Dynamics of growth factor production in monolayers of cancer cells and evolution of resistance to anticancer therapies

Tumor heterogeneity is well documented for many characters, including the production of growth factors, which improve tumor proliferation and promote resistance against apoptosis and against immune reaction. What maintains heterogeneity remains an open question that has implications for diagnosis and treatment. While it has been suggested that therapies targeting growth factors are robust against evolved resistance, current therapies against growth factors, like antiangiogenic drugs, are not effective in the long term, as resistant mutants can evolve and lead to relapse. We use evolutionary game theory to study the dynamics of the production of growth factors by monolayers of cancer cells and to understand the effect of therapies that target growth factors. The dynamics depend on the production cost of the growth factor, on its diffusion range and on the type of benefit it confers to the cells. Stable heterogeneity is a typical outcome of the dynamics, while a pure equilibrium of nonproducer cells is possible under certain conditions. Such pure equilibrium can be the goal of new anticancer therapies. We show that current therapies, instead, can be effective only if growth factors are almost completely eliminated and if the reduction is almost immediate.