Edited* by Peter T. Ellison, Harvard University, Cambridge, MA, and approved December 19, 2014 (received for review July 31, 2014)
Cancer cells compete for space and nutrients against healthy cells and other cancer cells but also cooperate by secreting growth factors. Clones that do not produce growth factors, however, have a proliferation advantage because they can use the factors produced by neighboring cells without the cost of producing them. Therefore, the cooperative production of growth factors by tumor cells should collapse. What maintains cooperation within the tumor? Here, we use evolutionary game theory to explain how heterogeneity can persist, and we use experiments with pancreatic cancer cells to test the predictions of the theory. Cancer is a process of clonal selection, and studying cancer cell populations using methods and concepts from evolutionary biology can reveal potential evolutionarily stable therapies.
The extensive intratumor heterogeneity revealed by sequencing cancer genomes is an essential determinant of tumor progression, diagnosis, and treatment. What maintains heterogeneity remains an open question because competition within a tumor leads to a strong selection for the fittest subclone. Cancer cells also cooperate by sharing molecules with paracrine effects, such as growth factors, and heterogeneity can be maintained if subclones depend on each other for survival. Without strict interdependence between subclones, however, nonproducer cells can free-ride on the growth factors produced by neighboring producer cells, a collective action problem known in game theory as the “tragedy of the commons,” which has been observed in microbial cell populations. Here, we report that similar dynamics occur in cancer cell populations. Neuroendocrine pancreatic cancer (insulinoma) cells that do not produce insulin-like growth factor II (IGF-II) grow slowly in pure cultures but have a proliferation advantage in mixed cultures, where they can use the IGF-II provided by producer cells. We show that, as predicted by evolutionary game theory, producer cells do not go extinct because IGF-II acts as a nonlinear public good, creating negative frequency-dependent selection that leads to a stable coexistence of the two cell types. Intratumor cell heterogeneity can therefore be maintained even without strict interdependence between cell subclones. Reducing the amount of growth factors available within a tumor may lead to a reduction in growth followed by a new equilibrium, which may explain relapse in therapies that target growth factors.
Author contributions: M.A. designed research; M.A., D.A.F., and G.C. designed experiments; M.A. designed theory; M.A. and D.A.F. performed experiments; M.A. analyzed data; and M.A., D.A.F., and G.C. wrote the paper.
The authors declare no conflict of interest.
↵*This Direct Submission article had a prearranged editor.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1414653112/-/DCSupplemental.
Freely available online through the PNAS open access option.
