Metabolic Theory of Cancer: Speculation on the Causes of Cancer -- in addition to 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 dorsum through the spider web log archives, I saw that the previous post inwards this serial on the metabolic theory of cancer was published on June 1, 2015. Yes, kids, it’s been a year. H5N1 total year! An entire yr to the day. If you lot have got been waiting in addition to waiting (and waiting!) for me to acquire dorsum to this in addition to address some substitution concepts nosotros haven’t gotten to yet, believe me, nobody wanted me to acquire dorsum to this to a greater extent than than I did. I absolutely did not innovation on it taking a year. But alas. Hopefully, inwards that time, you’ve learned a thing or 2 nearly insulin, stubborn obese loss, in addition to the utilisation of other neurological conditions. In fact, I am inwards the procedure of adding a novel installment to the “ITIS/It’s the Insulin, Stupid” series, but when I saw that I was coming upwards on the one-year anniversary of neglecting the cancer series, I knew I had to acquire my raise inwards gear in addition to merely DO IT. I genuinely wanted to do the insulin postal service first, but considering the date, I sentiment it would live apropos for me to do this 1 instead.

Also, merely to allow you lot know, since the writing of that in conclusion post, I have got had the respect of coming together Drs. Seyfried, D’Agostino, in addition to Poff inwards person. {Squee!!} I also got to encounter Dr. Cunnane, Dr. Newport, Dr. Rho, in addition to Dr. Maffetone. Holy moly…it was a nonstop conference of metabolism rock stars.

I am most definitely going to acquire to the mamma-jamma, granddaddy of all topics we’ve been waiting for inwards this cancer series—the ketogenic diet—but delight live patient. I’ve real latterly had to a greater extent than piece of work materials come upwards up (in a expert way), in addition to I am feeling a flake overwhelmed. I will write nearly ketosis. I can’t hope when, exactly, that volition happen, but I hope it won’t have got a year. (Maybe merely a twain weeks, considering I’m already working on it.) ;-)

If you’re novel to my spider web log in addition to have got no sentiment what’s going on correct now, the serial I’ve written on the metabolic theory of cancer is a “fan favorite” – at least, with the people who similar to geek out on the scientific discipline with me. The cancer serial is representative of when my spider web log becomes a gratuitous course of didactics inwards (very basic) biochemistry in addition to physiology, in addition to is peppered with links in addition to quotes from the scientific literature. If you lot prefer casual-type posts, no prob! Whatever floats your boat. But for those of you lot who demand to kill lots of fourth dimension at your desk job, or who maybe demand aid falling asleep, you lot mightiness desire to start way dorsum at the offset in addition to piece of work your way toward today’s post. (Actually, that’s sarcasm. The truth is, I think this materials is fascinating, in addition to maybe some of my best work. I swear, that hexokinase 2 stuff STILL blows my mind.)

Since it has been a yr (!!) since the in conclusion installment, I’ll acquire inwards slow for you lot in addition to listing all the posts inwards order, from foremost to most recent:

Buckle upwards in addition to hang on tight, everyone. HERE WE GO!

Up today: HYPOXIA

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

Before nosotros start dissecting this, allow me say upfront that at that topographic point are far to a greater extent than questions than answers when it comes to hypoxia in addition to cancer. I for sure don’t have got whatsoever answers. All I have got is a lot of speculation, some of it educated, some of it non so much. I’m going to do a lot of speculating inwards this postal service in addition to the next, but inwards each case, I volition explicate my logic in addition to you lot tin create upwards one's hear for yourself if whatsoever of it makes sense. Honestly, I wanted to pass a lot to a greater extent than fourth dimension reading nearly hypoxia in addition to cancer, but if I did that, it might’ve been another yr earlier I got around to this post. So instead of keeping you lot waiting merely so I could include links to to a greater extent than cool papers, you’ll merely have got to dig around for those yourself.

