Fraternal cooperation of hierarchical cancer parallels metazoan multicellularity and eusociality.

Metazoan multicellularity and eusociality - both outcomes of the fraternal major transitions - have numerous features in common such as uneven distribution of group-establishing potential. In addition to this framework, I argue herein that the group-forming principles of metazoan multicellularity and eusociality are analogous to hierarchical cancer in that the cancer stem cells generate other cancer cells deprived of tumorigenicity. As such, I introduce concepts of germinating reproducers and sterile workers widely applicable to those systems. In particular, exploitative replication is suggested as an efficient strategy for maintaining the cooperation of fraternal cooperative organisations accompanied by asymmetric replication/reproduction. From this point of view, the defectors that spontaneously appear in metazoan multicellular organisms, eusocial colonies, and cancer clusters are cancers, egg-laying workers, and hypertumours, respectively. In a way similar to the policing observed in eusociality and metazoan multicellularity, I propose the hypothesis that the lactate-producing Warburg effect of cancer cells could represent a policing mechanism against hypertumours. Specifically, the Warburg effect establishes an acidified microenvironment that can repress growth of defector hypertumours by restricting diffusion of cancer growth factors. Considering the altruistic nature of the Warburg effect and metabolic plasticity, the possibility of hypertumours performing oxidative phosphorylation is discussed. This structural analogy not only highlights the role of asymmetric replication/reproduction in highly cooperative systems, but also provides a novel perspective on the social interactions of cancer cells, potentially laying foundations for clinical strategies aimed at disrupting cancer cooperation.