title: Heterogeneity for IGF-II production maintained by public goods dynamics in neuroendocrine pancreatic cancer.
abstract: 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.
authors.affiliation: School of Biological Sciences, University of East Anglia, Norwich Research Park, Norwich NR4 7TJ, United Kingdom; and m.archetti@uea.ac.uk.
authors.forename: Marco
authors.initials: M
authors.lastname: Archetti
authors.affiliation: Department of Biomedicine, University of Basel, CH-4058 Basel, Switzerland.
authors.forename: Daniela A
authors.initials: DA
authors.lastname: Ferraro
authors.affiliation: Department of Biomedicine, University of Basel, CH-4058 Basel, Switzerland.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Christofori
mesh_terms: D000818:Animals; D005075:Biological Evolution; D019070:Cell Lineage; D049109:Cell Proliferation / Q000187:drug effects*; D003198:Computer Simulation; D005434:Flow Cytometry; D005716:Game Theory; D005717:Games, Experimental; D007335:Insulin-Like Growth Factor II / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D007340:Insulinoma / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D010190:Pancreatic Neoplasms / Q000378:metabolism*; D012641:Selection, Genetic
chemical_list: D007335:Insulin-Like Growth Factor II
keywords: evolution; game theory; tumor