Metabolic Theory of Cancer: Speculation on the Causes of Cancer -- and How to Mitigate Them (Pt.5A)

Graphic adapted from Seyfried et al., 2015

OH. EM. GEE!!!!!

It’s baaa-aaaaack!

Today is June 1, 2016. Looking back through the blog archives, I saw that the previous post in this series on the metabolic theory of cancer was published on June 1, 2015. Yes, kids, it’s been a year. A full year! An entire year to the day. If you have been waiting and waiting (and waiting!) for me to get back to this and address some key concepts we haven’t gotten to yet, believe me, nobody wanted me to get back to this more than I did. I absolutely did not plan on it taking a year. But alas. Hopefully, in that time, you’ve learned a thing or two about insulin, stubborn fat loss, and the use of ketogenic diets for Alzheimer’s disease and other neurological conditions. In fact, I am in the process of adding a new installment to the “ITIS/It’s the Insulin, Stupid” series, but when I saw that I was coming up on the one-year anniversary of neglecting the cancer series, I knew I had to get my rear in gear and just DO IT. I really wanted to do the insulin post first, but considering the date, I thought it would be apropos for me to do this one instead.

Also, just to let you know, since the writing of that last post, I have had the honor of meeting Drs. Seyfried, D’Agostino, and Poff in person. {Squee!!}  I also got to meet Dr. Cunnane, Dr. Newport, Dr. Rho, and Dr. Maffetone. Holy moly…it was a nonstop conference of metabolism rock stars.

I am most definitely going to get to the mamma-jamma, granddaddy of all topics we’ve been waiting for in this cancer series—the ketogenic diet—but please be patient. I’ve very recently had more work stuff come up (in a good way), and I am feeling a bit overwhelmed. I will write about ketosis. I can’t promise when, exactly, that will happen, but I promise it won’t take a year. (Maybe just a couple weeks, considering I’m already working on it.)  ;-)

If you’re new to my blog and have no idea what’s going on right now, the series I’ve written on the metabolic theory of cancer is a “fan favorite” – at least, among the people who like to geek out on the science with me. The cancer series is representative of when my blog becomes a free course in (very basic) biochemistry and physiology, and is peppered with links and quotes from the scientific literature. If you prefer my rants, shakedowns of food labels, and other casual-type posts, no prob! Whatever floats your boat. But for those of you who need to kill lots of time at your desk job, or who perhaps need help falling asleep, you might want to start way back at the beginning and work your way toward today’s post. (Actually, that’s sarcasm. The truth is, I think this stuff is fascinating, and perhaps some of my best work. I swear, that hexokinase 2 stuff STILL blows my mind.)

Since it has been a year (!!) since the last installment, I’ll make it easy for you and list all the posts in order, from first to most recent: 

1. Introduction
2. Cells Behaving Badly
3. Cellular Energy Generation 1 - Glycolysis
4. Cellular Energy Generation 2 - Mighty Mitochondria (Krebs Cycle, Electron Transport Chain)
5. Mitochondrial Dysfunction 1
6. Mitochondrial Dysfunction 2 - They ARE Broken
7. Glycolysis Run Amok & Mutant Hexokinase
8. Aerobic Fermentation (a.k.a. "The Warburg Effect")
9. Cancer Cells are Sugar Junkies
10. Mutations vs. Mitochondria
11. Cancer as a Protective Mechanism
12. Speculation on the Causes of Cancer (Pt.1)
13. Video Lesson! (Thomas Seyfried, PhD)
14. Speculation on the Causes of Cancer -- and How to Mitigate Risk (Pt.2)
15. Speculation on the Causes of Cancer -- and How to Mitigate Them (Pt.3 - Viruses)
16. Speculation on the Causes of Cancer -- and How to Mitigate Them (Pt.4 - Carcinogens)

Buckle up and hang on tight, everyone. HERE WE GO!

Up today: HYPOXIA

“Insufficient tissue oxygenation, or hypoxia, contributes to tumor aggressiveness and has a profound impact on clinical outcomes in cancer patients.” (Wigerup, Påhlman, Bexell, 2016)

Before we start dissecting this, let me say upfront that there are far more questions than answers when it comes to hypoxia and cancer. I certainly don’t have any answers. All I have is a lot of speculation, some of it educated, some of it not so much. I’m going to do a lot of speculating in this post and the next, but in each case, I will explain my logic and you can decide for yourself if any of it makes sense. Honestly, I wanted to spend a lot more time reading about hypoxia and cancer, but if I did that, it might’ve been another year before I got around to this post. So instead of keeping you waiting just so I could include links to more cool papers, you’ll just have to dig around for those yourself.

