Abstract
A theory that can best explain the facts of a phenomenon is more likely to advance knowledge than a theory that is less able to explain the facts. Cancer is generally considered a genetic disease based on the somatic mutation theory (SMT) where mutations in proto-oncogenes and tumor suppressor genes cause dysregulated cell growth. Evidence is reviewed showing that the mitochondrial metabolic theory (MMT) can better account for the hallmarks of cancer than can the SMT. Proliferating cancer cells cannot survive or grow without carbons and nitrogen for the synthesis of metabolites and ATP (Adenosine Triphosphate). Glucose carbons are essential for metabolite synthesis through the glycolysis and pentose phosphate pathways while glutamine nitrogen and carbons are essential for the synthesis of nitrogen-containing metabolites and ATP through the glutaminolysis pathway. Glutamine-dependent mitochondrial substrate level phosphorylation becomes essential for ATP synthesis in cancer cells that over-express the glycolytic pyruvate kinase M2 isoform (PKM2), that have deficient OxPhos, and that can grow in either hypoxia (0.1% oxygen) or in cyanide. The simultaneous targeting of glucose and glutamine, while elevating levels of non-fermentable ketone bodies, offers a simple and parsimonious therapeutic strategy for managing most cancers.
Highlights
Cancer is a systemic disease involving multiple time- and space-dependent changes in the health status of cells and tissues that lead to malignant tumors [1,2].Dysregulated cell growth, i.e., neoplasia, is the biological endpoint of the disease [3].Tumor cell invasion into surrounding tissues and their spread to distant organs is the primary cause of morbidity and mortality of most cancer patients [4,5,6,7]
The most compelling evidence against the somatic mutation theory (SMT) comes from the nuclear/cytoplasm transfer experiments showing that growth-regulated cells can be produced from tumorigenic nuclei, as long as the tumorigenic nuclei are localized in the cytoplasm containing normal mitochondria [40,41] (Figure 1)
If nuclear encoded driver genes were respondriver genes were responsible for dysregulated cancer cell growth, the results from sible for dysregulated cancer cell growth, the resultsbefrom the nuclear/mitochondrial the nuclear/mitochondrial transfer experiments would opposite to the results shown transfer would be opposite to the results shown inthe
Summary
Cancer is a systemic disease involving multiple time- and space-dependent changes in the health status of cells and tissues that lead to malignant tumors [1,2]. Tumor cell invasion into surrounding tissues and their spread (metastasis) to distant organs is the primary cause of morbidity and mortality of most cancer patients [4,5,6,7]. The US population increase over this same period was 4.5%, indicating no real progress in cancer management. Cancer is predicted to overtake heart disease as the leading cause of death in Western societies. Is the failure to reduce the cancer death rate due to an incorrect theory on the origin of the disease?
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