February 20, 2015

Metabolic Theory of Cancer: Cancer as a Protective Mechanism






“Cancer cells were producing energy in a way that evolution had set aside as an auxiliary pathway, a highly inefficient generator that kicked in when the power went out.” (Christofferson, p.20


“Tumors bypass many of the biochemical constraints that regulate metabolism, in order to maximize their survival at great expense to the host.” (Mathupala, Ko, Pedersen, 2010)


The amplified rates of glycolysis “indicate a strategy used by highly malignant tumors to survive as well as thrive within the host using a remarkable set of coordinated molecular mechanisms. These mechanisms, which are very similar to those utilized by some highly successful parasites, indicate a sophisticated strategy devised by tumors to survive even the most inhospitable microenvironments within the host.” (Mathupala, Rempel, Pedersen, 1997)


Throughout this series on the metabolic origins of cancer, I have been hinting that cancer—destructive, devastating, scary cancer—might be an evolutionarily conserved protective mechanism. I realize this is politically incorrect. But when we understand some of the biochemistry and physiology involved, this is actually a fairly logical conclusion to arrive at.   

I have gone to great lengths to explain some of the relevant biochemical pathways involved in how and why cancer cells accomplish all the seemingly horrible things they do. In looking at glycolysis, the shift to hexokinase 2, aerobic fermentation, the upregulation of glucose transporters, and more, we have explored a lot about the how of cancer. And we’ve certainly talked a bit about the why. Today, let’s go a little farther down the rabbit hole of the why, because, as I left off saying last time, if we can figure out why cells become malignant, we might have better odds at preventing cancer. We can certainly develop more effective treatment protocols if we understand the how of cancer, but understanding the why will give us even more of an advantage in devising treatments, as well as creating (potentially) better prevention strategies and strategies to prevent recurrence.    


CANCER: A LOGICAL ADAPTATION TO METABOLIC EVENTS


If you’re a regular reader here, you are probably at least somewhat familiar with the concept of “ancestral health.” And you might also agree with the scientist Theodosius Dobzhansky, who said something to the effect of, “Nothing in biology makes sense except in the light of evolution.”

When we study how organisms respond to and are shaped by their environmental inputs—diet, movement, exposure to natural light and darkness, circadian rhythms, sights & sounds, etc.—we come to understand that, at the most basic biochemical level, organisms “expect” and require certain inputs, while other inputs can cause harm, running the gamut from being mildly detrimental, to outright fatal.  

With that in mind, is it a “disease” when someone’s arteries harden like glass and their blood resembles molasses after a lifetime of heavy consumption of refined carbohydrates? Is it a “disease” when someone’s blood vessels look like someone took a cheese grater to them, after a lifetime of consuming vegetable oils, which might be loaded with damaged fats? Is it an “illness” when someone’s adrenal glands call it quits on producing cortisol after a few years of chasing after kids, working full-time, rising at the crack of dawn to do intense workouts six days a week on a low-calorie diet, and spending the rest of one’s time worrying about money, the past, the present, the future, and a million other things that do not need to be worried about? Is it a medical condition when a guy who’s stressed out, eating garbage, and burning the candle at both ends can’t get it up?

In my opinion, no.

These are the natural, logical outcomes of the situations that brought them about. Totally and completely predictable. And so, too, with cancer. For today, we’ll stick with the theme that weaves this whole series together: cancer is the logical response to an energy crisis inside cells, primarily due to mitochondrial dysfunction. The next few posts will explore dietary, lifestyle, and environmental inputs that might—MIGHT—be causing this mitochondrial dysfunction. But for now, we’re operating under the premise that it is, in fact, malfunctioning mitochondria that underlie the changes cells undergo as they become malignant

(BTW: that guy I mentioned -- he doesn't need Viagra; he needs to calm the heck down, take a day off, and stop going to Taco Bell. And the woman with the fried adrenals doesn't need a ketogenic diet and licorice supplements; she needs a massage and a babysitter once a week.)

A while back, I said that glycolysis and fermentation are “primitive” mechanisms. They are failsafes. They are cells’ ways of keeping themselves alive when they have no other choice. (For the sake of clarity, recall also that glycolysis and fermentation are totally normal and healthy things for cells to do. The difference with cancer cells is that they do them much, much MORE than healthy cells do, and they produce energy via the Krebs cycle and electron transport chain [OxPhos/cellular respiration] much, much LESS.)

