Metabolic Theory of Cancer: Mutations vs Mitochondria

“Let’s get ready to RUUUUMBLLLLLE!”

“Maybe we’ve mischaracterized the origin of cancer. Maybe cancer is not a genetic disease after all. Maybe we are losing the war against cancer because scientists are chasing a flawed scientific paradigm, and cancer is not a disease of damaged DNA but rather one of defective metabolism.” (Christofferson, xiii)

“If scientists have mischaracterized the origin of cancer, then we have lost three decades trying to target mutations that are a side effect rather than the motor driving the disease. (Christofferson, p.223)

“It is interesting to note that none of the current approaches to brain cancer management discussed at a recent symposium involved strategies to target tumor cell energy metabolism. Several presentations at this symposium discussed the failures associated with current approaches to management. As long as [brain] cancer is viewed as something other than a disease of energy metabolism, the failures will likely continue in our opinion.” (Seyfried et al., 2012)

(Warning: LONG post follows. Yes, even by my standards, this one is HUGE. [But awesome, if I do say so myself.])

We have covered an incredible amount of biochemical ground, haven’t we? We’ve still got a ways to go in this series on the metabolic origins of cancer, but so far, all the information we’ve explored—glycolysis; mitochondrial structure, function, and dysfunction; damaged mitochondria; aerobic fermentation (“the Warburg effect”); and cancer’s insatiable appetite for glucose—has been leading us to the waypoint we’ve arrived at today.

Way back in the very first post in this series, I said that there are two competing theories to explain the etiology of cancer.  One is called the somatic mutations theory (SMT), and it goes something like this: Cancer is the result of mutated DNA. DNA—the genetic material housed in a cell’s nucleus—contains the “codes” for everything a cell does. When this DNA gets mutated somehow—i.e., “mistakes” get made in the codes—the abnormal code gets transcribed and translated into proteins, enzymes, etc., and those things end up abnormal in structure, function, or both. These abnormalities lead cells to do things that normal/healthy cells don’t—like live forever (evade apoptosis), make their own blood supply (angiogenesis), migrate to other tissues (metastasis), and metabolize fuels differently (become sugar junkies).

Considering that cancer cells—all cancer cells of all cancer types—have at least some amount of mutated DNA, the SMT is really not very far-fetched. We find mutated DNA all over the place in all forms of cancer; therefore, it’s not that big a leap of logic to speculate that there might be a causal relationship between mutated DNA and cancer. (i.e., Cells are doing all sorts of weird/harmful things because DNA has programmed them to.)

But those of you who’ve ever tried -- and failed! -- to lose weight, manage your diabetes, reverse your heart disease, or improve your overall health by consuming a diet low in cholesterol, saturated fat, and red meat, and high in complex carbohydrates, fruit, vegetable oils, and whole grains, might have firsthand experience with two ideas: 

1. Correlation does not equal causation.
2. Just because something sounds logically plausible doesn’t mean it is.

With those ideas in mind, let’s take a look at the alternative theory of cancer etiology. This one is called the metabolic origins theory (MOT), and it holds that cancer is not caused by mutations to the genetic code, but rather, by abnormalities of cellular metabolism. The MOT says that the changes that occur when cells become cancerous are the result of an “energy crisis” caused by major quantitative and qualitative malfunctioning of cells’ main energy generators: the mitochondria.  The MOT does not ignore mutated DNA. BUT—and here we have the fundamental difference between the two theories—whereas the somatic mutation theory posits mutated DNA as the cause of cancer, the metabolic origins theory holds that mutated DNA is an effect of cancer.

It is critically important that we identify the cause(s) of cancer, because unless and until we know the causes, we don’t have much hope of devising particularly effective cures or prevention strategies. So far, the SMT is the generally accepted theory, and the vast majority of research dollars invested and treatment protocols developed have been guided by this paradigm. The MOT, on the other hand, has been the red-headed step-child of the oncology community, and it’s been severely short-changed where money, medicine, and media attention are concerned.

