Metabolic Theory of Cancer
Posted by Jondoeuk at ATS
Something is Very Wrong
For over 50 years researchers have been hunting down, cataloging, and developing drugs to combat the genetic mutations thought to cause cancer – with remarkably little success. Enormous amounts of time and money have been spent on cancer research yet contradictions, confusion, and frustration continue to dominate the landscape of the field.
Emerging evidence is beginning to put into question the very theory of the origin of cancer. A handful of experts’ are pounding the table proclaiming the whole cancer research community needs to step back and reconsider what was once unquestionable – that cancer originates from mutations to nuclear DNA. The evidence suggests, they say, cancer starts when cells are unable to produce energy with oxygen, and that mutations to DNA occur after the disease has already began. Others, still convinced cancer is a genetic disease, are acknowledging something is amiss, and maybe there is more to the metabolic defects found in tumor cells than previously thought.
Make no mistake— the origin of cancer is far from settled.
What is The Metabolic Theory of Cancer?
Put simply, the metabolic theory states that cancer originates from damage to the cell’s capacity to generate energy with oxygen (oxidative energy production), with a concurrent increase in energy generation without oxygen. In other words, cancer is not a genetic disease, but rather a disease of metabolism.
The metabolic theory of cancer is not a new theory. It was first proposed by Nobel Prize winning German biochemist Otto Warburg in 1924. The theory was subsequently discarded when it was discovered that cancer cells had mutations to DNA, the profound new molecule Watson and Crick had just reveled to the world. A determination was made – if cancer cells have mutations to the one molecule that dictates all cellular function; well then that must be the cause of the disease. And with that, if was off to the races for a cure – nobody ever looked back….until now.
A healthy cell produces 89% of its energy using oxygen, and 11% through non-oxidative metabolism (non-oxidative metabolism is also known as “fermentation”). Oxidative energy production is far more efficient than fermentation. Almost 20 times more energy is released when glucose is completely oxidized, as opposed to when it is fermented.
Oxidative energy production takes place in a cellular organelle called the mitochondria. The mitochondria are known as the cellular “power plant.” The metabolic theory of cancer contends that the disease begins with damage to the mitochondria. The cell is then forced to shift energy production to fermentation in order to survive. It is telling that this one feature of cancer, damaged mitochondria and increased fermentation is present in all cancer types. Also telling is the fact that the greater the degree of fermentation displayed by a given cancer, the more aggressive the cancer. Because a tumor cell’s mitochondria are damaged, and are therefore forced to generate energy by such an inefficient pathway, they have to consume much more glucose to remain viable. A glance at a PET scan, which uses a radioactive labeled glucose analog to image cancer, provides stunning visual evidence of the voracious appetite tumor cells have for glucose compared to normal tissue.
Emerging evidence revels that all of the hallmarks of cancer can be explained by mitochondrial damage followed by a shift to non-oxidative energy metabolism. Once the oxidative energy generating capacity of the cell is impaired, the cell undergoes a dramatic transformation; important oncogenes (cancer causing genes) are switched on, initiating the uncontrolled proliferation that is the hallmark of the disease.
Critically, recent sequencing data has been unable to implicate genetic mutations as causative to any type of cancer, while in contrast metabolic dysfunction has been shown to be present in every type of cancer, regardless of tissue of origin. In an ad hoc attempt to explain the seemingly random complexity of the 1000’s of mutations cataloged in cancer, researchers now claim cancer is a collection of over 200 different diseases. Intuitively, I think people know that cancer is cancer; it is one disease – as the metabolic theory proposes. It is not a collection of over 200 different diseases as the genetic theory proposes. Calling cancer a collection of over 200 different diseases is just an expansion of explanation; an attempt to make a failed theory continue to fit the data.
Healthy Mitochondria. Note the abundant looping structures inside the mitochondria (cristae), this is where all energy is produced through oxidative pathways.
Image of a mitochondria from a cancer cell. Note the almost compete absence of cristae.
PET scan showing widespread metastasis
The latest push by the NCI is called the Cancer Genome Atlas Project. Its stated mission: “To systematically explore the entire spectrum of genomic changes involved in more than 20 types of human cancer.” The goal of this ambitious project is to once and for all, find and sequence all of the genetic mutations responsible for cancer. But so far the search for causative mutations has remained elusive – in fact, to date, the data suggests that mutations are not involved in ways previously assumed. The genetic mutational profile of any given cancer type looks different form person to person, rendering it impossible to claim mutations are definitely responsible for the origin of the disease. To be sure, some genes are mutated more frequently than others, but it appears that no single gene, or even any combination of genes, is absolutely necessary for the development of a tumor within a person. And to make things even more confusing, the mutational profile is different from cell to cell within the same tumor, rendering development of drugs that target mutations next to impossible. The drug targets not only change from person to person, but even within the tumor of a single individual.
Of the 700 targeted drugs developed to date, only one, Gleevec, has made a difference. Even Gleevec, with all its success, is not a cure but is a lifetime therapy, not eliminating the disease, but managing it. These new “targeted” drugs can cost up to $100,000 per treatment, and offer no increase in survival time – the relationship between price and value is completely broken when it comes to oncology treatment. Call this what it is, it is taking advantage of people when they are at their most vulnerable.
One sentence that is worth repeating can sum up the sequencing data from the Cancer Genome Atlas Project – No mutation has yet to be identified that is reliably diagnostic of any type of cancer.
