Scales of Cancer Evolution: Selfish Genome or Cooperating Cells?

SIMPLE SUMMARY: Cancer continuously evolves its ability to survive in time-varying microenvironment, which results, regarding the therapeutic context, in its therapeutic resistance. As it is accepted that the development of resistance is the direct consequence of intratumour heterogeneity, its evolutionary etiology is intensively studied. Models of carinogenesis are often assessed accordingly to how well they fit into the evolutionary scenario. In the paper, the relevant observations and concepts in cancer research, such as intratumour heterogeneity, cell plasticity, and Markov cell state dynamics, are reviewed and integrated into an evolutionary model. The possibility that the interaction between cancer cells can be interpreted as cooperation is proposed. ABSTRACT: The exploitation of the evolutionary modus operandi of cancer to steer its progression towards drug sensitive cancer cells is a challenging research topic. Integrating evolutionary principles into cancer therapy requires properly identified selection level, the relevant timescale, and the respective fitness of the principal selection unit on that timescale. Interpretation of some features of cancer progression, such as increased heterogeneity of isogenic cancer cells, is difficult from the most straightforward evolutionary view with the cancer cell as the principal selection unit. In the paper, the relation between the two levels of intratumour heterogeneity, genetic, due to genetic instability, and non-genetic, due to phenotypic plasticity, is reviewed and the evolutionary role of the latter is outlined. In analogy to the evolutionary optimization in a changing environment, the cell state dynamics in cancer clones are interpreted as the risk diversifying strategy bet hedging, optimizing the balance between the exploitation and exploration of the cell state space.