Erythrocyte enucleation in mammals is an anticancer mechanism: A hypothesis

There is a strong link between the rate of cell division and the lifetime cancer risk for a given tissue. This relationship is a consequence of the random occurrence of genetic mutations with each cell division, which can potentially disrupt oncogenes and tumour suppressor genes. Consequently, tissues with a high rate of cell division, such as the colon and breast, have a higher risk of developing tumours than tissues with lower rates such as the heart or brain. Erythrocytes, or red blood cells, are generated at an immense rate of about two million per second in normal adults. Mammalian erythrocytes are also distinguished by the fact that uniquely in this lineage, they have evolved to eject their nucleus during their formation, a process known as enucleation. Since erythrocytes lack a nucleus, they also do not contain the genetic material that can become mutated and give rise to cancer. Therefore, erythrocyte cancer burden is minimal compared to malignancy of other blood lineages. Although cancer is often considered evolutionarily neutral, multicellular organisms have actually evolved several tumour suppressive mechanisms. We propose here that the repression of the tumour burden arising from the erythrocyte lineage is an unappreciated benefit and a driver for the evolution of erythrocyte enucleation in mammals. A prediction emerging from our hypothesis is that non-mammalian lineages which retain the ancestral nucleated erythrocyte state will either experience greater rates of cancers originating from this lineage or will have evolved alternative and distinct tumour suppressive mechanisms. A greater understanding and appreciation of animal tumour suppressive mechanisms at the species level may also offer insights into cancer prevention and treatments for humans.