One Single Comprehensive Theory
It is well established that once a cell has an impaired ability to produce energy through oxidative pathways, the genomic instability (increased potential for DNA mutations to occur) that accompanies tumor development, inevitable follows. While the genetic mutations acquired following mitochondrial impairment unquestionably contribute to the tumor cell’s qualitative features and aggressiveness, experimental evidence is unable to unequivocally assign them as the origin of the disease. They appear to be of secondary consequence or an epiphenomenon to the true cause, metabolic dysfunction. While it’s true that most of the agents known to cause cancer; chemical carcinogens, viruses, radiation, and inflammation can cause mutations to DNA, it is also true these provocative agents damage the mitochondria. Once the mitochondria of a given cell acquire a threshold degree of damage, and the cell reverts to fermentation to obtain energy, cancer has begun. It is subsequent to the shift in energy metabolism that genomic instability and mutations occur.
Diagram showing the progression of cancer. Once a threshold degree of mitochondrial damage occurs uncontrolled proliferation begins. The different colors depict cells with different mutational profiles within the same tumor. If a drug is developed targeting a specific mutation, the presence of sub clonal populations with different mutations will most likely render it ineffectual.
The truth is your cells are remarkably adept at protecting and repairing their own DNA. Researchers who study the mutational rates of human DNA readily admit something is amiss –mutations are extremely rare events, and are unable to account for the high rates of cancer development. Inversely and comprehensively, experimental evidence validates the metabolic theory of cancer – from the origin, to progression, to metastasis – yet many researchers and institutions have been slow to change course. Why is it this so important – finally and conclusively determining the origin of the disease? To achieve real therapeutic progress, the true origin of the disease has to be determined – all therapeutic progress, from prevention to treatment, must flow from a foundation of understanding. The metabolic theory fits the evidence as the one true origin.
Inherited Cancer Risk fits the Metabolic Theory
Many of you have probably heard of BRAC1. An inherited version of BRAC1 can increase a women’s risk of developing breast cancer by up to 60%. Even though genes like BRAC1 receive a lot of press and evoke fears of the inevitability of cancer, only 5 to 7% of all cancers are attributed to the genes inherited from your mother and father – most cancers arise spontaneously. An inherited predisposition to develop cancer has been historically cited as evidence that cancer is a genetic disease – and it certainly appears that way at first glance. However, an exhaustive look at these rare inherited mutations revel that all of them also increase the propensity of the cell to incur mitochondrial damage – leading to impaired oxidative energy production – the hallmark of the metabolic theory. Experiments have shown that in addition to its DNA repair function, BRAC1 appears to have a mitochondrial function as well. So a mutated version of BRAC1 could affect mitochondrial function, leading to a reduced capacity to create energy through oxidative pathways – the origin of cancer. Other genes implicated in an inherited propensity to develop cancer have also been shown to be involved in mitochondrial processes, showing that inherited mutations set the stage for cancer later in life by increasing the probability of metabolic dysfunction.
An electron microscope image showing the location of BRAC1 within the mitochondria.
It is certainly true that all scientific endeavors are not created equal, and some experiments provide a more profound understanding of the physical world compared to others. Put bluntly, some experiments are just better than others. An elegant series of nuclear/cytoplasm transfer experiments fall into this esteemed category, and are exceptionally important in revealing the true nature of the disease. In brief, the experiments consist of transferring the nucleus (this is where the DNA resides) of a cancer cell into a healthy cell that has had its nuclease removed prior. The newly created hybrid cell has the genetic material of a cancer cell, with all of its defects, but now has the healthy mitochondria of a normal cell. Intuitively, if the origin of cancer is indeed mutations to DNA, the newly created hybrid cells, that still retain all of the mutations should be tumorigenic. But they are not. They are perfectly healthy. These experiments were carefully executed, with strict controls, and were found to be very reproducible. Experiments like these provide irrefutable evidence that even a child could understand – proving that ultimately DNA mutations are not in the driver’s seat with respect to the origin of cancer; the mitochondria are.
A diagram summarizing a series of experiments conclusively determining that it is the mitochondria, and not nuclear DNA, that causes cancer.
Just getting started
If we are right, and cancer is truly a metabolic disease, the therapeutic implications are enormous. First, if we are right, it would explain why virtually no progress has been made in reducing the death rates from cancer since 1950. Second, it opens up profound possibilities for new avenues of treatment. Without question the metabolic therapeutic approaches explored so far have exhibited tremendous promise. The first and most obvious place to start is by implementing a ketogenic diet, starving the cancer cells of the glucose they so heavily rely on for survival. The results have been remarkably consistent. In virtually every experiment in which the ketogenic diet has been tested in mice, tumor growth rates have slowed dramatically. The results of the diet stand alone, but the results get really exciting when the diet is utilized in addition to other therapies. It appears that the ketogenic diet is able to put cancer cells under significant metabolic stress allowing addition therapies, like cisplatin, radiation, and hyperbaric -oxygen to push the cells over the edge, increasing their efficacy exponentially. And this is just scratching the surface. So much remains to be done.
We can all speculate why the cancer industry has been so slow to change it view of cancer – bad incentives – pharmacuetical companies are incenticed to make only small incremental improvements, entrenched beliefs, inadequate experimental models, whatever the case may be – we don’t want to sit on our hands waiting any longer
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