Okay. We have broken mitochondria. Our cells’ primary energy generators are on the fritz. But instead of engaging their self-destruct modes and committing cellular suicide (apoptosis), cancer cells do everything they can to evade death and keep themselves alive.    
  • “If respiratory damage is acute, the cell will die. On the other hand, if damage is mild and protracted, the cell will elevate lactate or amino acid fermentation in order to compensate for insufficient OxPhos.” (Seyfried et al., 2014)
  • “Recent studies suggest that increased tumor cell glycolytic metabolism may represent an adaptive response to escape metabolic oxidative stress caused by altered mitochondrial oxygen metabolism.” (Allen, et al., 2014)
  • “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 a malignant cancer.” (Seyfried, et al., 2014)

Whoa…
Powerful stuff, huh?

So the damage is bad, but not catastrophic enough for the cell to self-destruct. And why would it self-destruct when, instead, it can ramp up all these alternative mechanisms for generating energy? It’s as if the rest of the cell says to the mitochondria, “Don’t worry. Don’t worry at all about fixing yourselves, or trying to metabolize fatty acids and ketones. We’re on it! We’ve got your back. We’ll just ramp up glycolysis, and do everything we can to make sure we have a huge supply of glucose, and that we keep glycolysis going non-stop. We’re gonna stay alive forever, even if we have to kill everyone else in sight.”

This is pretty much what happens once cancer metastasizes and a patient becomes cachexic, right? The rest of the body wastes away and starves, while tumors grow larger and larger: 
  • “…the selective expression of HK-2 by malignant tumors as part of a clever survival mechanism that allowed the tumor to continue metabolizing glucose regardless of the nutritional status of the tumor-bearing host. In fact, it could now be inferred why even at the terminal stages of cancer progression in a patient (i.e., tumor induced cachexia) the tumor will continue to scavenge glucose from the patient's bloodstream and thrive while the patient's physiology progressively shuts-down.” (Mathupala, Ko, Pedsersen, 2009)


STAYIN’ ALIVE

(With apologies to the Bee Gees)


Cells with broken mitochondria perform a stunningly well-orchestrated symphony in order to continue producing ATP and evade death:

Step 1: Because they need such enormous amounts of glucose, they upregulate expression of the glucose transporters that have the highest affinity for glucose, as well as “overexpressing” the transporters with a lower affinity, to ensure they can get the glucose, regardless of whether blood sugar levels are high, low, or anywhere in between.

Step 2: Because they have to use all that glucose, mostly without the aid of mitochondria, they shift to the hexokinase 2 enzyme, which allows them to ramp up glycolysis by orders of magnitude. 

  • “At the genetic level the tumor cell adapts metabolically by first increasing the gene copy number of Type II hexokinase. The enzyme's gene promoter, in turn, shows a wide promiscuity toward the signal transduction cascades active within tumor cells. It is activated by glucose, insulin, low oxygen 'hypoxic' conditions…” (Mathupala, Rempel, Pedersen, 1997)
  • “In an ingenious example of the cancer cell’s efficiency in sustaining its own life long enough to proliferate and metastasize, it instructs the binding of HK II to VDAC (and likely other proteins) for another purpose. This is to inhibit mitochondrial-induced apoptosis and suppress cell death.” (Mathupala, Ko, Pedersen, 2006)
  • These crucial features present a genetic survival mechanism in these malignant tumors which enable them to overexpress hexokinase II under 'any' adverse physiological or metabolic condition, in order to scavenge glucose from the host’s systemic circulation for the tumor’s benefit.” (Mathupala, Ko, Pedersen, 2010)

Step 3: Cancer cells upregulate the expression of monocarboxylate transporters, in order get rid of the huge amounts of lactic acid they produce as a result of the massive fermentation. (Recall that exporting this lactic acid prevents the cancer cells, themselves, from being “poisoned” by acidity, but the acidity outside the cancer cells is part of what weakens that surrounding environment and primes it to be invaded, thus facilitating metastasis.)

Step 4: Production of additional enzymes involved in glucose metabolism is upregulated, and regulatory mechanisms involved in cellular senescence and apoptosis are bypassed. 


