Background: Cancer progression is an evolutionary process. As in whole organisms, there is the potential for cancer cells to evolve through a process of mutual benefit, or cooperation. This can occur when distinct mutations in different cells are mutually beneficial, enhancing the growth of both populations through cell-cell interactions. Carcinoma cells often undergo an epithelial-mesenchymal transition (EMT) during malignant progression, but this usually occurs within a predominantly epithelial cancer cell environment. We hypothesised that EMT carcinoma cells might be able to cooperate with well-differentiated carcinoma cells to produce an emergent behaviour that is more malignant than each population on its own.
Methods: To simulate carcinogenesis, we have produced an agent based mathematical model based on Voronoi tesselations. This enables us to visualise cells in a dynamic way, producing realistic representations of cell shape and motility in an animated form. At the same time, it enables us to quantitatively predict the effects of mutation rate, proliferation, adhesion, motility, extracellular matrix breakdown and cell-cell communication on tumour progression and response to therapies. Input biological parameters are chosen from data obtained empirically from live cell imaging and other observations of squamous cell carcinomas.
Results: We have used the model to compare the progression of a squamous cell carcinoma in 6 distinct scenarios of cancer evolution, including the traditional view in which the effects of all mutations are cell-autonomous and must accumulate within a clone for malignancy to be achieved. The endpoint for malignancy being reached was invasion of the underlying extracellular matrix. Late occurring mutations induce EMT-like changes in cell behaviour and uncontrolled active proliferation, which were complementary. Scenarios in which mutations are not cell-autonomous gave higher probabilities of malignancy and recurrence following treatment than the traditional, cell-autonomous scenario.
Conclusion: Cooperation between EMT cells and non-EMT cells is a plausible mechanism for the evolution of primary and recurrent carcinomas.