title: A systemic evolutionary approach to cancer: Hepatocarcinogenesis as a paradigm.
abstract: The systemic evolutionary theory of cancer pathogenesis posits that cancer is generated by the de-emergence of the eukaryotic cell system and by the re-emergence of its archaea (genetic material and cytoplasm) and prokaryotic (mitochondria) subsystems with an uncoordinated behavior. This decreased coordination can be caused by a change in the organization of the eukaryote environment (mainly chronic inflammation), damage to mitochondrial DNA and/or to its membrane composition by many agents (e.g. viruses, chemicals, hydrogenated fatty acids in foods) or damage to nuclear DNA that controls mitochondrial energy production or metabolic pathways, including glycolysis. Here, we postulate that the two subsystems (the evolutionarily inherited archaea and the prokaryote) in a eukaryotic differentiated cell are well integrated, and produce the amount of clean energy that is constantly required to maintain the differentiated status. Conversely, when protracted injuries impair cell or tissue organization, the amount of energy necessary to maintain cell differentiation can be restricted, and this may cause gradual de-differentiation of the eukaryotic cell over time. In cirrhotic liver, for example, this process can be favored by reduced oxygen availability to the organ due to an altered vasculature and the fibrotic barrier caused by the disease. Thus, hepatocarcinogenesis is an ideal example to support our hypothesis. When cancer arises, the pre-eukaryote subsystems become predominant, as shown by the metabolic alterations of cancer cells (anaerobic glycolysis and glutamine utilization), and by their capacity for proliferation and invasion, resembling the primitive symbiotic components of the eukaryotic cell.
authors.affiliation: Interdisciplinary Department of Medicine, University of Bari School of Medicine, Piazza G. Cesare, 11, 70124 Bari, Italy. Electronic address: antonio.mazzocca@uniba.it.
authors.forename: Antonio
authors.initials: A
authors.lastname: Mazzocca
authors.affiliation: Interuniversity Department of Physics, Polytechnic of Bari, Via Orabona, 4, 70126 Bari, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Ferraro
authors.affiliation: Scientific and Ethical Committee, University Hospital Policlinico, Piazza G. Cesare, 11, 70124 Bari, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Misciagna
authors.affiliation: Izmir Biomedicine and Genome Center, Dokuz Eylul University, 35340 Balcova, Izmir, Turkey.
authors.forename: Brian I
authors.initials: BI
authors.lastname: Carr
mesh_terms: D000818:Animals; D005075:Biological Evolution; D063646:Carcinogenesis; D006528:Carcinoma, Hepatocellular / Q000473:pathology*; D002454:Cell Differentiation; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D004272:DNA, Mitochondrial / Q000378:metabolism; D019143:Evolution, Molecular; D005355:Fibrosis; D006019:Glycolysis; D006801:Humans; D007249:Inflammation; D008099:Liver / Q000473:pathology; D008113:Liver Neoplasms / Q000473:pathology*; D008928:Mitochondria / Q000378:metabolism; D008962:Models, Theoretical; D009154:Mutation; D010641:Phenotype; D049490:Systems Biology; D013816:Thermodynamics
chemical_list: D004272:DNA, Mitochondrial
keywords: Archaea; Cancer origin theories; De-emergence; Endosymbiosis; Energy flow; Hepatocarcinogenesis