By what means and mechanism can we understand precisely why cancer is a disease of mitochondrial metabolism and not a genetic disease, and also why control of tumor metabolism's primary fuel substrates, glucose and glutamine, constitute the most coherent and effective means of successfully addressing the fundamental biology of disease?
Firstly, it is essential to consider the following: no pathogenic germline cancer mutations have been found that are 100% penetrant, meaning that most can be considered secondary risk factors, rather than direct primary causes of cancer. Just this one understanding dramatically undermines the somatic (ergo, genetic) theory of cancer.
Notably, the highest (90%) penetrant germline mutations reside in the Tp53 gene, typically found in people with Li-Fraumeni syndrome. Penetrance is generally less for other germline cancer mutations including those for breast cancer, leading to one very critical insight- while genetic predisposition may increase risk of acquiring disease, it does not constitute a causal condition.
Furthermore, an accumulation of mutations over time, does not necessarily lead to cancer, as many normal cells possess KRAS, PI3K and other mutations, and never turn cancerous.
So, with that in mind, what does cause cancer, and how can we have confidence that its cause can understood at a high level of certainty?
Basic biology can instruct us in this regard, insofar that one root concept offers deep insight into the origins of disease: form determines function.
Hence, any vector if insult (bacteria, virus, toxin, carcinogen, sustained nutritional abuse leading to cytokine inflammation) can exert chronic damage to mitochondria.
Notably, the number, structure and function of mitochondria in tumor cells are commonly dysregulated, in comparison to normal cells. For example, many tumor cells possess far fewer mitochondria than normal cells. Additionally, those mitochondria that do persist in a cancer cell often have broken cristae and a diminished concentration of diphosphatidylglycerol (both essential for energy production), resulting in downregulation of normal energy production in the form of Oxidative Phosphorylation.
Concurrent to this downregulation of Oxidative Phosphorylation, is a notable upregulation in Substrate Level Phosphorylation of glucose in the cytosol, and glutamine in the mitochondria, and the loss of the cell’s capacity to oxidize fatty acids and ketone bodies, as evidenced by the accumulation of lipid droplets in cancer cells.
One can validate this phenomenon by its products, namely, lactic acid and succinic acid in the extracellular space, as a result of glucose and glutamine fermentation, respectively.
Furthermore, we can learn via nucleic and mitochondrial transfer experiments, that taking a cancer cell nucleus and transferring to a normal cell, leaves that cell unharmed. However, transferring cancer mitochondria to a normal cell, turns them cancerous.
With these understandings in mind, one can begin to grasp the therapeutic implications of controlling systemic levels of glucose via the precise administration of calories and macronutrients, and controlling glutamine metabolism with drugs such as 6-Diazo-5-Oxo-L-Norleucine, thereby directly impugning tumor viability, by attacking its fundamental biology.
For an interesting discussion on these concepts, carefully read this scientific paer, and study this video: