Hepatocellular Carcinoma as a Paradigm for a Systemic Evolutionary Approach to Cancer

The systemic evolutionary theory of cancer pathogenesis posits that cancer is generated by the de-emergence of the eukaryotic cell system and by the reappearance of its ancestral subsystems, the archaea (genetic material and cytoplasm) and the prokaryote (mitochondria), which operate autonomously or uncoordinatedly. This unpaired coordination can be caused by changes in the eukaryote environment, mainly inflammation, damage to mitochondrial DNA or to mitochondrial membranes by viruses, chemicals, hydrogenated fatty acids in foods, and damage to nuclear DNA controlling mitochondria energy production or metabolic pathways including glycolysis. Here, we propose that an “energy package” is constantly required by the cell to maintain its differentiated status. When the energy flow works normally, the two subsystems, the archaea and the prokaryote, are perfectly integrated and there is no prevalence of one system on the other, so that cellular differentiation is maintained. However, as a consequence of a long-lasting injury (e.g. chronic inflammation), the energy at tissue level is restricted and this may cause, over time, the gradual decoupling of the two subsystems with the “prokaryote” subsystem that becomes predominant. The cirrhotic liver represents a paradigmatic scenario whereby this process may occur, due to altered vascular bed, fibrosis and reduction of the oxygen availability. The prevalence of the “prokaryote” subsystem may explain the metabolic alterations seen in liver cancer cells as well as the capacity for proliferation and invasion, especially toward areas of major oxygen availability (e.g. arterialization of portal vein in the liver). This approach highlights the notion that tissue integrity is essential for the proper flow and availability of energy for the maintenance of cellular homeostatic functions.