But now that we have at least a rudimentary understanding of the pathways and mechanisms involved with cancer, we can pick these two theories apart a little and see if we can figure out which one the science seems to support more.

Before I say anything else, I feel I should point out that if—IF—it looks like the metabolic origins theory fits the evidence more soundly than the somatic mutation theory, I do not in any way mean to malign the work of the researchers and clinicians who have oriented their careers under the guiding principles of the SMT. Cancer is a vile, vile beast. For everything we throw at it, it comes back at us twice as hard. If we cut it off at the knees, it sprouts extra elbows. It mutates. Is shifts and changes. Whatever uncomfortable thing we do to it, it adapts and overcomes. It is no joke, and we should be grateful for the intelligent and dedicated people who spend their time doing work that is often thankless and discouraging. I have every respect for the researchers and clinicians who go to their labs or hospitals every day and do everything they can think of to get a leg up on the wily, lithe, ultra-flexible and adaptive thing that is cancer.

SO: Going forward, if I inject a little sarcasm or incredulity into this discussion, please know I do so with the full recognition that NO ONE HAS ALL THE ANSWERS, least of all me. (Very, very least of all me.)

HOWEVER: When decades upon decades of clinical observations do not jive with our assumptions about how cancer works, then it’s not unreasonable to suggest it’s time to reevaluate those assumptions. We’ve learned it the hard way about saturated fat and cholesterol:  When evidence does not fit the working hypothesis, then the hypothesis does not work.

Is the mutated DNA seen in cancer the cause of cancer, or is it an effect? 

This is an absolutely critical question, because the answer has the potential to lead research dollars, clinical trials, nutritional therapies, and scientific careers, in a completely different direction than the one they’ve been headed in for the better part of a century.

Let’s assume the SMT is correct, and that genetic mutations are driving cancer. If this is true, then aside from surgery, chemotherapy, and radiation—the latter two of which are toxic to healthy cells as well as to cancerous cells—another way to attack cancer is via drugs targeted at the specific genetic mutations believed to be causing cancer.

There are several problems with this approach. Targeting individual mutations that might be driving cancer isn’t like looking for a needle in a haystack; it’s like looking for a zillion needles in a zillion different haystacks.

Here’s the problem: not all cancer cells contain the same mutations—not even in the same tumor, in the same person. That is, let’s say Sally and Fran both have breast cancer. Not only are the mutations in Sally’s cells different from the mutations in Fran’s, but the mutations in one of Sally’s cancer cells are different from those in another cancer cell from her own body! The DNA mutations are all over the place, and there’s not a whole lot of rhyme or reason to them (if any). Theoretically, then, in order to target cancer via drugs that home in on specific, individual mutations, to “cure” someone of cancer, you would have to develop a unique drug for every single one of the mutations. And even if you were successful in doing that for one patient, you’d have to develop a whole new set of unique drugs to treat the same type of cancer (not to mention some other kind of cancer) in a new patient. In the intro post of this series, I said that approaching cancer treatment this way is like playing Whack-a-Mole, and you can easily see why.

Travis Christofferson covered this quite well in his book, Tripping Over the Truth. (All the following quotations are from this work.)

• “Most solid tumors display a hurricane of genetic chaos.” (p.184)
•  “Because mutations varied so much from patient to patient…there was not a consistent therapeutic target. How could pharmaceutical chemists zero in on a given cancer when the target was so different from person to person?” (p.138)
• “Tumors were not just vastly different from person to person [INTERtumoral heterogeneity] but also within the same tumor [INTRAtumoral heterogeneity].” (p.141) 
• “The mutations determined to start and drive the disease were vastly different from person to person.” (p.133)
• The mutated DNA observed in cancer cells “failed to reveal any sort of consistent pattern. It contained a degree of randomness that caught everyone by surprise.” (p.132) 

Moreover, for all of these DNA mutations, for all of these chromosomes getting into trouble:

“None of the mutations found were conclusively determined to be responsible for the origin of the disease.” (p.133)

So we have mutations out the wazoo, but research to date has not established a causal link from any of them to the instigation of cancer. This is likely why drug therapies that target mutated DNA so often fail. Not to mention the whack-a-mole analogy again: the minute you go after one mutation, three more pop up someplace else.

