Cancer Results from the Disruption of Multicellular Constraints, Genomic Inversion to Unicellularity, and Evolution by Horizontal Gene Transfer

It is not widely known that the human genome retains ancestral emergency programs that can be activated in response to germline stress and irreparable DNA damage, freeing affected cells from the constraints of multicellularity. The reactivation of unicellular genome modules—via a process known as the multicellular-to-unicellular transition (MUT)—represents an ancient mechanism rooted in the gradual back-and-forth transition to multicellularity. MUT modules are preserved in a reactivatable state within the genomes of all metazoans and are activated in approximately 50% of humans, particularly at advanced stages of life. This inversion to a unicellular genome state gives rise to a subpopulation of precancerous cells that proliferate through defective symmetric cell division (DSCD). Once DSCD progeny acquire fusibility, they form hyperpolyploid genome repair syncytia (MGRS), which work to eliminate genomic defects and establish a unicellular cancer stemgermline capable of producing committed, non-proliferative cancer stem cells. Similar to the Ur-germline of unicellular ancestors, the cancer stemgermline, along with its clones and sublines, is hypoxic and becomes dysfunctional in tissues with oxygen levels above 6.0% O₂, a condition referred to as germline hyperoxia. Together with a somatic helper lineage that does not generate cancer stem cells, the stem-germline forms an autonomous cellular system that functions according to the principles of unicellular life. The stem-germline and its somatic counterpart work in concert to maintain and expand a stable, unicellularized stemgermline genome