Metabolic Theory of Cancer: Aerobic Fermentation (a.k.a. "The Warburg Effect")

Did I blow your mind with that mutated hexokinase stuff in the previous post? (To be honest, it blew my mind, when I first read about it. Still does, actually.)

You can see that as we gather more pieces of this puzzle, cancer cells’ voracious appetite for glucose is starting to reveal itself. So is—for lack of a better term— the intelligence of cancer cells. These little buggers are good at doing whatever they need to in order to stay alive, aren’t they? I mean, their mitochondria are broken. But they need fuel. And because the mitochondria are broken, the only fuel they can use successfully is glucose. So they start using this variation of hexokinase in order to make sure that glycolytic metabolism will never stop. Crazy! (Yet ingenious, no?)

As an aside, I have to mention here that cancer seems to be a metabolic condition every bit as much as Alzheimer’s disease is, but they are opposite sides of the same coin: In both conditions, the mitochondria have lost the ability to effectively generate ATP. In Alzheimer’s, the protective mechanism involves cells shutting off the glucose spigot, whereas in cancer, the spigot is turned on full blast and never shuts off.

Last time, we discussed cancer cells ramping up glycolysis in order to feed themselves. And we left off saying that, as a result of this abnormal amount of glycolysis, we have a ton of pyruvate building up. And the fate of this pyruvate, as I’ve mentioned in past posts, is fermentation—an anaerobic process. But cancer cells do something interesting that most healthy cells don’t: they perform incredible amounts of fermentation even in the presence of oxygen.

AEROBIC FERMENTATION

Recall from a note at the very end of the post about glycolysis that normal, healthy cells can and do ferment pyruvate into lactate. However, this mostly occurs when the supply of oxygen to a cell is insufficient, such as in hardworking muscles during intense physical activity. And in these healthy cells, fermentation isn’t the primary energy generation method, nor does it continue after those muscles stop working so hard. In fact, fermentation stops almost as soon as the intense activity stops, and the lactate clears out rapidly.

Let’s see what Dr. Seyfried et al, have to say on the matter:

• “A deficiency in oxidative phosphorylation (OxPhos) energy is responsible for lactate production in most cases. For example, muscle cells significantly increase their metabolic rate during intense exercise and as a result oxygen becomes limiting. The oxygen deficiency causes a lack of energy through OxPhos prompting lactate production in an effort to provide compensatory energy from fermentation.”
• “However…the lactate made by muscle cells during intense exercise falls significantly after oxygen is restored to the muscle tissue.”

The difference for cancer cells is that even when oxygen is present, they ferment like crazy. To distinguish this from a biologically normal amount of fermentation, and also to emphasize that it is abnormal because fermentation usually happens best in an anaerobic environment (that is, without oxygen), it is called aerobic fermentation—a.k.a. “the Warburg effect,” named after Otto Warburg, the scientist who first identified this startling property of cancer cells in the early 1900s. (More on this guy in a bit.)

We’re clear on what’s happening here, right? What distinguishes a cancer cell from a healthy cell is that a cancer cell will perform obscene amounts of fermentation even when there’s plenty of oxygen around. It shouldn’t need to do fermentation. It should be doing OxPhos. It should be using the Krebs cycle. Instead, it’s fermenting all the pyruvate into lactate because it has no choice! If the mitochondria were up to snuff, the pyruvate would be converted to acetyl CoA, and we’d be off to the races making tons of ATP. But because cancer cells DO NOT HAVE HEALTHY MITOCHONDRIA, they must do fermentation, whether oxygen is there or not.

Thus, aerobic fermentation is another of the metabolic hallmarks of cancer cells. 

You might sometimes see the Warburg effect referred to as “aerobic glycolysis,” but that’s not a good description. After all, glycolysis usually happens in the presence of oxygen. That’s normal. (Remember: glycolysis is the first step in harnessing energy from glucose, whether or not oxygen is present. So “aerobic glycolysis” isn’t saying anything special.) Again, I’ll let the experts speak:

• “Although many investigators of tumor cell energy metabolism use the term ‘aerobic glycolysis’ in referring to the Warburg effect, we consider the term ‘aerobic fermentation’ as a more accurate description of the Warburg effect since aerobic glycolysis occurs in most normal cells of the body.” (Seyfried et al, 2014.)

And from a similar group of experts:

• “Although confusion has surrounded Warburg’s hypothesis on the origin of cancer cells, his hypothesis has never been formally disproved and remains a credible explanation for the origin of tumor cells. Consequently, Warburg’s explanation for the origin of cancer can no longer be viewed as a hypothesis, but can now be viewed as a theory.” (Seyfried et al, 2015.)

