“The failure to discuss the role of energy metabolism in the origin of cancer is like failing to discuss the role of the sun in the origin of the solar system.” - Dr Thomas Seyfried
Several theories on the origin of cancer have been postulated since the 20th century.
During the early half of the 20th century, the metabolic theory of cancer, developed by the highly regarded German medical biochemist Otto Warburg, held a respectable position (1). After fighting in World War I, Warburg dedicated his life to a scientific career that would see him win the Nobel Prize in 1931 and become nominated for it three separate times for three separate achievements (2). His metabolic theory of cancer was not one of these.
Warburg’s metabolic theory contended that cancer originated from chronic, cumulative damage to the cell’s energy-producing mitochondria (1). Mitochondria damage from a variety of sources such as hypoxia, viruses, chemicals, and radiation chronically disabled the cell’s oxygen-based aerobic method of energy production, called respiration. The overwhelming majority of cells could not compensate for this chronic respiratory damage and so they died of energy failure. However, a resourceful few managed to compensate by cranking up their glucose-based anaerobic method of energy production, called glycolysis, and they did so even while producing lactate in the presence of oxygen, something normal cells do not do. This strange form of aerobic glycolysis, also known as the Warburg Effect, allowed these cells to survive the energy crisis brought about by their damaged mitochondria, and they became cancerous. Essentially, the metabolic theory argued that a cancer cell was a disadvantaged cell, forced to return to a primeval state of replication and relying upon aerobic glycolysis to survive.
Towards the middle of the 20th century, the somatic mutation or genetic theory of cancer gained momentum (2). In 1953, two scientists by the name of Watson and Crick discovered DNA, an event in history that shifted almost everyone’s attention away from mitochondria towards the DNA-containing genes of the cell nucleus.
The genetic theory contended that cancer originated from random, sporadic mutations to the genes of the cell’s nucleus. Chronic damage to genes from a variety of sources such as hypoxia, viruses, chemicals, and radiation resulted in an accumulating mutation burden within the nucleus. When these mutations occurred in genes involved in the control of cell growth and replication, certain genes promoting cell growth called oncogenes were up-regulated while other genes inhibiting cell growth called tumour-suppressor genes were down-regulated. Essentially, the genetic theory argued that a cancer cell was an advantaged cell, freed from its regulatory constraints to pursue a chaotic destiny of limitless replication.
During the latter half of the 20th century, the metabolic theory faded into obscurity while the genetic theory became the dominant theory on the origin of cancer (3). There are many reasons for this, but three reasons stand out. First, the metabolic theory contends that cancer originates within mitochondria, but this had not yet been shown in a cause-and-effect manner during Warburg’s era. Second, the metabolic theory contends that the cancer mechanism occurs through chronic respiratory damage to the mitochondria, yet the genes of cancer cells are heavily mutated with potentially thousands of different mutations even within a single cell, a fact that was not initially accounted for by the metabolic theory while seemingly supportive of the genetic theory. Third, until recently the metabolic theory lacked an explanation as to how cancer cells metastasize to spread throughout the organism, whereas an elaborate theoretical framework of collective gene mutations was proposed decades ago to explain metastasis in the context of the genetic theory.
Today, Warburg’s metabolic theory has been ignored to the point that it is now viewed as a colossal failure, a singular blemish on an otherwise spectacular lifetime of scientific achievement (2). Today, most cancer researchers and oncologists remain firmly convinced that cancer is a genetic disease.
That is a great tragedy, for they are almost certainly wrong. By examining the evidence to date, we will address each of the three criticisms above and see that the evidence supports the notion that cancer is a metabolic disease, not a genetic disease.
It has long been noted that the mitochondria of cancer cells are structurally abnormal, and the fact that they rely upon aerobic glycolysis for much of their energy needs also makes them functionally abnormal. It is perilous to ignore the fact that aerobic glycolysis is the defining signature of cancer cell metabolism (1). Although the genetic theory of cancer acknowledges that cancer cell mitochondria are structurally and functionally abnormal, it treats this fact as a mere curiosity, of minor relevance to the disease itself. That is a shame, for substantial evidence now indicates otherwise.