HYPOXIA

Hypoxia means “low oxygen.” It doesn’t mean no oxygen, just low. (No oxygen would be anoxia.) And what is the case we have been building all along? Cancer is primarily a metabolic condition driven by mitochondria that are dysfunctional, insufficient in number, or both. And what do we know about mitochondria?

In order to generate ATP—which is the primary (if not only) function of mitochondria—these organelles require oxygen. Recall that, in the absence of oxygen, glucose can be metabolized in the cytoplasm. This happens via glycolysis, which is an anaerobic process (i.e., it does not require oxygen). In the absence (or insufficiency) of oxygen, the end product of glycolysis—pyruvate—will be fermented into lactate, as we covered here. On the other hand, if oxygen is present, and we also have healthy mitochondria, then the pyruvate gets converted to acetyl-CoA and enters the Krebs cycle, and the end result is that, via the electron transport chain (which does require oxygen), much more ATP will be generated. (As we discussed in detail here.)

HOWEVER: Recall that the well-known “Warburg effect,” which is one of the hallmarks of many cancer cells, is fermentation even in the presence of oxygen. (Normal amounts of oxygen, we’ll assume.) So the first point I’d like to make is, cancer cells are not always hypoxic. Solid-mass tumors are not always hypoxic. There could be plenty of oxygen reaching the cells, but because the mitochondria are malfunctioning, they can’t use it. So the cells act as if they’re hypoxic.

BUT: some cancer cells and tumors are hypoxic.

SO: my question is, which comes first:  do cells/tissues become hypoxic, thus triggering metabolic changes inside the cell and “forcing” the cell into glycolysis & fermentation, or do the mitochondria malfunction first, and since malfunctioning mitochondria cannot utilize oxygen, the cell thinks its hypoxic, even though there might be plenty of oxygen available?

Is it low oxygen (hypoxia), or is there plenty of oxygen, but because the mitochondria are damaged, they can’t use it? And because they can’t use the oxygen, they can’t metabolize fats and ketones. (The oxidative phosphorylation that eventually converts fats and ketones into ATP is an aerobic process—i.e., it requires oxygen.) And because they can’t metabolize fats and ketones, in order to stay alive (which they want to do…it’s sort of cancer cells’ whole raison d’etre), they must—must—revert to the more “primitive” anaerobic metabolic pathways of glycolysis and fermentation.

I’m asking the question because I don’t know the answer. It’s probably both: maybe in some cases, tissue is poorly oxygenated, resulting in an upregulation of pathways that are meant to kick in during times of low oxygen, and in other cases, due to mitochondrial dysfunction, even when there is enough oxygen present, the glycolytic and fermentative pathways kick in because the cell thinks it’s hypoxic.

Indeed: In tumor cells, “the downregulation of oxidative metabolism is observed along with an enhanced fermentation despite the presence of oxygen.” (Diaz-Ruiz, Rigoulet, Devin, 2011)

Two points here:

First, these glycolytic and fermentative pathways that kick in during hypoxia are totally normal and healthy parts of human physiology. For example, during very intense exercise, the body can’t supply enough oxygen quickly enough to fuel the working muscles, so rather than using lots of fatty acids (requiring oxygen) to fuel that activity, it’s fueled more by glucose (oxygen not required). And a bunch of that glucose is going to get fermented into lactate. This happens—as it’s supposed to—during acute/transient hypoxia. The difference between this and cancer is, during exercise, as soon as you stop working so hard and take a rest—even just for a minute—the fermentation stops (because sufficient oxygen can now reach the muscle cells). In cancer, as we know, the fermentation doesn’t stop, because the hypoxia is not acute and transient.

Always keep in mind: the human body is damn smart, damn adaptable, and hell-bent on staying alive. Many of the modern chronic illnesses we see involve physiological and biochemical processes that are actually perfectly good and protective—under the appropriate circumstances. (Ex: insulin resistance; non-alcoholic fatty liver.) These processes may have been lifesaving during the environmental and dietary conditions under which they were shaped. In the face of the modern lifestyle and nutritional inputs (or lack thereof), however, they are quite literally killing us.

