It is a longstanding debate whether cancer is one disease or a set of very diverse diseases. For most researchers, a wide variety of diseases with different prognoses, sites of origin, patterns of spread, and kinetics seem to be linked with cancer. But despite this apparent complexity, there is underlying unity. Cancer is a simple disease.
(Hanahan, D.; Weinberg, R. A. “The Hallmarks of Cancer”. Cell 2000, 100, 57–70)
The authors of “The Hallmarks of Cancer” believe that the complexity of cancer can be reduced to a few underlying principles. The paper argues that all cancers share six common traits (“hallmarks”) that govern the transformation of normal cells to cancer cells.
These hallmarks stipulate that cancer cells:
- Stimulate their growth.
- Resist inhibitory signals that might otherwise stop their growth.
- Resist their own programmed cell death.
- Stimulate the growth of blood vessels to supply nutrients to tumors.
- Can multiply forever.
- Invade local tissue and spread to distant sites.
In an update (Hanahan, D.; Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 2011, 144, 646–74) Hanahan and Weinberg proposed two new hallmarks:
- Abnormal metabolic pathways.
- Evading the immune system.
All these eight hallmarks are a direct consequence of the Warburg’s effect, described one hundred years ago. The Warburg’s effect is a bottleneck. The cells cannot burn the glucose because the pyruvate cannot reach the mitochondria. For the specialist, the pyruvate dehydrogenase is turned off. Consequently, pyruvate cannot be transformed into acetyl-CoA. The cellular machinery is deficient and the energy yield is less than 5% of the normal cell. To survive, the cancer cell will open its gates to increased concentration of glucose. Part of the pyruvate that cannot be burned will be transformed into lactic acid excreted by the cell; the rest will be converted into biomass. In other words, if you eat more and burn less, you gain weight.
In the laboratory, evidence of the central role of the Warburg’s effect comes when the researcher inject normal mitochondria into cancer cells, with a micropipette. The cancer cell will be able to burn pyruvate and the growth will stop. These cells have become benign. This proves that the genes are not usually the key of cancer. The injection of the nuclei of cancer cells into normal cells does not increase growth. These cells can still burn glucose because the mitochondria are normal and do not form tumors.
(Seyfried T. (2014). “Cancer as a metabolic disease: implications for novel therapeutics”, Carcinogenesis).
Cell proliferation is a direct consequence of the Warburg’s effect. As the cell cannot burn its combustible completely, the cell uses the glucose to the synthesis of lipids, proteins and nucleic acid.
Cell division and proliferation are a consequence of the impaired metabolism of the cancer cell. In the limited space of the affected organ cell, proliferation results in increased pressure. Unlike benign tumors, cancer has irregular edges. It has a stellar, fractal shape and the cancer cells invade the surrounding tissue. Normal epithelial cells look like the cobblestones on the streets of Paris. They are arranged to one side of the other and lining the epithelium. Cancer is a barricade. Under the effect of the pressure from cancerous fermentation, cells change plan, jump on top of each other. This is the explanation of the star shape so typical of cancer.
Every doctor has been taught, during medical school, that the palpation of a cancer nodule is harder than the surrounding tissue. Under pressure some cells escape from these barricades, fuse into the surrounding tissues and penetrate the blood stream to form distant colonies or metastasis.
The bottleneck, at the level of the mitochondria, has another consequence. The cancer cell is alkaline (i.e., basic). The intracellular pH of the normal cell oscillates between 6.8 and 7.2. The intracellular pH of the cancer cells oscillates between 7.2 and 7.5. The mitochondria, which are defective, synthesize less carbon dioxide. Carbon dioxide combines with water to form carbonic acid. Less combustion means less carbonic acid and thus increases the pH.
The deoxyribonucleic acid (DNA) is an acid. In the alkaline pH of the cancer cells, DNA is open to transcription and multiplication. In the acidic pH of the normal cell, the DNA remains folded and thus inactive. There is no transcription or replication. The cell cannot divide. There is no cell division at a pH < 7.2.
(Pouyssegur, J., Franchi, A., L'allemain, G., Paris, S. (1985). Cytoplasmic pH, a key determinant of growth factor-induced DNA synthesis in quiescent fibroblasts. FEBS letters, 190(1), 115-119).
