Should tissue structure suppress or amplify selection to minimize cancer risk?

Abstract

BackgroundIt has been frequently argued that tissues evolved to suppress the accumulation of growth enhancing cancer inducing mutations. A prominent example is the hierarchical structure of tissues with high cell turnover, where a small number of tissue specific stem cells produces a large number of specialized progeny during multiple differentiation steps. Another well known mechanism is the spatial organization of stem cell populations and it is thought that this organization suppresses fitness enhancing mutations. However, in small populations the suppression of advantageous mutations typically also implies an increased accumulation of deleterious mutations. Thus, it becomes an important question whether the suppression of potentially few advantageous mutations outweighs the combined effects of many deleterious mutations.ResultsWe argue that the distribution of mutant fitness effects, e.g. the probability to hit a strong driver compared to many deleterious mutations, is crucial for the optimal organization of a cancer suppressing tissue architecture and should be taken into account in arguments for the evolution of such tissues.ConclusionWe show that for systems that are composed of few cells reflecting the typical organization of a stem cell niche, amplification or suppression of selection can arise from subtle changes in the architecture. Moreover, we discuss special tissue structures that can suppress most types of non-neutral mutations simultaneously.ReviewersThis article was reviewed by Benjamin Allen, Andreas Deutsch and Ignacio Rodriguez-Brenes. For the full reviews, please go to the Reviewers’ comments section.

Evolutionary regime transitions in structured populations

“…Our first search focused on extremal graphs (from the point of view of the evolutionary regime), and in this way we found some graph structures suppressing the advantage of mutant individuals occupying their vertices for any fitness value. This property seems particularly appealing for biological networks like brain and protein-protein interaction networks, but also in the tumor initiation process within healthy tissues as proposed in [ 17 ]. Most graph structures reduce in a very slight amount the advantage of a invading mutant, but some suppression mechanisms could be amplified by repetitive rules (such as those described in [ 18 ] and [ 19 ] for neuronal networks) involved in the modular architecture of many biological networks.…”

Hierarchical tissue organization as a general mechanism to limit the accumulation of somatic mutations

“…It is clear that stem cells that sustain hierarchies of progressively differentiated cells are well positioned to provide a safe harbour for genomic information. Qualitative arguments suggesting that hierarchically organized tissues may be optimal in reducing the accumulation of somatic mutations go back several decades 27 . As mutations provide the fuel for somatic evolution (including not only the development of cancer, but also tissue degeneration, aging, germ line deterioration and so on) it is becoming widely accepted that tissues have evolved to minimize the accumulation of somatic mutations during the lifetime of an individual 27 .…”

Phase transitions in evolutionary dynamics

“…Initially motivated by our interest in the robustness of biological and technological networks against invasion [16], we found in [7] some graph structures suppressing the advantage of mutant individuals occupying their nodes for any fitness value. This seems particularly appealing for biological networks like brain and protein-protein interaction networks, but also in the tumor initiation process within healthy tissues as proposed in [17]. Most graph structures reduce in a very slight amount the advantage of a invading mutant, but some suppression mechanisms could be amplified by repetitive rules (such as those described in [18] and [19] for neuronal networks) involved in the modular architecture of many biological networks.…”