HYPOXIA

Hypoxia way “low oxygen.” It doesn’t hateful no oxygen, merely low. (No oxygen would live anoxia.) And what is the instance nosotros have got been edifice all along? Cancer is primarily a metabolic status driven past times mitochondria that are dysfunctional, insufficient inwards number, or both. And what do nosotros know nearly mitochondria?

In fellowship to generate ATP—which is the principal (if non only) business office of mitochondria—these organelles require oxygen. Recall that, inwards the absence of oxygen, glucose tin live metabolized inwards the cytoplasm. This happens via glycolysis, which is an anaerobic process (i.e., it does non require oxygen). In the absence (or insufficiency) of oxygen, the halt production of glycolysis—pyruvate—will live fermented into lactate, as nosotros covered here. On the other hand, if oxygen is present, in addition to nosotros also have got good for you lot mitochondria, so the pyruvate gets converted to acetyl-CoA in addition to enters the Krebs cycle, in addition to the halt final result is that, via the electron carry chain (which does require oxygen), much to a greater extent than ATP will live generated. (As nosotros discussed inwards particular here.)

HOWEVER: Recall that the well-known “Warburg effect,” which is 1 of the hallmarks of many cancer cells, is fermentation even inwards the presence of oxygen. (Normal amounts of oxygen, we’ll assume.) So the foremost dot I’d similar to brand is, cancer cells are non e'er hypoxic. Solid-mass tumors are non e'er hypoxic. There could live plenty of oxygen reaching the cells, but because the mitochondria are malfunctioning, they can’t use it. So the cells deed as if they’re hypoxic.

BUT: some cancer cells in addition to tumors are hypoxic.

SO: my enquiry is, which comes first: do cells/tissues move hypoxic, thus triggering metabolic changes within the jail cellular telephone in addition to “forcing” the jail cellular telephone into glycolysis & fermentation, or do the mitochondria malfunction first, in addition to since malfunctioning mitochondria cannot utilize oxygen, the jail cellular telephone thinks its hypoxic, fifty-fifty though at that topographic point mightiness live plenty of oxygen available?

Is it depression oxygen (hypoxia), or is at that topographic point 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 in addition to ketones. (The oxidative phosphorylation that eventually converts fats in addition to ketones into ATP is an aerobic process—i.e., it requires oxygen.) And because they can’t metabolize fats in addition to ketones, inwards fellowship to remain live (which they desire to do…it’s sort of cancer cells’ whole raison d’etre), they must—must—revert to the to a greater extent than “primitive” anaerobic metabolic pathways of glycolysis in addition to fermentation.

I’m bespeak the enquiry because I don’t know the answer. It’s in all probability both: maybe inwards some cases, tissue is poorly oxygenated, resulting inwards an upregulation of pathways that are meant to boot inwards during times of depression oxygen, in addition to inwards other cases, due to mitochondrial dysfunction, fifty-fifty when at that topographic point is plenty oxygen present, the glycolytic in addition to fermentative pathways boot inwards because the jail cellular telephone 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 in addition to fermentative pathways that boot inwards during hypoxia are totally normal in addition to good for you lot parts of human physiology. For example, during real intense exercise, the torso can’t render plenty oxygen chop-chop plenty to fuel the working muscles, so rather than using lots of obese acids (requiring oxygen) to fuel that activity, it’s fueled to a greater extent than past times glucose (oxygen non required). And a bunch of that glucose is going to acquire fermented into lactate. This happens—as it’s supposed to—during acute/transient hypoxia. The deviation betwixt this in addition to cancer is, during exercise, equally presently equally you lot stop working so difficult in addition to have got a rest—even merely for a minute—the fermentation stops (because sufficient oxygen tin instantly achieve the musculus cells). In cancer, equally nosotros know, the fermentation doesn’t stop, because the hypoxia is not shrewd in addition to transient.

Always move on inwards mind: the human torso is damn smart, damn adaptable, in addition to hell-bent on staying alive. Many of the modern chronic illnesses nosotros reckon involve physiological in addition to biochemical processes that are genuinely perfectly expert in addition to protective—under the appropriate circumstances. (Ex: insulin resistance; non-alcoholic obese liver.) These processes may have got been lifesaving during the environmental in addition to dietary atmospheric condition nether which they were shaped. In the confront of the modern lifestyle in addition to nutritional inputs (or lack thereof), however, they are quite literally killing us.