The cancer cell has an alkaline intracellular pH and an acidic extracellular pH, owing to the secretion of lactic acid outside the cancer cell. In the cancer cell, the lactic acid cannot be burnt by its defective mitochondria. It is a waste for the cancer cell, explaining its preferential localization outside the cell. But for the surrounding cells lactic acid is valuable food. The immune cells need to eat, and they will travel long distance to reach this environment rich in valuable nutrient.These immune cells can burn this lactic acid that cancer cell cannot digest. Here is the very reason of the activation of the immune system. Eating wastes is the very reason for the presence by immune cells around cancer cells. It is like dogs or rats that travel long distance to feed in the trash of the human.
When Peyton Rous discovered, in 1910, that a virus could transmit cancer, one may have thought that cancer was a viral disease. The fact that the captured gene could, like many other oncogenes, cause cancer, one may have thought that cancer was a genetic disease, linked to the oncogenic cellular concept. However, as Warburg wrote in 1956, “The chicken Rous sarcoma, which is labeled today as a virus tumor, ferments glucose, and lives as a partial anaerobe like all tumors.”
Carcinogenesis, whether arising from viral infection, oncogene activation or chemical agent, produces similar impairment in the cellular respiration. Infection by an oncogenic virus or exposure to a carcinogen inhibits the mitochondria and causes the Warburg effect. As stated by Thomas Seyfried: “Any unspecific condition that damages a cell’s respiratory capacity but is not severe enough to kill the cell can potentially initiate the path to cancer. Some of the many unspecific conditions that can diminish a cell’s respiratory capacity thus initiating carcinogenesis include inflammation, carcinogens, radiation, intermittent hypoxia, rare germ line mutations, viral infections, and age”.
The papillomavirus is responsible for cervical cancer. They are carried by semen and lodge in the cells of the cervical epithelium at the point of impact. Vaccines like Gardasil target these human papillomaviruses.
These papillomaviruses infect the cell of the uterine cervix, enter the cellular machinery and divert metabolic flows to their sole benefit. Infection with the papillomavirus causes the Warburg effect and therefore cancer of the cervix. The infected cell can no longer burn sugar into carbon dioxide and water. It cuts the glucose that has six carbons in two pyruvate ions bearing each three carbon atoms. This delivers some energy but much less than if it could burn glucose into carbon dioxide and water. In normal cells, digestion of glucose into pyruvate usually yields carbon dioxide and water after combustion in the mitochondria.
The cancer cell cannot use this pyruvate; it is thus excreted as lactic acid in the extracellular space.
There is an endless list of carcinogens. Ultraviolet rays are responsible for certain skin cancers. X-rays penetrate deeply and will also be carcinogenic.
When financial interests are at stake, recognition of the carcinogenicity has been more difficult. We all remember the asbestos scandal or, more recently, the Diesel scandal where the industry put its weight to delay the recognition of the obvious.
We need to see what these oncogenic viruses , asbestos, ultraviolet rays, X-rays and all these carcinogens have in common. The answer comes from toxicology labs. To sell a new chemical entity, the industry has to prove that it is not carcinogenic. This is a slow process. Biologists know that the analyses of the mutation of isolated cells grown in Petri dishes are unreliable. The only way to know if a compound is carcinogenic is to test it in animals. The animal's skin (usually a rodent) is shaved and then rubbed with the product to be analyzed repeatedly for days to cause cancer. Testing the toxicity of new products requires the sacrifice of millions of mice. The protocols all say the same thing. If the product causes skin inflammation, it must be considered carcinogenic. But not all mice are born equal. Some of them are more prone to inflammation and cancer; others are less prone to it. The breed of mice is a subject of heated debate among toxicologists. One may choose a mouse, which is less susceptible to cancer to get better results.
What these carcinogens, viruses, X-rays or ultraviolet rays or chemicals have in common is that they all cause inflammation. An infection with a papillomavirus causes inflammation of the cervix and then cancer. Ultraviolet rays cause sunburns (erythema). Tobacco causes chronic bronchitis, excessive consumption of alcohol leads to hepatitis.
Both the doctor and the toxicologist see that:
inflammation is the most potent carcinogen