Numerous studies have been done using cybrids, cells that have been created by combining the nucleus of one cell with the mitochondria from the cytoplasm of another cell. When the nucleus of a cancer cell is combined with the mitochondria from a normal cell, up to 100% of the resulting cybrids show no ability to become cancerous (4). In contrast, when the nucleus of a normal cell is combined with the mitochondria of a cancer cell, up to 97% of the resulting cybrids produce tumours (5,6). Taken together, these studies clearly demonstrate that a normal nucleus cannot prevent cancer in the presence of cancerous mitochondria and that a cancerous nucleus cannot produce cancer in the presence of normal mitochondria. Thus, mutations in the nucleus are not the prime determinant of the fate of the cell.
If the genetic theory of cancer is correct and mutations within the nucleus are the source of cancer, the mutations of a cancerous nucleus ought to produce cancer regardless of the state of the surrounding mitochondria, and a normal nucleus ought to suppress cancer regardless of the state of the surrounding mitochondria. This does not happen, and these findings have been documented across multiple studies by many different investigators (7,8,9).
On the other hand, these findings are perfectly consistent with the metabolic theory of cancer, which posits that cancer originates with damage to the mitochondria. If the mitochondria population is healthy, it does not matter how many mutations there are in the nucleus - the healthy mitochondria provide ample energy through respiration and so there will be no energy crisis, thus no need for the cell to resort to aerobic glycolysis, thus it will not become cancerous. Yet if the mitochondria population is damaged, even a pristine nucleus is unable to prevent the cell from resorting to aerobic glycolysis, which paves the road to cancer.
Collectively, the cybrid experiments show, in a cause-and-effect manner, that the fate of a cell is dictated by the state of its mitochondria, not its nucleus, and therefore cancer originates in the mitochondria, not the nucleus. This fact alone delivers a knock-out blow to the genetic theory of cancer while remaining perfectly consistent with the metabolic theory.
In almost every type of cancer studied, the mitochondria are damaged in their ability to create energy from respiration, and these cells rely upon glucose to fuel aerobic glycolysis and compensate for their chronic respiratory damage. In addition to glucose, recent evidence suggests that cancer cells can also use the amino acid glutamine to compensate for their chronic respiratory damage (1). The genetic theory acknowledges that glucose and glutamine may fuel cancer cells, yet it places far less importance on these observations compared to the fact that the genes of cancer cells are also heavily mutated, a fact that “obviously” proves that mutations spur the disease. While this may seem reasonable at face value, a bit of reflection reveals it to be patently false.
A large body of empirical evidence shows that the mutations of nearly all cancers are sporadic; they occur in a random, non-hereditary fashion (10,11,12). Moreover, it is also known that the sporadic mutation rate in most human genes is very low, far too low to produce the hundreds of different mutations observed in cancer cells, not to mention the thousands of different mutations that may be observed within a single tumour (10,11,12). Therefore relying solely upon the sporadic mutation rate, there’s simply not enough time for these huge numbers of mutations to accumulate in the lifespan of a single cell or organism.
Since the genetic theory of cancer preaches that sporadic mutations alone are the source of cancer, the very low rate of the sporadic mutation rate is an inconvenient truth that eliminates the possibility that sporadic mutations drive cancer. Defenders of the genetic theory have tried to argue around this truth by suggesting that caretaker genes, select genes such as p53 that guard against mutations in the rest of the genome, might become mutated first and if so this might produce a loss of caretaker function followed by a rapid build-up of mutations throughout the nucleus (13,14). Yet this pathetic argument merely begs the question as to why nature would ever create caretaker genes, the genes that supposedly guard all others, that are themselves excessively prone to mutations; indeed, p53 is one of the most commonly mutated genes found in tumours (15).
