Heterogeneity for IGF-II production maintained by public goods dynamics in neuroendocrine pancreatic cancer

http://www.pnas.org/content/112/6/1833.full

Marco Archetti, Daniela A. Ferraro, and Gerhard Christofori

Significant heterogeneity exists in intratumour populations. At first glance, this appears to be at odds with the strong selective pressure for the most proliferative subclones. The authors explore this by considering neuroendocrine pancreatic cancer cells, which produce a growth factor called IGF-II. They mix populations of IGF-II positive (producer) cells and IGF-II knockout (nonproducer) cells, to explore under what circumstances heterogeneity can be supported. 

They find that, when cells are grown in nutrient-high conditions, the fraction of producer cells reduces to zero over time. This is because the nonproducer cells are able to free-ride on the IGF-II produced by the producer cells, in a tragedy of the commons. However, at low nutrient conditions, producer cells dominate over the nonproducer cells (at intermediate concentrations of nutrient there was no clear winner). The authors argue that this can be understood in terms of the nonlinear cost of generating IGF-II. When the cost/benefit ratio for producing IGF-II is low (i.e. in nutrient poor conditions), cells that can endogeneously produce the growth factor have an advantage. However, as nutrient availability increases, there is a diminishing return on generating the growth factor, so cells that are nonproducers have an advantage. The authors show via simulation that when such agents are spatially distributed on a lattice, coexistence between producers and nonproducers can occur due to heterogeneity in nutrient availability.