Second: When I say the glycolytic and fermentative pathways “kick in,” what I mean is, they receive signals via the cellular environment that tell them to get in gear. These signals could be enzymes, proteins, or other “stuff” that gets turned on or off under certain conditions (such as hypoxia). Depending on the condition present, different enzymes and pathways will be upregulated. For example: hypoxia induces signaling molecules called hypoxia-inducible factors. (There are a few different ones, so I’ll just lump them together as HIFs.) This is pretty straightforward: hypoxia induces hypoxia-inducible factors (obviously), and HIFs trigger other changes inside the cell—specifically, changes that enhance or upregulate metabolic pathways that flourish under low oxygen.

And now that I’ve explained that, we can make sense of this:

“Cellular energy metabolism is intricately linked to the oxygenation status of the tissue. When oxygen is readily available, normal cells produce up to 90 percent of their ATP by mitochondrial respiration. When oxygen availability becomes limited, such as in the exercising muscle, cells convert to using anaerobic fermentation to preserve ATP production. This metabolic switch sustains cellular function and promotes survival in the face of transient hypoxia, and its mechanism is largely driven by the HIF-1 transcription factor. HIF-1 enhances the expression of over 60 genes, many involved in glycolysis and fermentation, angiogenesis, growth, and survival. The aberrant signaling that drives tumor angiogenesis creates immature and leaky blood vessels which are unable to adequately perfuse the entire tumor. This leads to the formation of hypoxic regions inside the tumor which enhance the Warburg effect and promote cancer progression, invasion, and metastasis. Tumor hypoxia and HIF-1 signaling are both strongly correlate with aggressive capacity and poor prognosis.” (Poff, Ward, Seyfried, et al., 2015)

In DNA, there are sequences that code for specific amino acids, and, therefore, specific proteins, enzymes, hormones, etc. But there are also a lot of sequences that don't code for proteins. But that doesn’t mean they’re there for nothing. Was it Einstein who said nature doesn’t play dice? There is no way human DNA (or any other animal’s DNA, for that matter) contains millions of base pairs just ‘cuz. They are there for a reason. Most likely, those are the “switches” – the bits encoded to flip on or off and thereby send signals/instructions to the cell in response to the biochemical environment. (This is what we mean when we say “genetics loads the gun, but environment pulls the trigger.” Our DNA is encoded a certain way, handed down from our parents, but the way those genes are expressed depends on the cellular environment—low oxygen, too much glucose, not enough testosterone, etc.)

It seems that HIFs can signal/trigger the production of other molecules, many of which are implicated in carcinogenesis or the progression and worsening of cancer that was already there:

“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)

“Significantly, not only are both pyruvate kinase (PK) and lactate dehydrogenase (LDH) up-regulated by hypoxia (HIF-1) (and thus can channel the glycolytic cascade toward lactate), pyruvate dehydrogenase kinase (PDK), a key modulator of pyruvate dehydrogenase complex activity (PDH), which serves as the gatekeeper for entry of pyruvate into mitochondria), is also upregulated by hypoxia. Thus, HIF-1 mediated effects act in a synergistic manner to veer the glycolytic cascade towards lactate generation.” (Mathupala, Ko, Pedersen, 2010)

Just so you can understand all that: lactate dehydrogenase converts pyruvate to lactate (fermentation); pyruvate kinase is involved in the final step of glycolysis; pyruvate dehydrogenase kinase inhibits the pyruvate dehydrogenase complex, with the pyruvate dehydrogenase complex being what converts pyruvate to acetyl-CoA in the mitochondria. SO: hypoxia (via HIF-1) signals the cell to upregulate glycolysis and fermentation, and inhibits the formation of acetyl-CoA, which is required to keep the Krebs cycle humming along and mitochondrial energy production running smoothly.

