Why is the Origin of Cancer Metabolic?
While it is not controversial to observe that the standing, consensus view of cancer, is that it is regarded as a disease of accumulated inherited or random genetic mutations based on the somatic mutation theory, whereby mutations in proto-oncogenes and tumor suppressor genes cause dysregulated cell growth, this explanation now struggles to sustain itself under the enormous weight of evidence demonstrating that in fact, cancer is a disease of mitochondrial metabolism.
Unequivocally, the National Cancer Institute states that:
“Cancer is a genetic disease- that is, it is caused by changes to genes that control the way our cells function, especially how they grown and divide.”
Notably, many tumor cell lines do not contain driver gene mutations or chromosomal abnormalities in P53, PI3K or RB1 pathways, while these mutations can be observed in many normal human tissue cells where oxidative phosphorylation remains intact. Hence, the somatic mutation theory offers no comment on malignant tumor cells which contain no driver mutations, and normal human tissue cells which contain any number of driver mutations, but do not develop into malignant tumor cells.
Furthermore, and perhaps a slightly weaker, but nevertheless fascinating argument by way of comparison, is the longitudinal observation that in other primates, such as chimpanzees, which share 98% gene and protein sequence identity with humans, cancers are extremely rare, and to date, there has never been a documented case of breast cancer in a female chimpanzee, despite parity between humans and chimps at the BRAC1 locus.
Of historical note, Theodor Boveri, the scientist credited with establishing the somatic theory of cancer was quite self-deprecating in his assessment of what he himself had proposed, stating that:
“I have no personal experience worth mentioning in any of the numerous specialized fields of tumour research. My knowledge comes almost exclusively from books. Given this, it is inevitable that I am unaware of many reports in the literature, that I overestimate the significance of many known facts and that I do not set enough store by others. But this article will doubtless contain even more serious defects, as is so often the case when an author makes an incursion into a field with which he is unfamiliar”
Additionally, nucleic and mitochondrial transfer experiments demonstrate quite compellingly that the origin of cancer begins with mitochondria, insofar that transferring a tumor nucleus to a normal cell has no effect- the cell remains normal. Correspondingly, transferring a normal nucleus to a tumor cell does not rescue the cell- it remains cancerous. However, transferring tumor mitochondria to a healthy cell, can turn it cancerous, and conversely, transferring normal mitochondria to a tumor cell can rescue it.
With these facts in mind, one can begin to understand with greater clarity that while there may be any number of secondary causes to cancer, the primary cause of cancer begins with damage to the number structure and function of mitochondria.
Crucially, this phenomenon is observed as the common phenotype of cancer, immaterial of the tissue of origin, given any tumor cell’s reliance on fermentation of glucose and glutamine in the absence of oxidative phosphorylation, leading to an upregulation in reactive oxygen species which directly damages mitochondrial function, which can be both carcinogenic and mutagenic. Downstream somatic mutations and genomic instability seen in tumor cells thus arise from fermentation metabolism as a result of oxidative stress.