title: Mitochondria and the evolutionary roots of cancer.
abstract: Cancer disease is inherent to, and widespread among, metazoans. Yet, some of the hallmarks of cancer such as uncontrolled cell proliferation, lack of apoptosis, hypoxia, fermentative metabolism and free cell motility (metastasis) are akin to a prokaryotic lifestyle, suggesting a link between cancer disease and evolution. In this hypothesis paper, we propose that cancer cells represent a phenotypic reversion to the earliest stage of eukaryotic evolution. This reversion is triggered by the dysregulation of the mitochondria due to cumulative oxidative damage to mitochondrial and nuclear DNA. As a result, the phenotype of normal, differentiated cells gradually reverts to the phenotype of a facultative anaerobic, heterotrophic cell optimized for survival and proliferation in hypoxic environments. This phenotype matches the phenotype of the last eukaryotic common ancestor (LECA) that resulted from the endosymbiosis between an α-proteobacteria (which later became the mitochondria) and an archaebacteria. As such, the evolution of cancer within one individual can be viewed as a recapitulation of the evolution of the eukaryotic cell from fully differentiated cells to LECA. This evolutionary model of cancer is compatible with the current understanding of the disease, and explains the evolutionary basis for most of the hallmarks of cancer, as well as the link between the disease and aging. It could also open new avenues for treatment directed at reestablishing the synergy between the mitochondria and the cancerous cell.
authors.affiliation: SETI Institute. 189 N. Bernardo Avenue, Suite 100 Mountain View, CA 94043, USA. adavila@seti.org
authors.forename: Alfonso F
authors.initials: AF
authors.lastname: Davila
authors.forename: Pedro
authors.initials: P
authors.lastname: Zamorano
mesh_terms: D020561:Alphaproteobacteria / Q000502:physiology; D000818:Animals; D017209:Apoptosis; D001105:Archaea / Q000502:physiology; D005075:Biological Evolution; D015687:Cell Hypoxia; D006019:Glycolysis; D006801:Humans; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D018384:Oxidative Stress; D010641:Phenotype; D013559:Symbiosis