Proliferation to suppress neoplasia: a general model and a first test in the moon jelly

Cell proliferation is necessary to maintain tissue homeostasis, but proliferation carries with it a risk of cancer. Nevertheless, nature abounds with examples of organisms that achieve low rates of cancer while also proliferating to maintain tissue homeostasis. To understand how organisms might achieve both of these goals, we developed a dynamical model describing cell birth, death, and mutation in a population. The model identifies two distinct regimes. In one regime, as expected, decreasing proliferation delays accumulation of neoplastic cells. In another regime, unexpectedly, increasing proliferation suppresses accumulation of neoplastic cells. In this regime, when more cells proliferate, more cells correspondingly die as a consequence of homeostatic feedback. As long as neoplastic cells are detected and killed preferentially, the high flux of cells acts as a proofreader, eliminating neoplastic cells. High-flux proofreading may seem costly, but it can be effective even when the system does not have a precise detector of neoplastic cells. As a first experimental test of whether high-flux proofreading is biologically relevant, we examined the moon jelly, a cnidarian. Neoplasms have rarely been observed in cnidarians, and yet simply inhibiting proliferation is sufficient to promote neoplasms in the moon jelly. Together, the model and experiments show that high-flux proofreading is an effective cancer resistance strategy. Because cell birth, death, and mutation are fundamentally conserved processes, high-flux proofreading may be widespread. The quantitative framework presented in this study offers clear experimentally testable predictions to assess high-flux proofreading in other systems, and its potential utility for cancer prevention and treatment.