D arwinian Evolution of Tumours

Abstract

Tumours as a human disease have been studied mostly from a mechanistic perspective in the past decades. It is now increasingly clear that tumourigenesis as an evolving process can be fully understood only in the light of evolution. Recent studies highlight the necessity of connecting the microevolution of a tumour with the macroevolution from unicellular life to metazoan multicellularity, which occurred ∼600 million years ago. With this background in mind, we discuss here the diverse, sometimes conflicting, views with regard to the driving forces of tumour evolution. Specifically, we show how mutation, selection, drift, migration, gain of function versus loss of function, genetic factors versus non‐genetic factors and deterministic forces versus stochasticity may affect the trajectory of a tumour evolution as well as our understanding. Key Concepts Tumourigenesis is a by‐product of the macroevolutionary event from unicellular life to metazoan multicellularity that occurred ∼600 million years ago. Tumour progression is a microevolutionary process of the asexual tumour cell population, driven in part by forces typical to organismal evolution. Unlike long‐term organismal evolution, which is driven exclusively by genetic forces, the short‐term tumour evolution can be affected heavily by epigenetic alterations. As a result, the decoupling between genetic divergence and expression divergence is expected. Tumour evolution represents a reversal of the macroevolution from unicellularity to multicellularity, by erasing the constraints evolved for the maintenance of multicellularity. As a result, loss of function plays a more important role than gain of function. Regardless of the external tissue environments, nearly all tumours evolve towards a predetermined cellular destination with properties typical to unicellular life. Tumour evolution is driven by both deterministic factors and stochastic factors. Recognition of this helps reconcile development and evolution, two distinct languages in the cancer research community, with the former spoken mostly by cell biologists who advocate fixed cellular programmes as driving forces and the latter spoken by geneticists who appreciate the apparent stochasticity of driver gene mutations.