Cooperation among cancer cells: applying game theory to cancer

Abstract

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.

Fig. 1 |. Cooperative interactions within the tumour and with the stroma.

a | Two cancer subclones exchange mutually beneficial growth factors. b | One cancer subclone provides a growth factor to itself and to another, non-producer subclone. c | Cancer cells producing adhesion molecules provide a benefit to those nearby that do not produce adhesion molecules. d | Cancer cells producing growth factors trigger the formation of new blood vessels, which provide oxygen to the tumour. e | Cancer cells produce cytokines that activate stromal cells, which in turn provide growth factors to the cancer cells.

Fig. 2 |. Nonlinear dynamics.

The fitness values of producer and non-producer cells as a function of the fraction of producer cells for different costs of growth factor production c are shown. Equilibria and the direction of the dynamics (arrows) are shown. a | When the cost–benefit ratio of growth factor production (c) is high (c = 0.2), non-producer cells have a fitness advantage for any fraction of the two types, and hence, their frequency increases over time until the producers are eliminated from the population. b | When the cost is low enough (c = 0.05), however, the small advantage of having an extra producer (itself) in the group can be enough to confer a net fitness advantage to producers when they are at intermediate frequencies within the population; in this case, the population can converge to a mixed equilibrium of the two cell types.