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Cooperation among cancer cells: applying game theory to cancer

Nature Reviews Cancer (2018) | Download Citation


Cell cooperation promotes many of the hallmarks of cancer via the secretion of diffusible factors that can affect cancer cells or stromal cells in the tumour microenvironment. This cooperation cannot be explained simply as the collective action of cells for the benefit of the tumour because non-cooperative subclones can constantly invade and free-ride on the diffusible factors produced by the cooperative cells. A full understanding of cooperation among the cells of a tumour requires methods and concepts from evolutionary game theory, which has been used successfully in other areas of biology to understand similar problems but has been underutilized in cancer research. Game theory can provide insights into the stability of cooperation among cells in a tumour and into the design of potentially evolution-proof therapies that disrupt this cooperation.

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This work was supported by P01-CA093900, U01-CA196390 and U54-CA210173 and the Prostate Cancer Foundation to K.J.P. and the 7th European Community Framework Program grant agreement No 627816 to M.A.

Reviewer information

Nature Reviews Cancer thanks A. Aktipis, D. Basanta and F. Fu for their contribution to the peer review of this work.

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  1. Department of Biology, Pennsylvania State University, State College, PA, USA

    • Marco Archetti
  2. School of Biological Sciences, University of East Anglia, Norwich, UK

    • Marco Archetti
  3. Brady Urological Institute, Johns Hopkins School of Medicine, Baltimore, MD, USA

    • Kenneth J. Pienta


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Both authors researched data for the article, substantially contributed to the discussion of content, and wrote, reviewed and edited the manuscript.

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The authors declare no competing interests.

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Correspondence to Marco Archetti.


Clonal selection

Natural selection (the preferential survival of the fitter phenotypes) within populations of cells.


Players that pay a cost to produce a benefit for their opponents or contribute to a public good (for example, a growth factor producer).


Players that do not produce a benefit for their opponents or do not contribute to a public good (for example, a growth factor non-producer).


An evolutionarily stable state to which a population converges over time.


A type of natural (clonal) selection in which fitness depends on the frequency of other phenotypes in the population.


The formal description of strategic interactions; they include the definitions of the players, strategies and payoffs.

Linear effects

The effects of cooperation on fitness when the sum of the contributions is additive (each contribution produces the same increment in benefit).

Multiplayer games

Games with multiple players (which can be made of multiple pairwise interactions or a single public goods game).

Nonlinear effects

The effects of cooperation on fitness when the sum of the contributions is not additive but has increasing and/or diminishing returns.


The choice of the best set of actions to maximize a payoff function.

Pairwise game

A game with only two players.


The reward from the outcome of the interaction (in biology, this is evolutionary fitness).


The individuals (or cells or other entities) that adopt strategies and obtain payoffs.

Public goods games

Multiplayer games in which the payoff depends on the collective decision of multiple players rather than their pairwise interactions.


The decision or type adopted by a player (in biology, this is phenotype).

Warburg effect

The switch from aerobic energy production through oxidative phosphorylation to anaerobic energy production through glycolysis.

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