On the other hand, emerging evidence from studies on yeast and mammalian cells shows that the heavy mutation burden noted in the nucleus does not contradict the metabolic theory at all; in fact, it is to be expected. When mitochondria are damaged and respiratory energy production is disrupted, a collection of persistent “distress“ signals collectively called the retrograde response is relayed from the damaged mitochondria to the nucleus (16,17). The retrograde response upregulates the oncogenes and pathways needed to increase the cell’s reliance on glucose and glutamine metabolism; in other words, it prepares the cell to become cancerous. If the retrograde response occurs for long enough, it leads to widespread gene instability in the nucleus, followed by a rapid accumulation of mutations in the nucleus (1). Seen this way, the high numbers of gene mutations noted within cancer cells are downstream consequences, or epiphenomena, of a metabolic disease.
Collectively, the evidence shows that cancer progresses through chronic respiratory damage, a prelude to a persistent retrograde response that secondarily produces widespread gene instability and an increased rate of mutations, as epiphenomena. The sporadic mutation rate is far too slow to produce the large numbers of mutations seen in cancer cells.
It is interesting that most cancer researchers do not study the effects of cancer metastasis, which is the spread of cancerous cells from the primary tumour to surrounding tissues and distant organs, in their cancer models. Yet it is also unfortunate, for metastasis is responsible for 90% of human deaths from cancer (18). Therefore, it is essential for any respectable cancer theory to rationally explain the mechanism of metastasis.
Cancer metastasis involves a complex series of sequential and interrelated steps. To metastasize, cancer cells must detach themselves from the primary tumour, enter the circulatory and lymphatic systems, evade attack from the immune system, exit the circulatory and lymphatic systems at a distant site, and invade and proliferate in a distant organ. In this distant organ, the metastatic cells then undergo what is known as the mesenchymal-epithelial transition - their metastatic behaviour disappears and they revert to their original primary tumour behaviour (19,20). Clearly, not a simple process.
The genetic theory of cancer explains that metastasis is the “endpoint” of a series of gene mutations and cancer cell selection. Let us consider this possibility, the one that every medical student learns about in medical school. The genetic theory of cancer proposes that a collective set of random mutations somehow produces cells with the ability to detach themselves from the primary tumour, breach vessel walls to enter the circulation, evade immune attack the entire time, breach vessel walls again to exit the circulation, and then invade and proliferate in a distant organ. Not only this, the genetic theory of cancer then explains that the mesenchymal-epithelial transition simply occurs as a reversal of the complex steps responsible for the metastatic behaviour in the first place. Viewed in an objective light the idea that a collection of completely random mutations can reliably produce this complex metastatic behaviour and its subsequent reversal, in virtually all types of cancers, is utterly absurd.
On the other hand, the metabolic theory of cancer proffers a far simpler explanation. Evolutionarily, metastasis first appeared in lower chordates, in parallel with the origin of the immune system (1). In fact, the characteristics of metastatic cells are almost identical to those of immune cells called macrophages, cells that display all the migratory capabilities of metastatic cells, and avoid immune detection for the simple fact that they are immune cells themselves. One of the main functions of macrophages is to phagocytize or “engulf” foreign cells by fusing with them. This is intriguing, for phagocytic behaviour is well described in many cancers, especially the most malignant ones; metastatic cells can even phagocytize cells of the immune system (21,22). Thus, both metastatic cells and macrophages share the ability to fuse with other cells (1). The metabolic theory of cancer contends that when macrophages encounter a primary tumour, they fuse with the cancer cells before destroying them, and in doing so they acquire damaged mitochondria from the cancer cells. If the macrophages repeat this process often enough, they themselves will acquire enough damaged mitochondria to become reliant on aerobic glycolysis and therefore cancerous. This process converts each normal macrophage into a hybrid consisting of a normal macrophage nucleus combined with damaged mitochondria, a hybrid capable of utilizing all of the properties already inherent to normal macrophages - detaching from other cells, entering the circulation, evading immune attack, exiting the circulation at a distant site, and invading distant organs (1).
Collectively, the evidence suggests that metastatic cells are hybrid tumour macrophages, normal macrophages that have acquired enough damaged mitochondria to become cancerous themselves; metastasis naturally follows as these tumour macrophages go about their usual behaviour. This explanation for metastasis is much more reasonable than the genetic explanation, which would lead us to believe that a collection of random mutations can somehow produce the entirety of metastatic behaviour in virtually all types of cancers.