Obviously, we can’t use any of this gee-whiz information about the total randomness of the genetic mutations seen in cancer to conclude that DNA mutations are not the cause. That logic would be terribly faulty:  It’s extremely difficult to treat/cure cancer by targeting genetic mutations, therefore, genetic mutations probably aren’t the cause. No, unfortunately, science and medicine can’t operate that way.

(As for the other approaches to treating cancer—chemotherapy and radiation—they’re more like carpet-bombing the entire organism. Instead of precision-targeting the mutations, these “poison and burn” methods basically inflict grave damage upon the whole body, and the hope is that healthy cells will manage to survive, and cancer cells won’t. Good luck with that.)

So now, let’s look at the metabolic origins theory and see what the implications are for mutated DNA as a result of cancer, rather than its cause.

You will recall from biology class that the nucleus is “the brain” or “control center” of the cell. Inside the nucleus is DNA—the genetic material that ultimately programs every single teeny tiny thing we are and do. (Blue eyes? That’s your DNA. Sickle-cell anemia? Also your DNA. Digesting protein? That’s DNA that was transcribed into RNA & then translated into proteins to make trypsin, carboxypeptidase, and other protein-digesting enzymes. Heart disease that your father, grandfather, and great-grandfather also had? Your DNA…being influenced by your diet and environment. [Or so we currently believe.] )

The somatic mutation theory says that cancer arises as a result of mutations to this DNA. Because DNA programs us to do what we do at a cellular level, it makes sense that if this DNA were damaged somehow (for example, from cigarette smoking, long-term exposure to heavy metals, or ionizing radiation), cells will end up doing abnormal things, such as all the bad behavior we talked about a while back. If cancer cells are behaving abnormally, something is telling them to, and that something is messed-up DNA.

But there’s a problem here:

Even if mutated DNA is causing cells to do all the horrible things cancer cells do, what is causing the DNA to mutate? WHAT IS MESSING UP THE DNA?

Aaaaah, NOW we have some thinking to do.

Let me share with you an idea I had while considering the implications of a drastic reduction in cellular energy generation—the kind that happens when mitochondria are damaged to the degree that they are in cancer cells:

When you are tired and have no energy, you get sloppy, clumsy, and you make silly (and not-so-silly) mistakes you wouldn’t ordinarily make, right? Isn’t it possible that this is happening with DNA replication in cancer cells? DNA replication, RNA transcription, and translation are energy-intensive process (meaning, they require ATP), so what will happen when there isn’t enough energy to be had? Isn’t it possible the cell will get sloppy, clumsy, and make errors in DNA replication and/or transcription/translation? Moreover, there are enzymes that come along and "proofread" duplicated DNA strands, fixing errors along the way. Yes, that's right: our cells have built-in DNA repair enzymes. But what if the cell is getting sloppy because of low energy? What if the cell is tired, and these repair enzymes are asleep at the wheel? Then DNA replication errors--which happen all the time (this is normal)--will not get corrected.

If there is any validity to that notion, then MUTATED DNA IS AN EFFECT, NOT A CAUSE, OF CANCER.

Based on what the good Dr. Seyfried and his colleagues have said on this issue, I am spot-on: 

• “The integrity of the nuclear genome is dependent to a large extent on the efficiency of mitochondrial respiratory function. Evidence indicates that a persistent … mitochondrial stress response leads to abnormalities in DNA repair mechanisms and to the upregulation of fermentation pathways. Oncogene upregulation becomes essential for increased glucose and glutamine metabolism following respiratory impairment.” (Seyfried et al., 2014.)