Okay. Fine. Cancer cells are performing lots & lots of glycolysis, and lots & lots of fermentation. Let’s look at the ramifications of this.

Fermentation:  Pyruvate --> Lactate (lactic ACID)

Fermentation: great for some things; 

for others, not so much.

So we have a lot of lactic acid building up in the body. This extreme buildup of lactic acid is the result of a physiologically abnormal amount of fermentation. The acid is not causing cancer. So let’s get something straight right now:  People don’t get cancer because their bodies are acidic; their bodies are acidic because they are riddled with cancer cells, and because cancer cells have broken mitochondria, they are forced to engage in obscene amounts of fermentation, thus generating overwhelming amounts of lactic acid. 

Systemic acidosis is not a cause of cancer; it is an effect.

This is likely why “alkalinizing” diets are not a cure for cancer. I am sorry for being so crass here, but if your body is overrun with cancerous tissue, you can choke down all the kale and spirulina smoothies you want; you are not going to kill cancer. 

Please note I’m not saying systemic acidosis doesn’t bring negative consequences. (It does. More on this in a minute.) I am saying only that it is a result of cancer, not a cause. (And if you like kale and spirulina, have at ‘em! Just don’t expect them to cure you of cancer, m’kay?)

As an interesting aside, “fatty acid metabolism produces mostly water and CO2, but not lactate.” So a metabolism based on burning fat, rather than glucose, is less likely to generate crazy amounts of lactic acid. Hmmm…… (Let’s keep that little gem in the back of our minds for later, shall we?)

This hints at two things:

1. With all that lactate being produced, we can infer that the predominant fuels for cancer cells are not fatty acids. 
2. If we want to start reducing the acid load in someone’s body, we might think about switching them to a fat-based metabolism. 

See, even though the acidosis is not causing cancer, it’s still harmful for the body—kind of like how a fever is a protective mechanism (the body raises its temperature in order to kill the invading pathogens), but if it goes too high, it can have disastrous effects. So regardless of what’s causing the acidosis, it would be a good thing to restore the body’s proper pH, and since the crazy amount of fermentation is what’s causing the acidosis, switching to a fat-based metabolism kills two birds with one stone: we [presumably] put the brakes on overproducing lactate via fermentation, and we generally don’t produce any more by running on fat. Whoa… (It should not surprise you when I say we’ll come back to this a few posts down the line, when we get to dietary strategies for fighting cancer.)

METASTASIS

Recall from a post a while back that one of the hallmarks of cancer cells is their ability to metastasize—to migrate from their site of origin and invade other organs and tissues. Well, according to people who know way more about this than I do, one of the things that enables/facilitates metastasis is the acidosis resulting from all that fermentation.

If lactate built up endlessly inside a cell, the cell would eventually go kaput. (The acid would eventually "poison" the cell.) So in order to get rid of excess lactate, cells export it via something called monocarboxylate transporters (MCTs, not to be confused with medium-chain triglycerides, the other things that go by the same abbreviation). So, to get rid of all that lactate and keep their own pH at an appropriate level, cancer cells upregulate expression of those MCTs. So we now have lots of lactate building up just outside the cancer cells, poisoning their surrounding environment:

• “This acid (i.e., its low pH) may both protect tumors (that are resistant to it) against attacks by the immune system while inducing negative effects (chemical warfare) on normal surrounding cells, thus preparing them for invasion.” (Pedersen, 2007.)
• The conversion of pyruvate to lactic acid leads to microenvironmental acidosis and facilitates both invasion and metastasis. In addition, lactic acid suppresses the proliferation of and cytokine production by human cytotoxic T lymphocytes and causes a significant decrease in their cytotoxic activity. The latter finding may explain the frequently observed inability of the immune system to control aggressive cancer despite a specific T-cell response against tumour-associated antigens. (Otto et al, 2008)

Man, I told you cancer cells were nasty SOBs. It reminds me of a stampede at Wal-Mart on Black Friday – cancer cells are thinking only about themselves and their own survival – taking care of #1, as they say. They are gonna get what they need, and they don’t care what happens to any other cells. In fact, they will actively harm cells around them in order to make sure their own needs are met. So, correcting the pH outside the tumor isn’t going to kill the cancer cells, but it could reduce their invasiveness & metastasis by making the surrounding environment more robust and more resistant to invasion. And this seems to be the case:

• “Recent reports indicate that neutralizing the low pH of the tumor microenvironment via physiological buffers (in this case bicarbonate) can reduce the invasiveness of tumors and thus minimize the incidence of distant metastases.” (Mathupala et al, 2010.)