Let’s get back to thinking of these super-elevated levels of glycolysis and fermentation as “primitive.” They are metabolic pathways used by less advanced organisms, including some that lack mitochondria. As we’ve discussed, there are several different versions of most of these enzymes (called “isoforms,” “isoenzymes,” or “isozymes”). Nature really never has a single point of failure. When conditions inside a cell are such that the cell “needs” much more glucose than normal, different isoforms exist in order make sure the cell gets that amount of glucose:

  • “Most tumors ‘switch’ to the fetal type isoforms of these enzymes. These in turn enable the tumor to maximize its ability to harness and channel key metabolites at the expense of surrounding tissues, which commonly express the ‘adult’ or ‘differentiated’ types of isoforms that are usually subjected to feedback regulation at the enzyme level (or their gene expression patterns are tightly regulated by the physiological condition of the tumor bearing host). Thus, by shifting to the fetal isoforms, the tumors bypass many of the biochemical constraints that regulate metabolism, in order to maximize their survival at great expense to the host.” (Mathupala, Ko, Pedersen, 2010)


HORMESIS


  
Here’s the deal: Cancer cells think they’re doing something good. They’re staying alive, even in the face of very grave metabolic challenges. We can think of this as a kind of hormesis. Those of you who are steeped in ancestral health know exactly what I’m talking about. For those of you who have never heard the term hormesis, it means an adaptation to some kind of input, sometimes referred to as a “stressor,” but really, just an input. A helpful way to think of hormesis is with the phrase, "That which does not kill you makes you stronger." Generally speaking, but not always, hormetic adaptations make an organism stronger -- that is, better equipped to survive [and maybe even thrive] in the face of fluctuations and/or disruptions in its environment and received inputs. (The nerds among you who eat this stuff for breakfast will recognize this along the lines of the concept of antifragility, as introduced by Nassim N. Taleb. I say that with love; I'm a giant nerd, myself!)  For example, calluses forming on the hands of weightlifters is a hormetic response: after repeated micro-injury to the skin from the friction of the weight rubbing against it, the skin hardens and forms a callus to protect itself from further damage. In a way, obesity resulting from chronic insulin & blood glucose dysregulation can be seen as a hormetic response: rather than exposing itself to the disastrous effects of permanently elevated blood glucose, the body protects itself by sequestering some of that glucose in the form of triglyceride, which it stores so kindly & thoughtfully for us in our adipose tissue. (Thats body fat, to you novices out there. So the next time youre standing in front of a mirror, cursing your love handles, double chin, or thunder thighs, reframe your perspective and be grateful to your body for working exactly the way its supposed to.) 

So with cancer, instead of metabolically struggling cells giving up and starving to death, they go the opposite way and ramp up ways to survive even in the face of such difficult circumstances. Extra-high levels of glycolysis and fermentation are not normal. Abnormally excessive employment of these pathways is a backup, relied upon in a time of crisis, and if broken mitochondria isn’t one of the biggest crises a cell can face, I don’t know what is.

Okay. I think I’ve made the point now about the biochemical alterations observed in cancer cells being a protective mechanism. Before we get into the higher level potential causes of cancer (that is, the things that are actually damaging the mitochondria and compromising cellular respiration in the first place), let’s look at some general states that influence the shift to some of these “fetal”-type enzymes that are, in their weird way, protecting the cells from starving to death:

  • “Reduced respiratory capacity could arise from damage to any mitochondrial protein, lipid or mtDNA [mitochondrial DNA]. Some of the many unspecific conditions that can diminish a cell’s respiratory capacity thus initiating carcinogenesis include inflammation, carcinogens, radiation (ionizing or ultraviolet), intermittent hypoxia, rare germline mutations, viral infections and age.” (Seyfried, et al., 2014)  

  • “The enzymes that catalyze the already high glycolytic rate are themselves not dependent directly on oxygen. In fact, the genes that encode them are activated by hypoxic conditions. Thus, evidence that a given tumor exhibits the 'Warburg effect' is also evidence that the same tumor is likely to survive longer (not necessarily grow) when oxygen is either limiting or absent (hypoxic or anoxic conditions).” (Pedersen, 2007) 

  • “…promoter region [of HK-2] indicated that it is up-regulated by glucose, insulin, glucagon, and by pathways for both protein kinase A and protein kinase C. The activation of the promoter by both insulin and glucagon, which are normally opposing hormones, reveals its promiscuous nature, which for survival purposes may help tumors maintain an enhanced glucose catabolic rate regardless of the host's nutritional status.” (Mathupala, Rempel, Pedersen, 1997)

So both insulin and glucagon can influence a transition to these ramped-up glycolytic pathways. This is all pretty fascinating to me. (What can I say…I don’t get out much.) This should also give us more clues as to why—as I’ve hinted at in previous posts—a ketogenic diet, by itself, is not enough to kill cancer cells. When blood glucose is high (triggering insulin), these changes can occur. And when blood glucose is low (triggering glucagon), these changes can occur. And remember, the GLUT isoforms cancer cells express more of than healthy cells are the ones that are designed to suck up glucose even when blood glucose is low-ish. So eating tons of carbohydrate definitely feeds cancer, but cutting back doesn't automatically starve it. To use the high-level technical explanation here: you’re damned if you do, and damned if you don’t.