• “The abnormal genomic landscape seen in tumor cells is considered a downstream epiphenomenon of dysfunctional respiration and protracted oncogene-driven fermentation. In other words, THE SOMATIC MUTATIONS ARISE AS EFFECTS RATHER THAN AS CAUSES of tumorigenesis.” (Ibid.)

• “Tumor cells arise from defects in the cytoplasm rather than from defects in the nucleus.” (Ibid.)

• It appears that the function of DNA repair enzymes and the integrity of the nuclear genome is dependent to a large extent on the energy derived from normal respiration. In other words, the Warburg effect and genomic instability ultimately arise FROM damage to OxPhos.” (Seyfried et al., 2012.) 

One of Seyfried's papers recounts an experiment in which they took apart some “normal”/healthy cells, and merged them in different ways with cancer cells:

1. Transplanted healthy (non-cancerous) nuclei into tumor cells whose own nuclei (containing mutated DNA) had been removed. The rest of these cells (including their mitochondria and cytoplasmic environment) was as it was in the tumor.
2. Transplanted nuclei from cancer cells (which contained the presumably cancer-causing mutated DNA) into non-cancerous cells, with healthy mitochondria and normal cytoplasm.

EXPECTED RESULTS PER THE SOMATIC MUTATION THEORY:

If DNA mutations are the cause of cancer, then upon cell division, a tumor nucleus transplanted into the healthy cytoplasm (containing healthy mitochondria) will give rise to cancerous daughter cells, and a healthy nucleus transplanted into a damaged mitochondrial & cytoplasmic environment will give rise to normal daughter cells.

EXPECTED RESULTS PER THE METABOLIC ORIGINS THEORY:

If cancer is the result of abnormal mitochondria and cytoplasmic environment, then upon cell division, a healthy nucleus transplanted into a cell with damaged mitochondria will give rise to cancerous daughter cells, and a tumor nucleus transplanted into a healthy cytoplasmic environment will give rise to normal daughter cells.

You get one guess as to how this went down.

If you were betting on the MOT, pat yourself on the back, because that is exactly what the experiment supported. When the cancer cell nuclei (containing mutated DNA) were transplanted into cells with healthy mitochondria, the daughter cells were normal. They were NOT CANCEROUS. And when nuclei from healthy, non-cancerous cells (with normal, non-mutated DNA) were transplanted into cells that contained damaged mitochondria, the daughter cells WERE CANCEROUS. So we have a situation here in which mutated DNA did not result in cancer, but damaged mitochondria did.

From the paper, with the original caption:

Role of the nucleus and mitochondria in the origin of tumors. This image summarizes the experimental evidence supporting a dominant role of the mitochondria in the origin of tumorigenesis as described previously. Normal cells are depicted in green with mitochondrial and nuclear morphology indicative of normal respiration and nuclear gene expression, respectively. Tumor cells are depicted in red with abnormal mitochondrial and nuclear morphology indicative of abnormal respiration and genomic instability. Normal cells beget normal cells. Tumor cells beget tumor cells. Delivery of a tumor cell nucleus into a normal cell cytoplasm begets normal cells despite the persistence of tumor-associated genomic abnormalities. Delivery of a normal cell nucleus into a tumor cell cytoplasm begets tumor cells or dead cells but not normal cells. The results suggest that tumors do not arise from nuclear genomic defects alone and that normal mitochondria can suppress tumorigenesis.

With all of this in mind—not just this little experiment, but everything we’ve covered in this entire series so far, here are some reasonable conclusions: 

• “Tumorigenesis is dependent more on mitochondrial function than on the types of mutations in the nucleus.”  (Seyfried et al., 2014.)

• “Tumor cells arise from defects in the cytoplasm rather than from defects in the nucleus.” (Ibid.)