Second: When I say the glycolytic in addition to fermentative pathways “kick in,” what I hateful is, they have signals via the cellular surround that tell them to acquire inwards gear. These signals could live enzymes, proteins, or other “stuff” that gets turned on or off nether sure atmospheric condition (such equally hypoxia). Depending on the status present, dissimilar enzymes in addition to pathways volition live upregulated. For example: hypoxia induces signaling molecules called hypoxia-inducible factors. (There are a few dissimilar ones, so I’ll merely lump them together equally HIFs.) This is pretty straightforward: hypoxia induces hypoxia-inducible factors (obviously), in addition to HIFs trigger other changes within the cell—specifically, changes that get upwards or upregulate metabolic pathways that flourish nether depression oxygen.

And instantly that I’ve explained that, nosotros tin brand sense of this:

“Cellular liberate energy metabolism is intricately linked to the oxygenation status of the tissue. When oxygen is readily available, normal cells make upwards to xc per centum of their ATP past times mitochondrial respiration. When oxygen availability becomes limited, such equally inwards the exercising muscle, cells convert to using anaerobic fermentation to save ATP production. This metabolic switch sustains cellular business office in addition to promotes survival inwards the confront of transient hypoxia, in addition to its machinery is largely driven past times the HIF-1 transcription factor. HIF-1 enhances the human face of over lx genes, many involved inwards glycolysis in addition to fermentation, angiogenesis, growth, in addition to survival. The aberrant signaling that drives tumor angiogenesis creates young in addition to leaky blood vessels which are unable to adequately perfuse the entire tumor. This leads to the formation of hypoxic regions within the tumor which get upwards the Warburg effect in addition to promote cancer progression, invasion, in addition to metastasis. Tumor hypoxia in addition to HIF-1 signaling are both strongly correlate with aggressive capacity in addition to misfortunate prognosis.” (Poff, Ward, Seyfried, et al., 2015)

In DNA, at that topographic point are sequences that code for specific amino acids, and, therefore, specific proteins, enzymes, hormones, etc. But at that topographic point are also a lot of sequences that don't code for proteins. But that doesn’t hateful they’re at that topographic point for nothing. Was it Einstein who said nature doesn’t play dice? There is no way human deoxyribonucleic acid (or whatsoever other animal’s DNA, for that matter) contains millions of base of operations pairs merely ‘cuz. They are at that topographic point for a reason. Most likely, those are the “switches” – the bits encoded to flip on or off in addition to thereby ship signals/instructions to the jail cellular telephone inwards response to the biochemical environment. (This is what nosotros hateful when nosotros say “genetics loads the gun, but surround pulls the trigger.” Our deoxyribonucleic acid is encoded a sure way, handed downwardly from our parents, but the way those genes are expressed depends on the cellular environment—low oxygen, likewise much glucose, non plenty testosterone, etc.)

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

“The enzymes that catalyze the already high glycolytic charge per unit of measurement are themselves non subject straight on oxygen. In fact, the genes that encode them are activated past times hypoxic conditions. Thus, bear witness that a given tumor exhibits the ‘Warburg effect’ is also bear witness that the same tumor is probable to live longer (not necessarily grow) when oxygen is either limiting or absent (hypoxic or anoxic conditions).” (Pedersen, 2007)

“Significantly, non only are both pyruvate kinase (PK) in addition to lactate dehydrogenase (LDH) up-regulated past times hypoxia (HIF-1) (and thus tin channel the glycolytic cascade toward lactate), pyruvate dehydrogenase kinase (PDK), a substitution modulator of pyruvate dehydrogenase complex action (PDH), which serves equally the gatekeeper for entry of pyruvate into mitochondria), is also upregulated past times hypoxia. Thus, HIF-1 mediated effects deed inwards a synergistic fashion to veer the glycolytic cascade towards lactate generation.” (Mathupala, Ko, Pedersen, 2010)

