Mitochondria malfunctions as mediators of stem-cells’ related carcinogenesis: A hypothesis that supports the highly conserved profile of carcinogenesis

• Published in: Medical hypotheses 2013-01, Vol.80 (1), p.70-74
• Main Authors: Hatzi, Vasiliki I, Terzoudi, Georgia I, Pantelias, Gabriel E, Makropoulos, Vasilios
• Format: Article
• Language: English
• Subjects: Adenosine Triphosphate - metabolism; Apoptosis - physiology; Autophagy - physiology; Cell Transformation, Neoplastic - metabolism; Energy Metabolism - physiology; Humans; Internal Medicine; Mitochondria - physiology; Models, Biological; Neoplasms - physiopathology; Neoplastic Stem Cells - physiology
• ISSN: 0306-9877; 1532-2777
• DOI: 10.1016/j.mehy.2012.10.002

Abstract Cancer development is an evolutionary process that has been highly conserved among centuries within organisms. Based on this, the interest in cancer research focuses on cells, organelles and genes that possess a genetic conservatism from yeasts to human. Towards this thought, mitochondria, the highly conserved and responsible for the cellular bioenergetic activity organelles, might play crucial role in carcinogenesis. Interestingly, tumors with low bioenergetic signature have worse prognosis and show a decreased expression of ATPase protein. Furthermore, according to the stem-cell theory of carcinogenesis, aggressive tumors are characterized by an increase number of malignant stem-like cell population and their resistance to chemotherapy has been found to be mitochondrially driven. The above considerations triggered us to hypothesize that mitochondrial bioenergetic processes in stem-like cancer cells plays a crucial role in the highly conserved process of carcinogenesis. Specifically, we support that mitochondrial and/or nuclear DNA alterations that control stem cells’ ATP production drive stem cells to “immortalization” (Otto Warburg theory) that mediates cancer initiation and progression. Substantiation of our hypothesis requires evidence that: (1) alterations in mitochondria bioenergetic metabolites and enzymes encoded either from the mtDNA or the nuclear DNA are linked to human cancer and (2) mitochondrial functions are regulated by highly conserved genes involved in cancer-related cellular processes such as apoptosis, aging and autophagy. Experimental approach on how this hypothesis might be tested and promising strategies in cancer therapeutics are also discussed. In case the hypothesis of stem-cell bioenergetic malformations’ related carcinogenesis proves to be correct, it would contribute to the development of new prognostic, diagnostic and even more effective therapeutic interventions against various types of cancer.