Reevaluating cancer stem cells and polyploid giant cancer cells from the evolutionary cancer cell biology perspective

According to the principles of Evolutionary Cancer Cell Biology (ECCB), cancer stem cells (CSCs) do not derive from normal stem cells; rather, they originate from a distinct functional phenotype of germline cells characterized by asymmetric cell division (ACD). This phenotype proliferates through ACD, producing self-renewing cells alongside non-proliferating daughter cells with CSC qualities. ECCB posits that CSCs do not proliferate. Similar to protists, there exists a close reciprocal relationship between sister cells that collectively form a germline and stem cells. These sister cells perform complementary roles: proliferating cancer germline cells generate stem cells, whereas the non-proliferating CSCs give rise to progenitor cells for the formation of new germline clones. ECCB distinguishes between primary CSCs, which are associated with carcinogenesis and primary tumors, and secondary CSCs, which are linked to metastases. This unicellular stem cell system is homologous to that of parasitic protists, such as amebae. Both CSCs and amebae stem cells are produced by an oxygen-sensitive germline and are vulnerable to damage when oxygen levels exceed 6.0% (germline hyperoxia), as elevated oxygen concentrations can harm the germline genome. Germline cells that lose their stemness quality continue to cycle through defective symmetric cell divisions (DSCD). However, to restore functionality, the DSCD genome must be repaired through hyperpolyploidization. This process occurs in native polyploid giant cancer cells, which are homologous to the multinucleated genome repair structures found in protists.