation even at low glucose intakes. It is remarkable that the resources -driven shift still occurs at uG, as in this case it corresponds to a largely suboptimal value of ATP production. In other words, the HCCN might devote cellular resources to increase ATP production, but to do so it must explicitly be pursuing ATP maximization. This implies that the crossover from a high- to a low-yield strategy is a robust, embedded property of the network (and of the constraints imposed) and not an exclusive characteristic of the extremal solution that maximizes the 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)

An isolated HCCN maximizes the ATP yield by directing glucose to OXPHOS even in absence of an active ATP maximization.(a) Average ATP production as a function of the re-scaled average glucose supply. (b) Average flux through LDH (crosses) and PDHm (circles) as a function of the re-scaled average glucose supply. (c) Fraction of ATP produced via glycolysis (crosses) or via OXPHOS (circles) as a function of the re-scaled total ATP produced. The flux through each pathway is re-scaled by half the amount of glucose intaken by the cell (because with one molecule of glucose cells produce two molecules of pyruvate). Curves describe the behaviour of an ATP-maximizing HCCN (black lines, β = 50), a loosely maximizing donor (red lines, β = 5) or the result of a uniform sampling of the allowed flux states for a HCCN (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

f4: An isolated HCCN maximizes the ATP yield by directing glucose to OXPHOS even in absence of an active ATP maximization.(a) Average ATP production as a function of the re-scaled average glucose supply. (b) Average flux through LDH (crosses) and PDHm (circles) as a function of the re-scaled average glucose supply. (c) Fraction of ATP produced via glycolysis (crosses) or via OXPHOS (circles) as a function of the re-scaled total ATP produced. The flux through each pathway is re-scaled by half the amount of glucose intaken by the cell (because with one molecule of glucose cells produce two molecules of pyruvate). Curves describe the behaviour of an ATP-maximizing HCCN (black lines, β = 50), a loosely maximizing donor (red lines, β = 5) or the result of a uniform sampling of the allowed flux states for a HCCN (blue lines, β = 0). Error bars for the s.e.m. are smaller than symbols.
Mentions: In Fig. 4a we show the ATP production of a single HCCN cell as a function of the available glucose. If ATP production is maximized (large β), one first encounters a regime with a yield of roughly 30 ATPs per glucose molecule (to be compared with the theoretical value of 38) and then a regime where the yield is about 1.7 ATPs per glucose. ATP is produced by OXPHOS in the former case, and by fermentation in the latter (see also Fig. 4b and Fig. 4c). As expected, networks maximizing ATP shift their metabolic strategy at the glucose intake for which the resources available for ATP production by oxidation is exhausted. Note that for β = 5 one obtains an ATP efficiency very close to optimal. Quite importantly and surprisingly, however, for β = 0 (i.e. when no ATP maximization is performed) the emerging picture is qualitatively preserved, albeit with lower ATP yields. Indeed solutions sampled at β = 0 appear to employ a mixture of OXPHOS and fermentation even at low glucose intakes. It is remarkable that the resources -driven shift still occurs at uG, as in this case it corresponds to a largely suboptimal value of ATP production. In other words, the HCCN might devote cellular resources to increase ATP production, but to do so it must explicitly be pursuing ATP maximization. This implies that the crossover from a high- to a low-yield strategy is a robust, embedded property of the network (and of the constraints imposed) and not an exclusive characteristic of the extremal solution that maximizes the 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