Just so you lot tin sympathise all that: lactate dehydrogenase converts pyruvate to lactate (fermentation); pyruvate kinase is involved inwards the terminal footstep of glycolysis; pyruvate dehydrogenase kinase inhibits the pyruvate dehydrogenase complex, with the pyruvate dehydrogenase complex beingness what converts pyruvate to acetyl-CoA inwards the mitochondria. SO: hypoxia (via HIF-1) signals the jail cellular telephone to upregulate glycolysis in addition to fermentation, in addition to inhibits the formation of acetyl-CoA, which is required to move on the Krebs wheel humming along in addition to mitochondrial liberate energy production running smoothly.

It’s sort of a self-perpetuating brutal cycle: “Human cells tend to have got a substantial gap betwixt ATP demand in addition to render during chronic hypoxia, which would inevitably Pb to increased uptake of glucose in addition to accumulation of its metabolites.” (Zhang, Cao, Toole, Xu, 2015)

We know this, right? That’s what this whole serial has been about: the gap betwixt ATP render in addition to demand. Healthy mitochondria generating liberate energy through oxidative phosphorylation (OxPhos) make way more ATP than glycolysis does. But because cancer cells don’t have good for you lot mitochondria, they have got to rely much to a greater extent than (not exclusively, but much more) on glycolysis, which produces very little ATP inwards comparison. And because so much less ATP is generated per unit of measurement of glucose via glycolysis than via OxPhos, cancer cells require a truckload of glucose. So much glucose that they volition “steal” the fuel for themselves, siphoning it away from good for you lot tissue, which is component subdivision of what causes cachexia, or the whole-body “wasting” many cancer patients experience. Basically, the cancer cells remain live at the expense of the host. (Recall nosotros talked nearly this when nosotros looked at cancer equally an evolutionarily conserved arrangement intended to move on cells live during times of physiologic stress.) And yes, the cancer volition eventually kill the host, but cancer cells don’t much tending nearly that. It’s sort of similar a parasite: it wants to remain live in addition to reproduce, in addition to the fact that it volition eventually choke when it kills its ain host doesn’t genuinely affair to it inwards the curt term.

In fact, banking concern correspond out the championship of the paper I got that “gap betwixt ATP demand in addition to supply” quote from: Cancer may live a pathway to jail cellular telephone survival nether persistent hypoxia in addition to elevated ROS: a model for solid-cancer initiation in addition to early on development.

A pathway to jail cellular telephone survival. Indeed.

Do you lot shout out back the ultra-fascinating, blow-your-mind materials nosotros learned nearly hexokinase II (HK2)? Nutshell version to remind you: HK2 is an isoform of an enzyme involved inwards glycolysis, in addition to it is upregulated inwards many types of cancer cells. For reasons I explained inwards particular inwards that post, HK2 facilitates the metabolism of way to a greater extent than glucose than other forms of this enzyme. Other forms of hexokinase acquire a “shut off” signal when the halt products of glycolysis start edifice up. HK2 does not acquire this signal, so it feeds glucose through the arrangement nonstop, thus allowing cancer to grow similar crazy. (It also plays a role inwards preventing apoptosis, but that is for some other time.)

With that inwards mind: There is “a latterly discovered chemical constituent that responds to hypoxia. Analysis of the Type II hexokinase promoter nether hypoxic atmospheric condition also indicated upregulation.” (Mathupala, Rempel, Pedersen, 1997) (The “promoter” mightiness live a non-protein coding deoxyribonucleic acid sequence triggering the transcription in addition to translation of deoxyribonucleic acid that codes for HK2, in addition to equally the authors stated, it is upregulated past times hypoxia.)

Chicken or the Egg?

My large enquiry is still, which comes first: hypoxia, or mitochondrial dysfunction? Does insufficient oxygen drive the mitochondria to malfunction (since they require oxygen to convert fuel substrates to ATP), or do the mitochondria move dysfunctional first, in addition to equally a consequence, whether there’s sufficient oxygen or not, the mitochondria can’t utilisation it, in addition to the jail cellular telephone acts equally if it’s hypoxic? (Again, maybe it’s both.)