Like I said: taking deliberate measures to alkalinize the body isn’t going to cure the cancer, but it might make it harder for it to metastasize. 

Okay, I’m pretty sure everybody’s clear on aerobic fermentation now. Since we’re talking about things happening in the presence of oxygen, let’s look at a couple of other interesting things.

We know cancer cells have dysfunctional mitochondria, right? (Or not enough mitochondria.) So even when a cell has access to plenty of good ol’ oxygen, it’s not going to use it.

Just in case there are any doubters out there, Seyfried and colleagues have the following to say:

• “Lactate production in these [tumor] cells arises as a consequence of abnormal respiration, which can be linked to either the structural defects seen in tumor tissue mitochondria or to reduced number of mitochondria.”
• “Any mitochondrial defect that would uncouple electron transport from OxPhos could reduce respiratory sufficiency and thus contribute to lactate formation or a Warburg effect.” (Remember a while back I said something about “uncoupling proteins” being involved in messing with the electron transport chain. And I confessed that I am woefully unfamiliar with the mechanisms there. Seriously, someone get Bill Lagakos to write a layperson-friendly guest post for my blog! Or Peter, from Hyperlipid! Uncoupling isn’t necessarily a bad thing.)

The oxygen issue is quite interesting. Some cancer cells have plenty of oxygen and just aren’t using it because of their malfunctioning mitochondria, but some are actually hypoxic—meaning, they don’t have enough oxygen. We are going to revisit these things when we talk about potential causes of cancer, as well as new & emerging treatment strategies, one of which calls for introducing hyperbaric oxygen into the body. (Nutshell version: cancer cells can’t use oxygen very well? Let’s bombard ‘em with it! Also: a preview of my wild speculation on prevention/treatment: maybe there's a reason deep breathing is said to be so good for us. Just some food for thought: consider how shallow your average inhalations are throughout the day, unless you are specifically focusing on taking in more air. Again, wild speculation.)

DR. OTTO WARBURG

Before we end things for the day, I said we’d talk a little bit about Dr. Warburg.

According to some of the easily accessible biographical information on him, Warburg was a bit of a weirdo. (Seems like a common thing among brilliant scientists. They dedicate their lives to their research, at the expense of almost any kind of romance, personal life, and human socialization in general. [If you know anything about Nikola Tesla, he is probably the prime example.] But really, we can't blame them. If you spend any time on Facebook or Twitter these days, you’ll see pretty quickly why geniuses have better things to do than mix with the common riffraff here in 2015, and the same was probably true in Warburg’s day.)

Anyway, Warburg certainly had an interesting life. His father was a physicist, and it seems Albert Einstein and Max Planck were regular guests at the Warburg dinner table. Hello!! Also—remember the Krebs cycle—the mechanism that produces ATP inside healthy mitochondria? Well, Dr. Hans Krebs was Warburg’s student!

There’s no denying that Warburg was brilliant. He won a Nobel Prize in 1931, for his research on this cancer/fermentation stuff. But not everyone was so thrilled with him. According to Travis Christofferson, author of the book that inspired this series:

• [Warburg] “had acquired a reputation for his unwavering conviction and belief in his assertions, a trait often perceived as arrogance. Many felt that he was unreasonably stubborn…For sure he did not suffer fools…He knew in his gut that he was right and would be vindicated in the end.”

That description immediately reminded me of Dr. Robert Atkins. Atkins was considered an ornery S.O.B., but that is probably because, with his promotion of a luxurious, high-fat & high-cholesterol diet in the era of rice cakes, fat-free yogurt, and Jane Fonda-style aerobics, he was swimming against a current flowing very strongly in the opposite direction. So too with Warburg. And now, over four decades after Dr. Atkins’ original 1972 book introduced low-carb to the masses, we have thousands of people with vibrant health and wellness, some of whom are maintaining triple-digit weight loss on long-term low-carb diets. Countless people owe their lives—and their quality of life—to Dr. A.

We can only hope that—assuming he was correct—laboratory research, clinical observations, and new therapeutic options for people affected by this devastating condition will give Dr. Warburg’s work the same vindication. 

More exciting stuff on the way. We’re starting to see how much cancer cells love and need their glucose. Coming up next: one more metabolic hallmark of cancer cells: they are sugar junkies. After that, we'll revisit the dueling cancer theories. Now that we've worked so hard to understand the biochemistry involved, we'll be able to see which cancer theory is better supported by the science: DNA mutations, or mitochondrial dysfunction. (And once we answer that, we'll be able to get to the really good stuff: unconventional treatment methods and possible prevention strategies.)

*Continue to the next post: Cancer Cells are Sugar Junkies

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.