By examining the evidence, it should be apparent that cancer is a metabolic disease - it originates in the mitochondria, progresses through chronic respiratory damage with the retrograde response producing widespread gene mutations as an epiphenomenon, and metastasizes by conferring that respiratory damage to the very cells hired to eradicate it, the macrophages. When scrutinized in a reasonable light, the genetic theory of cancer does not hold water. Why do we still cling to this preposterous theory?
The failures of genetic strategies to treat cancer are legendary and ongoing for the simple reason that they focus on mutations, which are merely epiphenomena of a metabolic disease. By examining the statistics on cancer deaths over the last several decades it is apparent that the “war on cancer” is not going well. In the US, from 1990 to 2010, the number of new cancer cases per year increased from 1,040,000 to 1,529,560 while the number of new cancer deaths per year increased from 510,000 to 569,490 (1). Despite all the surgery, chemotherapy, and radiotherapy, despite the more than 700 new drugs targeting gene mutations that have been developed (2), despite the monolithic genome sequencing projects with their empty promises of targeted gene therapies, cancer escalates. Can any rational person really contest otherwise? The current era of cancer treatment represents a period of unenlightened barbarism. When it comes to metastatic cancer, the current “treatments” provide a few extra months at most while accelerating the disease in the long run. Surgery is usually a delaying tactic at best. Chemotherapy destroys both cancerous and normal cells alike, including immune cells which help to keep cancer at bay in the long run. Radiotherapy may be therapeutic over the short term, but it damages mitochondria (1), enhances fusion hybridization (23,24), and provokes metastatic behaviour (25,26,27) for a variety of cancers in the long run. The steroids given alongside chemotherapy and radiotherapy greatly increase the glucose supply in the blood, which is the fuel needed most for the survival of cancer cells. Both chemotherapy and radiotherapy induce tissue necrosis and inflammation thereby increasing glutamate release for later conversion into glutamine (27,28), the other main fuel needed by cancer cells to survive. Current cancer “treatments” provide short-term gains while making thedisease worse in the long run, and they usually damage vast swathes of normal cells in the process. Is it any wonder that the number of people who reject the advice of oncologists is increasing (29)?
Cancer is a metabolic disease, and a metabolic disease requires metabolic treatments aimed at enhancing the health of mitochondria. Since the “Achilles heel“ of cancer cells is their reliance on glucose and glutamine for energy, it makes sense to target these two metabolic pathways. Blood glucose can be lowered using fasting protocols and ketogenic diets; such dietary measures have plenty of scientific evidence backing up their effectiveness in treating animal cancers and ought to constitute the backbone of any cancer treatment strategy (1). Both fasting and ketogenic diets starve cancer cells of their most essential fuel, glucose, while providing plenty of fats and ketones which are readily usable fuel sources for normally respiring, metabolically flexible cells. Moreover, there are drugs out there that specifically target glutamine metabolism, such as the glutamine analog 6-diazo-5-oxo-L-norleucine (DON), a drug that is well tolerated by humans and has been shown to prevent metastatic spread in animals (1). Furthermore, aerobic glycolyis itself can be targeted with the hexokinase II inhibitor 3-bromopyruvate (3BP), a drug that leaves normal cells alone yet totally eradicates cancer cells in animals (2). We need more treatments like these, metabolic treatments that take advantage of the reliance of cancer cells on glucose and glutamine while exploiting the metabolic flexibility of cells with normal, healthy mitochondria. Why do we continue to disfigure, poison, and nuke cancer patients when we have the power to implement effective therapies already in existence and potentially create even better ones? Why are cancer patients not given more options?
I believe that if we really wanted to, we could remove the stranglehold on human health created by the so-called “emperor of all maladies” that is cancer.
The only reason it still retains this title is that through a combination of ego, ignorance, and greed, we choose to let it.
Solace (inspired by Thomas Seyfried).
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