Let’s line upwards a few to a greater extent than snazzy quotes regarding the role of hypoxia inwards instigating or exacerbating cancer, in addition to so we’ve got a minefield of additional unanswered questions in addition to wild speculation on my component subdivision to wade through:

“The intracellular consequences of decreased oxygen grade (hypoxia) inwards 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 final result of decreased oxygen. But this side past times side 1 says that the HIFs aid cancer cells adapt to oxygen in addition to food deprivation fifty-fifty nether NORMOXIC atmospheric condition (that is, normal oxygen):

“Accumulating lines of experimental bear witness have got revealed that hypoxia-inducible factors, HIF-1α in addition to HIF-2α, are substitution regulators of the adaptation of cancer- in addition to metastasis-initiating cells in addition to their differentiated progenies to oxygen in addition to food deprivation during cancer progression nether normoxic in addition to hypoxic conditions.” (Ibid)

Since I am fairly iffy on the details of hypoxia, I conferred with Raphi Sirt, whom some of you lot mightiness recognize from diverse forums, other blogs (the 2nd postal service inwards this series that angiogenesis is the creation of novel blood vessels. It should live obvious past times instantly what the purpose of tumors creating novel blood vessels would be: past times having their ain blood vessels so unopen at hand, they tin acquire to a greater extent than of what blood delivers: glucose. (And other nutrients, in addition to oxygen, but we’ll acquire to that inwards a minute.)

So, inwards theory, a cancer patient would have got anti-angiogenic drugs with the intent to trim back the tumor’s blood supply. But the authors of this newspaper are maxim these drugs could “promote the aggressive conduct of cancer cells.” What gives?!

Well, similar so much inwards modern medicine, this tin backfire. “Unintended consequences,” in addition to all that. It’s similar antibiotic resistance: some of the cancer cells volition adapt to the reduced blood period of time (and reduced glucose in addition to oxygen) past times increasing those hypoxia-inducible factors in addition to thus continuing to perpetuate their ain existence. So, where nosotros instantly have got “superbugs” inwards damage of bacteria that are drug-resistant, nosotros would run the run a jeopardy of having “super cancer cells” that are non susceptible to something that mightiness otherwise kill them. Some of the cancer cells would in all probability die, but what nearly the ones that genuinely acquire stronger? (Or, non genuinely acquire “stronger,” but adapt to the insult/challenge nosotros threw at them.)

We’ve got a bunch to a greater extent than to cover, but earlier nosotros movement on to my wild speculation, banking concern correspond out this chart. Because of the multiple, complex, overlapping in addition to interacting factors involved inwards the crazy, weird, wily beast that is cancer, at that topographic point are few charts that don’t hold back similar this inwards trying to explicate cause, effect, in addition to feedback loops. In fact, with most of the arrows going inwards merely 1 direction, this is genuinely 1 of the simpler ones I’ve seen.

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

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

I don’t know, in addition to no 1 else has figured it out yet, either, but at that topographic point are some damn bright people doing their best, in addition to coming upwards with some pretty fascinating avenues to explore.

This postal service has been to a greater extent than than long enough, particularly since it was our foremost foray dorsum into this cloth since in conclusion year. So rather than brand this longer, I’ll cutting it off hither in addition to we’ll choice upwards side past times side fourth dimension with 2 large issues:

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

Continue to part 2 on hypoxia here.

Disclaimer: Amy Berger, MS, CNS, NTP, is non a Dr. in addition to , LLC, is non a medical practice. The data contained on this site is non intended to diagnose, treat, cure, or foreclose whatsoever medical status in addition to is non to live used equally a substitute for the tending in addition to guidance of a physician. Links inwards this postal service in addition to all others may direct you lot to amazon.com, where I volition have a minor amount of the purchase cost of whatsoever items you lot purchase through my affiliate links.

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

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