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Is Cancer a Genetic or Metabolic Disease? Part 5

ByProfessor Thomas SeyfriedFebruary 13, 2019

To continue our discussion of the somatic mutation theory of cancer (SMT) vs. the mitochondrial metabolic theory (MMT), we here review the scientific literature concerning additional experiments or studies that challenge the foundation of the SMT.

non-mutagenic origin of metastatic behavior

Recent studies from Brook Chernet and Michael Levin have shown that alterations in bioelectric membrane signaling can produce the metastatic behavior of Xenopus melanocytes in the absence of somatic mutations, which further suggests that the tumorigenic phenotype is not dependent on nuclear gene mutations (43,44). In other words, nuclear gene mutations alone are insufficient for producing tumors, whereas the tumorigenic phenotype can be produced in some cells without nuclear mutations.

the absence of gene mutations in cancer cells

The SMT is based on the premise that nuclear gene mutations are responsible for the dysregulated division of cancer cells. Stuart Baker, however, has reviewed gene sequencing studies that failed to detect any pathogenic somatic mutations in several types of cancers (45). Michael Kiebish et al. also found no pathogenic mutations in mitochondrial DNA from five independently derived mouse brain tumors (46). Moreover, Donald Williams Parsons et al. could find no mutations in any of the three signaling systems of sample Br20P that was obtained from aggressive glioblastoma (47).

cancer driver genes found in normal cells

Recent studies show that normal cells in various tissues contain cancer driver genes. Inigo Martincorena and his team recently found large numbers of cancer driver genes in normal human skin (48,49). Indeed, the prevalence of NOTCH1 mutations in normal esophagus tissue was several times higher than in esophageal cancers. Somatic driver mutations found in brain tissue have been linked to psychiatric disorders rather than to cancer (50). These findings are concerning given that new immunotherapies could target driver mutations in normal cells as well as in tumor cells (48). Significant adverse effects involving inadvertent targeting of normal tissue cells have already been seen in some patients treated with immunotherapies (51).

The cancer drug temozolomide increases driver mutations in brain tumors

The toxic alkylating agent Temozolomide (TMZ) is the most common chemotherapy drug used for managing malignant brain tumors and produces a slight increase in progression-free survival for patients (52). Recent studies show that TMZ increases driver mutations in the brain tumor tissue of treated patients (53). How is it possible that a drug, which increases driver mutations, could also improve progression-free survival? The findings make no sense in light of the SMT but could be linked to the MMT. For example, some of the adverse effects of TMZ include fatigue, nausea, vomiting, diarrhea, and loss of appetite (54). All of these adverse effects are indirect forms of calorie restriction that would lower blood glucose levels, thus targeting the Warburg effect and the dependency of tumors on glucose.

Temozolomide molecule


the fallacy of tumor cell growth advantage

According to the SMT, the mutations in tumor cells confer a growth advantage over normal cells. These mutations were thought to produce cells with greater fitness and adaptability to survive in hostile microenvironments than normal cells. This comparison between cancer cells and normal cells makes no sense, as differentiated normal cells are programmed to divide only when needed. However, if normal cells need to grow, they can grow faster than most tumor cells. For example, the growth rate of regenerating liver cells is faster than that of most tumor cells (17).  

Tumor cells survive in hypoxic environments not because they are more fit than normal cells, but because they have lost their ability to respire and rely on the ancient pathway of fermentation to generate energy. This should not be considered an advantage but rather a pathological condition. The fermentation metabolism together with defective respiration produces oxygen radicals that damage the genome. Cells with a damaged genome are generally less fit than cells with an intact genome.

In addition to glucose fermentation, tumor cells also can generate energy from amino acid fermentation. Besides excessively consuming glucose, tumor cells consume excessive amounts of glutamine. Glutamine is the most abundant amino acid in the blood and is abundantly present in the microenvironment of most tumors. Glutamine generates energy through mitochondrial substrate-level phosphorylation. This is another ancient metabolic pathway for energy generation in hypoxic environments.

In the final post in this series, we will consider the totality of evidence indicating that the mitochondrial metabolic theory may explain the facts of cancer better than the somatic mutation theory.


“Is Cancer a Genetic or Metabolic Disease? Part 1”
“Is Cancer a Genetic or Metabolic Disease? Part 2”
“Is Cancer a Genetic or Metabolic Disease? Part 3”
“Is Cancer a Genetic or Metabolic Disease? Part 4”

Thomas N. Seyfried is professor of biology at Boston College. He received a doctorate in genetics and biochemistry from the University of Illinois—Urbana-Champaign in 1976. He did his undergraduate work at the University of New England, where he recently received the distinguished Alumni Achievement Award. He also holds a master’s degree in genetics from Illinois State University. Seyfried served with distinction in the United States Army’s 1st Cavalry Division during the Vietnam War and received numerous medals and commendations.

He was a postdoctoral fellow in the Department of Neurology at the Yale University School of Medicine and then served on the faculty as an assistant professor in neurology. Seyfried previously served as chair of the Scientific Advisory Committee for the National Tay-Sachs and Allied Diseases Association. He recently received a Lifetime Achievement Award from the Academy of Complementary and Integrative Medicine and the Uncompromising Science Award from the American College of Nutrition for his work on cancer.

He presently serves on several editorial boards, including those for Nutrition & Metabolism, Neurochemical Research, the Journal of Lipid Research, and ASN Neuro. Seyfried has over 180 peer-reviewed publications and is author of the book “Cancer as a Metabolic Disease: On the Origin, Management, and Prevention of Cancer” (Wiley Press).


Note: These references include those previously published in “Is Cancer a Genetic or Metabolic Disease? Part 1,” “Part 2,” “Part 3” and “Part 4.”

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All links accessed Feb. 12, 2019. 

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