Somatic Mutation Theory vs. Mitochondrial Metabolic Theory of Cancer
It’s been well established in the scientific literature that cancer is associated with genetic mutations and aberrations based on Somatic Mutation Theory (SMT), where mutations in proto-oncogenes and tumor suppressor genes result in dysregulated cell growth. However, this theory has inconsistencies based on the observation that nuclear genomic defects aren’t the origin of cancer, and cancer cells arise from defects in the cytoplasm. This leads to a critical question: Are genetic mutations the cause of the uncontrolled growth of cells or the result of epigenetic factors? (Seyfried et al., 2014)
The mitochondrial metabolic theory of cancer (MMT) provides a different analysis: cancer is a mitochondrial metabolic disease based on Otto Warburg’s Hypothesis. In the past decade, Dr. Thomas Seyfried further shook the foundation of cancer research. As a trailblazer, he revealed that cancer should be considered one single disease with a common pathophysiological mechanism involving mitochondria dysfunction. He explained that genetic mutations in cancer and identified cancer hallmarks are downstream effects of the disturbances of cellular energy metabolism. (Cancer as a Metabolic Disease: Implications for Novel Therapeutics - PMC, n.d.; Liu et al., 2021; Seyfried & Shelton, 2010)
In contrast to SMT, emerging evidence suggests that MMT can better explain the hallmarks of cancer because regardless of the tissue origin or genomic abnormalities, tumor cells primarily depend on fermentation metabolism through the glycolysis and glutaminolysis pathways for producing energy and growth metabolites, which no tumor cells can survive or grow without. (Seyfried & Chinopoulos, 2021)
Implications of Novel Therapeutics
MMT of cancer opens cancer treatment strategies to non-toxic and effective alternative therapeutics. Here are a couple of novel therapies proposed by Dr. Seyfried:
A Calorie-Restricted Ketogenic Diet (KD-R) + Hyperbaric Oxygen Therapy (HBO2T):
Using KD-R+HBO2T simultaneously targets glycolysis and glutaminolysis pathways by restricting glucose and glutamine availability to tumor cells while setting the body in a state of nutritional ketosis. This approach is economical, non-toxic, and effective in managing most cancers. (Seyfried & Chinopoulos, 2021)
Here are the rationales of the benefits of this strategy compared to conventional cancer treatments in comparison with chemotherapy and radiation therapy, respectively: (Seyfried et al., 2014)
Chemotherapy vs. KD+ HBO2T:
Chemotherapies target energy metabolism primarily with mutations in specific receptors linked to the IGF-1/PI3K/Akt pathway. A KD-R can also target these pathways in cancer cells. In the meantime, reducing dietary caloric intake can also target metabolic signaling pathways safely without producing side effects and toxicities.
Studies have shown a synergistic interaction between the KD-R and HBO2T. One on hand, the KD-R has an antioxidant potential by reducing glucose for glycolytic energy and NADPH levels. On the other hand, HBO2T may increase reactive oxygen species (ROS) in tumor cells. If putting the two together, ketones can protect normal cells by offsetting ROS damage and potential oxygen toxicity in the central nervous system.
Glucose deprivation while on a KD-R will increase oxidative stress in tumor cells, and elevated oxygen from HBO2T can slow down tumor cell proliferation.
Because tumor cells depend on glucose and cannot use ketones for energy, they are vulnerable to this therapeutic strategy.
Radiation Therapy vs. KD-R+HBO2T: Both radiation therapy and KD-R+HBO2T therapy work by killing tumor cells. The difference is radiation therapy causes collateral damage to healthy cells, whereas KD-R+HBO2T therapy does not. It should be acknowledged that the significant side effect of radiation therapy is it damages respiration in healthy cells, which can result in secondary cancer.
A KD has an additional benefit: it may enhance the therapeutic action of radiation therapy against brain and lung tumors. Therefore, it will be important to evaluate the efficacy of the simultaneous use of radiation therapy and the KD-R+HBO2T.
Press-pulse:
The change from cellular respiration to fermentation is a common hallmark of cancer. This change makes glucose and glutamine the prime fuels for the growth of tumors. Press disturbances create chronic metabolic stresses on tumor cell energy metabolism, whereas pulse disturbances generate a series of acute metabolic stressors. Pairing these two together not only can they restrict glucose and glutamine as fuel supplies to cancer cells but also stimulate cancer-specific oxidative stress.
More specifically, the press-pulse strategy combines a KD-R with drugs or procedures to create both chronic and intermittent acute stress on tumor cell energy metabolism while protecting and enhancing the energy metabolism of normal cells. This requires carefully considering the dosing, timing, and scheduling to facilitate eradicating tumor cells with minimal toxicity. (Seyfried et al., 2017)
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References:
Cancer as a metabolic disease: implications for novel therapeutics - PMC. (n.d.). Retrieved September 23, 2022, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3941741/
Liu, C., Jin, Y., & Fan, Z. (2021). The Mechanism of Warburg Effect-Induced Chemoresistance in Cancer. Frontiers in Oncology, 11, 3408. https://doi.org/10.3389/FONC.2021.698023/BIBTEX
Seyfried, T. N., & Chinopoulos, C. (2021). Can the Mitochondrial Metabolic Theory Explain Better the Origin and Management of Cancer than Can the Somatic Mutation Theory? Metabolites, 11(9). https://doi.org/10.3390/METABO11090572
Seyfried, T. N., Flores, R. E., Poff, A. M., & D’Agostino, D. P. (2014). Cancer as a metabolic disease: implications for novel therapeutics. Carcinogenesis, 35(3), 515. https://doi.org/10.1093/CARCIN/BGT480
Seyfried, T. N., & Shelton, L. M. (2010). Cancer as a metabolic disease. Nutrition & Metabolism 2010 7:1, 7(1), 1–22. https://doi.org/10.1186/1743-7075-7-7
Seyfried, T. N., Yu, G., Maroon, J. C., & D’Agostino, D. P. (2017). Press-pulse: a novel therapeutic strategy for the metabolic management of cancer. Nutrition & Metabolism 2017 14:1, 14(1), 1–17. https://doi.org/10.1186/S12986-017-0178-2