Although cancer is one of the most intensively studied phenomena in biology and occurs in almost all multicellular species (1, 2), an explanation for its existence and properties within the context of evolutionary history has received comparatively little attention. However, it is widely recognized that progress in treatment and prevention depends on a deeper understanding of the biology of cancer (3).
Many of the hallmarks of cancer (4, 5) are reminiscent of unicellular life, suggesting that neoplasms represent a type of throwback or reexpression of ancestral traits. Theodore Boveri first suggested that cancer recapitulates ancient phenotypes (6). This basic idea has recently been developed into the atavistic theory of cancer, which seeks to trace cancer’s deep evolutionary roots to make specific predictions about gene expression in tumorigenesis (7, 8). The atavistic theory postulates that the biological origin of cancer can be found in the early transitional phase from unicellularity (UC) to multicellularity (MC), before the emergence of complex metazoans about 600 Mya. These ancestral traits reappear because the regulation that suppresses them or restricts them to specific contexts (e.g., embryogenesis or wound-healing) becomes disrupted. In broad terms, the atavistic theory predicts up-regulation of genes with UC evolutionary origins and down-regulation of genes that evolved after the advent of MC (Fig. 1). The work of Trigos et al. (9), reported in PNAS, sets out to test this prediction.