It’s sort of a self-perpetuating vicious cycle: “Human cells tend to have a substantial gap between ATP demand and supply during chronic hypoxia, which would inevitably lead to increased uptake of glucose and accumulation of its metabolites.” (Zhang, Cao, Toole, Xu, 2015)

We know this, right? That’s what this whole series has been about: the gap between ATP supply and demand. Healthy mitochondria generating energy through oxidative phosphorylation (OxPhos) produce way more ATP than glycolysis does. But because cancer cells don’t have healthy mitochondria, they have to rely much more (not exclusively, but much more) on glycolysis, which produces very little ATP in comparison. And because so much less ATP is generated per unit of glucose via glycolysis than via OxPhos, cancer cells require a truckload of glucose. So much glucose that they will “steal” the fuel for themselves, siphoning it away from healthy tissue, which is part of what causes cachexia, or the whole-body “wasting” many cancer patients experience. Basically, the cancer cells stay alive at the expense of the host. (Recall we talked about this when we looked at cancer as an evolutionarily conserved system intended to keep cells alive during times of physiologic stress.) And yes, the cancer will eventually kill the host, but cancer cells don’t much care about that. It’s kind of like a parasite: it wants to stay alive and reproduce, and the fact that it will eventually die when it kills its own host doesn’t really matter to it in the short term.

In fact, check out the title of the paper I got that “gap between ATP demand and supply” quote from: Cancer may be a pathway to cell survival under persistent hypoxia and elevated ROS: a model for solid-cancer initiation and early development.

A pathway to cell survival. Indeed.

Do you remember the ultra-fascinating, blow-your-mind stuff we learned about hexokinase II (HK2)? Nutshell version to remind you: HK2 is an isoform of an enzyme involved in glycolysis, and it is upregulated in many types of cancer cells. For reasons I explained in detail in that post, HK2 facilitates the metabolism of way more glucose than other forms of this enzyme. Other forms of hexokinase get a “shut off” signal when the end products of glycolysis start building up. HK2 does not get this signal, so it feeds glucose through the system nonstop, thus allowing cancer to grow like crazy. (It also plays a role in preventing apoptosis, but that is for another time.)

With that in mind: There is “a recently discovered element that responds to hypoxia. Analysis of the Type II hexokinase promoter under hypoxic conditions also indicated upregulation.” (Mathupala, Rempel, Pedersen, 1997) (The “promoter” might be a non-protein coding DNA sequence triggering the transcription and translation of DNA that codes for HK2, and as the authors stated, it is upregulated by hypoxia.)

Chicken or the Egg?

My big question is still, which comes first: hypoxia, or mitochondrial dysfunction? Does insufficient oxygen cause the mitochondria to malfunction (since they require oxygen to convert fuel substrates to ATP), or do the mitochondria become dysfunctional first, and as a consequence, whether there’s sufficient oxygen or not, the mitochondria can’t use it, and the cell acts as if it’s hypoxic? (Again, maybe it’s both.)

Let’s line up a few more snazzy quotes regarding the role of hypoxia in instigating or exacerbating cancer, and then we’ve got a minefield of additional unanswered questions and wild speculation on my part to wade through:

“The intracellular consequences of decreased oxygen level (hypoxia) in cancer cells including the switch of mitochondrial oxidative phosphorylation to anaerobic glycolysis…” (Mimeault & Batra, 2013)

This quote implies that the hypoxia comes first. The switch from mitochondrial OxPhos is the consequence of decreased oxygen. But this next one says that the HIFs help cancer cells adapt to oxygen and nutrient deprivation even under NORMOXIC conditions (that is, normal oxygen):

“Accumulating lines of experimental evidence have revealed that hypoxia-inducible factors, HIF-1α and HIF-2α, are key regulators of the adaptation of cancer- and metastasis-initiating cells and their differentiated progenies to oxygen and nutrient deprivation during cancer progression under normoxic and hypoxic conditions.” (Ibid)

Since I am fairly iffy on the details of hypoxia, I conferred with Raphi Sirt, whom some of you might recognize from various forums, other blogs (such as his own), and Twitter. He’s doing research on cancer and I ran a few things by him to get clarification. According to Raphi, HIF-1α is a “master transcriptional regulator of cellular & developmental response to hypoxia.” It can remain present under normoxia – a condition called “pseudo-hypoxia.” My head is spinning a little. All I know is, this stuff is complicated.