• “The underlying biochemical basis of the “Warburg effect”, i.e., increased glycolysis even in the presence of oxygen, resides at the level of the mitochondria…” (Pedersen, 2007.)

IF this is true, and IF the metabolic origins theory fits the evidence more closely, THEN:

“Maybe we’ve mischaracterized the origin of cancer. Maybe cancer is not a genetic disease after all. Maybe we are losing the war against cancer because scientists are chasing a flawed scientific paradigm, and cancer is not a disease of damaged DNA but rather one of defective metabolism.” (Christofferson, xiii)

“If scientists have mischaracterized the origin of cancer, then we have lost three decades trying to target mutations that are a side effect rather than the motor driving the disease. (Christofferson, p.223)

Yes, these are the same two quotes you saw at the beginning of this post. I think they are powerful enough to warrant repeating, and I hope you’ll agree.

And the kicker is, none of this even addresses mitochondrial DNA! That’s right, mitochondria have their own DNA! And “data suggests that the susceptibility of mitochondrial DNA to mutations is largely due to the increase in ROS levels in this organelle.”  (Allen et al., 2014.) (Hmmm…I’m pretty sure somebody mentioned ROS damage to the mitochondria five posts ago…)

“The chromosomes are vulnerable to mutations by the increasing generation of free radicals from the damaged mitochondria. […] Rather than driving cancer, mutations were just features of its personality.” (Christofferson, p.175)

Are you as amazed by all this as I am?

Perhaps you’re not amazed, but angry, instead. I can’t blame you. If you’ve lost a loved one to the scourge that is cancer (as I have), you have a right to be angry—at the universe, at damaged mitochondria, at mutated DNA, and even at the fucking (sorry, can’t help it) white bread, jello, and Ensure shakes being served to cancer patients in hospitals! But we can’t get angry with the doctors and researchers. Like I said before, they are extremely intelligent people, and cancer is an extremely slippery snake. Just when we think we have it in our grasp, it slithers away, leaving us completely dumbstruck at some new, ingenious way it has of evading our attempts to box it in and annihilate it.

But let’s not be angry.

Let’s be hopeful.

Yes, hopeful!

If the metabolic origins theory is correct—or, at least, “more correct” than the somatic mutation theory—then there are promising therapeutic avenues that are radically different from what we’re doing now. And it’s likely that the reason what we’re doing now has been such a failure is because we have been treating the effects, not the cause—the symptoms, rather than the disease.

 

And in fact, doctors, researchers, and nutritionists who are willing to explore these possibilities are hard at work conducting clinical trials and amassing data that grows more impressive each day that we may be able to make far more progress far more rapidly by exploiting cancer cells’ broken metabolism, their malfunctioning mitochondria, and, of course, the Achilles’ heel of their existence: their addiction to glucose.

Stay tuned. We’re going to devote a few posts to exploring some of these promising therapies. But first, we’ll take a look at the unsettling notion of cancer as an evolutionarily conserved protective mechanism. This will help us set the stage for the discussion of potential treatment & prevention strategies. If cancer is (in a twisted way) a protective mechanism, (i.e., the strategy by which metabolically compromised cells keep themselves alive), then it makes more sense just why it’s SO DAMN DIFFICULT to get rid of, and it also suggests that we’ve got to come at it with everything we’ve got: not just a radical change in diet, but from several other angles as well.  

Until then, I'll leave you with this quote from Seyfried et al., 2012:

“As long as [brain] cancer is viewed as something other than a metabolic disease, we contend that there will be little progress in improving progression free survival. If viewed as a metabolic disease, on the other hand, we can anticipate major advances in treatment and substantial enhancement of progression free survival.”

Continue to the next post in the series: Cancer as a Protective Mechanism

Remember: Amy Berger, M.S., NTP, is not a physician and Tuit Nutrition, LLC, is not a medical practice. The information contained on this site is not intended to diagnose, treat, cure, or prevent any medical condition.