HYPOXIA


We haven’t touched much on the hypoxia issue yet. (For anyone who has never seen that word before, hypoxia means low oxygen.) We will talk more about it in the next couple of posts, but I have to confess, my understanding of it is nowhere near as solid as the other concepts we’ve covered so far. (How much do you think I would have to pay Dom D’Agostino to write a guest post for me? Hehheh.) For now, let me just point out that one of the reasons hypoxia reduces mitochondrial respiratory capacity is that oxygen is required for proper functioning of the electron transport system (which is, remember, the way ATP is generated in the inner mitochondrial membrane). Oxygen is known as “the final electron acceptor” in the ETS. No oxygen, no ETS.

Why might a cell be struggling to get sufficient oxygen? Probably lots of reasons, some of which have nothing to do with how much or how deeply the host (i.e., the person) is breathing. (Although I do think this plays into things. More on this in a future post.) We’re not so much talking about someone taking in enough oxygen by breathing, but rather, about the oxygenation of tissue—the efficiency and effectiveness of the blood delivering oxygen to cells.

After all: remember, glycolysis and fermentation are anaerobic pathways. They do not require oxygen. So it makes total sense that if a cell is hypoxic, it has no choice but to upregulate these primitive anaerobic pathways, instead of using the mitochondria, which must have oxygen. And the influence of oxygen on cancer cells underlies hyperbaric oxygen treatment, which is showing extraordinary promise as an adjunct to a ketogenic diet and conventional cancer therapy.


Well, folks, we’re almost in the home stretch! In the next few posts, we’ll cover some potential causes of these malignant changes to mitochondria, and once we do that, we’ll be able to think about treatment and potential prevention strategies.  



Continue to the next post in the series: Speculation on the Causes of Cancer (Pt.1)





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.

6 comments:

  1. Thanks for another great post Amy. I had no idea about glucagon being involved in the transition to the ramped-up glycolytic pathways. Waiting with baited-breath for the next post

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  2. Thanks, Amy - this has been a great series. I have learned from every new post.

    Regarding cancer as an "evolutionarily conserved protective mechanism", I am still not clear on the ways in which the cellular processes that run amok in cancer make the entire evolutionarily selected animal (e.g. homo sapiens) more resilient. I don't see how the spectacular resilience of cancer cells and tumors confers any reproductive/evolutionary advantage to our species. I still see cancer susceptibility as something that remains in the gene pool because it generally affects older individuals who have already reproduced. Am I missing something?

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    2. Good question, Marc. I should have clarified a bit in the post. When I say cancer is a protective mechanism, I mean it for the individual cells themselves, and then, eventually, for tumors as a whole. The changes that a cell undergoes when it becomes cancerous are the cell's way of keeping itself alive, right? But it's like a parasite -- it keeps itself alive in the short term, but over the long-term, it's done *at the expense of the host.* Obviously, once cancer cells are widespread enough, and tumors big enough, the changes that at first were beneficial for those cells become detrimental, because eventually, the host will die, and therefore, so will the cancer cells.

      So you're right -- I think cancer is an adaptation at the *cellular* level, but in the long term, at the level of the whole *organism,* it's a disaster. It makes individual cells more resilient, but how smart a strategy is it when, in the end, they kill the person *supplying* them with all that glucose? Definitely not a reproductive advantage on a macro level.

      As for cancer being primarily a disease of older people, I disagree a little. (Going to talk about this in the next post or two. Toddlers & teenagers get cancer, too. Maybe not as commonly as older people -- older people have been subject to more years of environmental & metabolic assaults, after all, but younger people, unfortunately, are no more immune than the aged. And I think there are probably many different things potentially causing cancer, and the causes might be different in these population groups.)

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    3. Thanks for the clarifications, Amy.

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  3. Puzzled.
    If cancer cells can effectively scavenge glucose, even at low blood glucose levels then why does ketogenic dieting work at all. More puzzling is why Seyfried says explicitly in his book that only a small number of low glucose/high ketone level days per year will work to stave off cancer if you don't already have it.

    Have to read on I guess. Fascinating.

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