The next one implies that the hypoxia is a result, not a cause, of cancer. (Well, no, they’re not really saying that. They’re just pointing out that hypoxia is present in some tumors and cancerous tissue):

“…rapidly growing tumours are typically characterized by disorganized vasculature with an abnormal leaky and tortuous structure. These rapidly growing tumours also exhibit hypoxic intratumoral regions that did not supply sufficient oxygen and nutrients to cells and require a high adaptation of cancer cells for their survival. It has been shown that changes in the local microenvironment of cancer stem/progenitor cells and their progenies, including the induction of hypoxic intratumoral regions within poorly vascularized tumours, may result in alterations of different gene products that contribute to their acquisition of more aggressive phenotypes and survival advantages.” (Ibid)

Survival advantages.

More aggressive phenotypes.

Indeed: whether hypoxia is a cause or an effect, once it’s a factor, it makes cancer worse by making cancer cells harder to kill.

“Data from clinical trials have revealed that some anti-angiogenic drugs may reduce tumour tissue oxygenation and consequently promote the aggressive behaviour of cancer cells and treatment resistance.” (Ibid)

Woah…

This is actually a pretty big point right here. They mentioned “anti-angiogenic” drugs. Recall from way back in the second post in this series that angiogenesis is the creation of new blood vessels. It should be obvious by now what the purpose of tumors creating new blood vessels would be: by having their own blood vessels so close at hand, they can get more of what blood delivers: glucose. (And other nutrients, and oxygen, but we’ll get to that in a minute.)

So, in theory, a cancer patient would take anti-angiogenic drugs with the intent to reduce the tumor’s blood supply. But the authors of this paper are saying these drugs could “promote the aggressive behavior of cancer cells.” What gives?!

Well, like so much in modern medicine, this can backfire. “Unintended consequences,” and all that. It’s like antibiotic resistance: some of the cancer cells will adapt to the reduced blood flow (and reduced glucose and oxygen) by increasing those hypoxia-inducible factors and therefore continuing to perpetuate their own existence. So, where we now have “superbugs” in terms of bacteria that are drug-resistant, we would run the risk of having “super cancer cells” that are not susceptible to something that might otherwise kill them. Some of the cancer cells would probably die, but what about the ones that actually get stronger? (Or, not really get “stronger,” but adapt to the insult/challenge we threw at them.)

We’ve got a bunch more to cover, but before we move on to my wild speculation, check out this chart. Because of the multiple, complex, overlapping and interacting factors involved in the crazy, weird, wily beast that is cancer, there are few charts that don’t look like this in trying to explain cause, effect, and feedback loops. In fact, with most of the arrows going in just one direction, this is actually one of the simpler ones I’ve seen.

Image from: Mimeault M, Batra SK. Hypoxia-inducing factors as master regulators of stemness properties and altered metabolism of cancer- and metastasis-initiating cells. Journal of Cellular and Molecular Medicine. 2013;17(1):30-54. 

As you can see, hypoxia triggers the HIFs, which in turn signal an enormous cascade of other signaling molecules, most of which we haven’t even touched on (because there’s only so much I can do), but a few of which we have. For example, you can see that HIF upregulates HK2 and GLUTs 1 & 2, which facilitate increased glycolysis. It also upregulates vascular endothelial growth factor (VEGF), which is involved in angiogenesis. Taking all those other scary looking things into account, we come to one conclusion: cancer is the way these deranged cells are trying to keep themselves alive. And they’re doing a damn good job of it. The question—the question with the kazillion-dollar answer—is, how do we get them to stop?

I don’t know, and no one else has figured it out yet, either, but there are some damn brilliant people doing their best, and coming up with some pretty fascinating avenues to explore.

This post has been more than long enough, especially since it was our first foray back into this material since last year. So rather than make this longer, I’ll cut it off here and we’ll pick up next time with two big issues: 

1. Assuming hypoxia is, at least in part, a causal or exacerbating factor in cancer, how does tissue become hypoxic?
2. What is the role of hyperbaric oxygen therapy in combating cancer? (For those of you who’ve never heard of hyperbaric oxygen: “Hyperbaric oxygen therapy [HBOT] is the administration of 100% oxygen at elevated pressure. In vivo, HBOT saturates blood plasma with oxygen, allowing it to diffuse further into the tissues and oxygenate hypoxic tumor regions.” (Poff, Ward, Seyfried, et al., 2015)

Continue to part 2 on hypoxia here.

Disclaimer: Amy Berger, MS, CNS, 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 and is not to be used as a substitute for the care and guidance of a physician. Links in this post and all others may direct you to amazon.com, where I will receive a small amount of the purchase price of any items you buy through my affiliate links.