Thursday, July 17, 2014

Game Theory Modeling Shows When Tumor Cells are Most Vulnerable

Cooperation between oxygen-poor cells (red)
and oxygen-rich ones (green). Source.
Increasingly, biologists are turning to other scientific fields to study the complexities of life.  Particularly, math and biology are becoming more and more intertwined as systems biologists attempt to model the properties of various systems, from metabolic pathways, to cells and tissues, to whole populations and ecosystems.  A new open access study out of John Hopkins Hospital used game theory, an economic model for studying strategic decision making, to identify cancer cell types that are more vulnerable to anti-cancer therapy.

Tumors are ecosystems that are composed of different types of cell populations.  They can reprogram their metabolism and cooperate with each other.  For example, oxygenated cells can use the metabolic by-products produced by oxygen-starved (technical term: hypoxic) cells during metabolism.  Hypoxic cells use glucose to produce energy with a compound called lactate as a by-product; lactate can then be used by oxygenated cells to produce far more energy.  This process is called metabolic coupling.  In this way, the two cell populations cooperate with each other to keep the cancer alive and thriving.

In evolutionary game theory, strategies are being used by different populations, with the outcome being decided by natural selection.  It is not required that the players make rational decisions (like in economic game theory), but only that they have a strategy - which is determined by the presence of genes that influence behavior.  Evolution tests how good the strategy is in the presence of alternative strategies.  The authors used the ideas behind evolutionary game theory to look at the interaction between tumor cell types.  In the case of a tumor, strategic decisions are based on the utilization of energy resources in handling nutrient and oxygen availability.  In that case, a cell can be considered an agent that responds to changing environmental conditions by changing its strategy based on the energy sources it has available. 

Using the two cell types, oxygenated and hypoxic, as players in a "game", the selection of different energy metabolic pathways as "actions", and the production of energy as a "reward", the authors were able to model tumor cell metabolism in the same way populations could be modeled with evolutionary game theory.  What they ultimately found is that there are conditions under which oxygenated cells undergo "critical transitions", where they switch from using glucose to using lactate in energy production (illustrated in the figure, right).  During this switch, lactate transporters and enzymes involved in lactate metabolism, like lactate dehydrogenase (LDH) are crucial to cell survival.  That means that in this critical transition between the glucose and lactate metabolic pathways in oxygenated tumor cells, the cells are especially vulnerable to changes in lactate-related protein levels.

So what does this all mean?  Well, while they have not identified a time frame during which tumor cells are most vulnerable, they have shown that there is a stage at which tumor cell metabolism can be effectively targeted.  During this stage, treatments that focus on reducing the levels or activity of LDH or other important proteins in lactate signaling, uptake, or metabolism could be quite successful.  Breaking the metabolic coupling in tumor cells may have therapeutic benefits.  

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