Defining the role of cooperation in early tumor progression.

Competition among cells has long been recognized as an important part of carcinogenesis. However, the role of cellular cooperation in cancer has been largely ignored. In this work, we investigated the role of cooperation in early tumor progression using a mathematical and agent-based modeling approach. We hoped to learn how the introduction of cooperative cells into a cell population would affect the dynamics of the system. We modeled the stem cell compartment of tissue using a spatial structure organized into cell patches, with stem cells able to replicate or leave the stem cell compartment through apoptosis or differentiation. The cells could also acquire mutations in three oncogenes and two tumor suppressor genes. Cooperative cells in our model provided a cooperative signal that increased the fitness of their immediate neighbors, but did not affect their own fitness. Running simulations of the model, we found that if cooperative cells are introduced into a cell population, they steadily proliferate and confer a growth advantage to the entire population. This leads us to conclude that providing a cooperative signal is likely to be under positive selective pressure. When cooperative ability and mutation are concurrently present in the same cells, the overall cell population experiences a significant growth advantage, much greater than with cooperation or mutation alone. This growth advantage is diminished if cells with only oncogene/tumor suppressor mutations are also present in the population, suggesting that the optimal scenario for tumor growth would be for cooperative cells to take over a cell population, and then for mutations in oncogenes and tumor suppressors to arise on a background of cooperation. We predict that cooperation is particularly important in the very early stages of carcinogenesis, when tissue is morphologically and histologically normal. Our results have implications for the screening and early diagnosis of cancer.