The inherent fragility of collective proliferative control

Tissues achieve and maintain their sizes through active feedback, whereby cells collectively regulate proliferation and differentiation so as to facilitate homeostasis and the ability to respond to disturbances. One of the best understood feedback mechanisms-renewal control-achieves remarkable feats of robustness in determining and maintaining desired sizes. Yet in a variety of biologically relevant situations, we show that stochastic effects should cause rare but catastrophic failures of renewal control. We define the circumstances under which this occurs and raise the possibility such events account for important non-genetic steps in the development of cancer. We further suggest that the spontaneous stochastic reversal of these events could explain cases of cancer normalization or dormancy following treatment. Indeed, we show that the kinetics of post-treatment recurrence for many cancers are often better fit by a model of stochastic re-emergence due to loss of collective proliferative control, than by deterministic models of cancer relapse.