Cancer: a genetic or metabolic origin?

In tumors, cancer cells proliferate uncontrollably: they grow, divide indefinitely, and, over time, can leave the tumor site and metastasize. All scientists agree that cancer arises from the deregulation of the cell cycle. But how can we explain this “incoherent” behavior of cells?

For a long time, the genetic track was favored. Today, several researchers are putting forward another avenue: that of cancer “metabolic disease”, like diabetes. If the cancer is metabolic in origin, then treatments should target the mitochondria. In his new book The keys to cancerLaurent Schwartz describes several avenues for metabolic treatment of cancer.

The theory of somatic mutations

Taught for decades to biology and medical students, the “theory of somatic mutations” is the most commonly accepted one. This hypothesis is based in particular on the observation of the genetic predispositions of individuals to cancer: in certain families, cancers are more frequent than in others. For example, mutations in the BRCA1 and BRCA2 genes increase the risk of breast and ovarian cancer in women. These two genes are part of the “tumor suppressor” gene family.

According to this theory, it is somatic mutations, that is to say which do not affect the reproductive cells of the germ line, which are at the origin of the tumors.

The cell cycle

Usually, in our body, the cell goes through several phases during a cycle:
– G1 phase: growth and preparation for DNA synthesis;
– S phase: DNA synthesis;
– phase G2: growth and preparation for mitosis (M);
– phase M: division of the cell into two daughter cells.
These phases are controlled by genes, such as cyclin-dependent kinases, Cdks. Mutations affecting genes that control the cell cycle can lead to dysregulation of the rate at which the cell divides.

There are two large families of genes whose mutations can promote cell cancer:

• proto-oncogenes: if they are mutated, these genes promote the uncontrolled proliferation of cells. Non-mutated proto-oncogenes have physiological roles, they often participate in the normal growth of the cell. Examples of proto-oncogenic genes: ras, fos, jun…
• tumor suppressor genes: genes that usually inactivate the cell cycle; if they are mutated, they become inactive and the cell cycle goes into overdrive. Thus, the p53 protein is a transcription factor that binds to DNA to activate the expression of genes that repair cellular damage when DNA is damaged. p53 prevents the cell from turning into a cancer cell and can induce apoptosis, programmed cell death.

According to the theory of somatic mutations, cancer is a complex genetic disease that results from hereditary (BRCA1…) or random mutations in proto-oncogenes (flush…) or in tumor suppressor genes (p53…).

But several inconsistencies remain in this theory, as explained by Thomas Seyfreid (Boston College) and Christos Chinopoulos (Semmelweis University of Budapest) in an article published in the journal Metabolites :

• not all cancers are associated with mutations;
• certain normal tissues can carry mutations without transforming into tumors;
• the results of nucleus transplantation experiments (see figure below): if we transfer a cancer cell nucleus into a normal cell, its behavior remains normal. Conversely, if we transfer a nucleus from a normal cell into a cancer cell, its growth is anarchic. It therefore seems that the elements which deregulate the cell cycle are not found in the nucleus (which contains genomic DNA).

Core transfer experiments. In green: normal cell. In red: tumor cell. According to Seyfried and Chinopoulos (Metabolites 2021)

This is why scientists from various backgrounds propose another theory, based on the disruption of metabolism: the mitochondrial metabolic theory.

The mitochondrial metabolic theory

This alternative hypothesis maintains that cancer arises from a dysfunction of the mitochondria, the cell’s energy factory. Usually, cells use glucose to make ATP in the mitochondria: this is cellular respiration, which for one molecule of glucose provides 36 molecules of ATP. But in cancer cells, cellular respiration is defective.

This hypothesis has its origins in the 1920s when Otto Warburg, Nobel Prize winner in physiology and medicine, observed that cancer cells ferment. However, sugar fermentation, which takes place without oxygen, produces much less ATP than cellular respiration: only two molecules for one molecule of glucose.

For scientists who support the mitochondrial metabolic theory, it is the only one that can explain “the oncogenic paradox”: the fact that a multitude of factors (asbestos, oncogenic viruses, radiation, aging, inflammation, etc.) all lead to the same consequence, the cancerization of cells.

All of these disturbances would have the common point of hindering cellular respiration and increasing oxidative stress. Excess reactive oxygen species create damage to lipids, proteins and nucleic acids.

Many cells that can no longer breathe properly will die. Tumors could therefore come from cells which, in this context, are capable of increasing their fermentation to compensate for failures in their mitochondrial respiration.

Metabolic treatments for cancer

For Thomas Seyfreid and Christos Chinopoulos, “Most tumor cells, regardless of their tissue origin or genomic abnormalities, rely largely on fermentation metabolism through glycolysis and glutaminolysis pathways for the synthesis of growth metabolites and ATP. No tumor cell can grow or survive without metabolites and energy. Simultaneous targeting of these pathways provides a non-toxic therapeutic strategy to effectively manage most cancers. The simplest and most parsimonious strategy for managing cancer within the framework of mitochondrial metabolic theory is to restrict the availability of glucose and glutamine while placing the entire body in a state of nutritional ketosis. »

It is for these reasons that, to starve cancer cells of glucose, some patients turn to the ketogenic diet: ketone bodies become the cells’ fuel. However, if patients report an improvement in their well-being, cancer cells may also use ketone bodies. The ketogenic diet does not cure the disease. Other treatments are needed to attack the cancer on different fronts.

Read: Ketogenic diet and cancer: the dietitian’s experience

Old non-toxic drugs

If the cancer is metabolic in origin, then treatments should target the mitochondria. In his new book The keys to cancerLaurent Schwartz puts forward several avenues in this direction.

The goal of these new treatments is to restart the mitochondrial machinery. Several molecules already well known to scientists could have the potential to restore normal cell metabolism: methylene blue, lipoic acid in combination with hydroxycitrate, etc. Methylene blue is a dye used in the biology laboratory to color cells. It is also an antiseptic, an anti-malarial agent and induces apoptosis of cancer cells.

For Laurent Schwartz, “These old molecules are potentially very effective against cancer; This is what the tests carried out on cells and mice show us. »

Watch the full interview with Laurent Schwartz in the video below