Title: Can Stochastic Fluctuations in Cell Cooperation Contribute to Carcinogenesis
Abstract: Age-incidence data imply that stochastic steps are required to initiate cancer. Some steps clearly correspond to random mutation, but do all? Beyond changes that, like mutation, are cell-intrinsic, we wondered whether stochastic events could push groups of interacting cells toward cancer without need for any durable, cell-intrinsic change. This question was suggested by our work on Braf-transformed mouse melanocytes, which, in vivo, usually undergo collective growth arrest (producing benign nevi, aka moles), apparently as a result of cell-cell interactions [1]. Rarely, however, such cells generate melanoma tumors—apparently without additional mutation. Using mathematical modeling and spatial stochastic simulation of collective growth arrest, we searched for circumstances in which cell populations that normally all stop growing switch, on rare occasions, to unstoppable growth. We readily observed such “stochastic escape” either when cells exhibited both positive and negative effects on each other’s growth, or when arrested and dividing cells displayed a tendency to spatially segregate, through cell sorting or cell migration. As both kinds of events are common in tissues, we conclude that risk of irretrievable failure likely exists for many growth-control circuits. Evolution undoubtedly adjusts the parameters of growth-control to minimize these risks, but is likely limited by tradeoffs (e.g. in robustness or dynamic range of growth control). Our finding that fluctuations in cell cooperation can produce collective transitions to uncontrolled growth both helps explain how influences not directly related to mutation (e.g. tumor promoting agents, genetic background, environmental factors) alter cancer incidence, and suggests new ways to stop cancers before they happen.
Supported by U54CA217378.
1.Ruiz-Vega, et al. (2020) eLife. doi: 10.7554/eLife.61026.