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

Okay!

I left off last time saying that we have two big issues to address with regard to hypoxia as a cause or exacerbating factor in cancer: 

1. What causes tissue to become hypoxic?
2. Is there a role for hyperbaric oxygen therapy in fighting cancer?

  

Let’s tackle them in order.

To be honest with you, I still don’t know which comes first: low oxygen, or mitochondrial dysfunction. The fact is, even when there’s plenty of oxygen available, if the mitochondria are malfunctioning, they can’t use it. But what if what’s causing the mitochondria to malfunction is insufficient oxygen? (I told you last time this stuff is complicated!)

It almost doesn’t matter, right? The bottom line is, whether the tissue is hypoxic or not, the mitochondria are not using whatever oxygen might be present. (Well, they’re using some of it. Remember, kids, when it comes to biology and biochemistry, there are very rarely any absolutes, yes or no, on or off. Things aren't binary, but rather, there's a balancing act. Even cancer cells have some mitochondria that are okay; it’s just that the majority of them are messed up.)

I just have a hard time wrapping my head around it all. Think about angiogenesis: the creation of blood vessels specifically so that the cancerous tissue ensures it has a steady supply of fuel and nutrients. But what does blood carry besides fuel and nutrients? OXYGEN. So you would think that angiogenesis would give cancer cells more oxygen, not less. So going one step further, this being the case, it seems like the mitochondrial dysfunction comes first, because theoretically, there should be sufficient oxygen delivery to the cancer cells, what with all those blood vessels they created for their own nefarious purposes. So there is sufficient oxygen (“normoxia”), yet we have hypoxia-inducible factors out the yin-yang upregulating all sorts of nasty pathways and reactions in these cells to keep themselves alive because they think they’re hypoxic. And the reason they think they’re hypoxic is because the mitochondria aren’t using the oxygen. (That’s my logic, anyway. I told you there was going to be a lot of wild speculation here, and so it begins.)

I shared a quote last time that explained why some tumors are truly hypoxic: “…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.” (Mimeault & Batra, 2013)

Rather than go on and on in my weird, circular logic, and not arrive at any answers, let’s move on to something else I can speculate really wildly about. I mentioned last time that I had asked Raphi Sirt a few questions about all this, because I knew he knew more about it than I do. Some of the questions I asked him were—at least in my opinion—somewhat rudimentary. As if I should have already known the answers, but I didn’t. I felt like an idiot asking, but it turns out they were actually very good questions. I was seriously a little embarrassed at what I asked, because I didn’t know if they were silly questions or not. I was really afraid they were. (I even asked if he was laughing at me after reading them.) But here’s Raphi’s response:

“First off, no one’s laughing at you - and if they are, they just haven’t thought about all this as deeply as you have.  :)  The simplest ‘child-like’ questions are the biggies…the ones the best scientists try to answer because although they’re simple to formulate, finding answers to them is incredibly hard.”

So I didn’t come off as a total idiot. Nice!

Among many other details, I asked him about the angiogenesis thing:

Q: If tumors show angiogenesis and increase their blood supply, you would think that would give them more oxygen, not less, right?

A: That’s an astute question. Yes, it has to do with their dysfunctional mitochondria.

I knew it! (So it does look like the mitochondrial dysfunction comes first. At least sometimes. Like I said: no absolutes. Especially not with cancer.)

But then, I asked the question I was most hesitant to ask, because if I was wrong, and my logic was completely ridiculous, then I would really be humiliated. But since I was not humiliated, and Raphi actually saw where I was going—and agreed—I’ll share the whole exchange with you:

Q: Oxygen is delivered primarily (or only) via the blood, right? (And only by us first breathing it in, right?) This might be my dumbest question, but I need to ask, partly because I’m curious on a personal level, but also, again, so I don't make a fool of myself when I write about this: Is there a potential anti-cancer role for activities that (might) increase oxygen in the body in general? Deep breathing, meditation, maybe especially if deep breathing is done outdoors in a wooded/green space? It just strikes me sometimes how shallowly most people breathe all day, especially while just sitting around. We don't take slow, deep breaths unless we’re deliberately focusing on our breath. Most people take very shallow breaths. Plus, being indoors all the time -- of course there's plenty of oxygen indoors, but am I a complete idiot for thinking there might be better oxygenated air in the woods, or someplace where lots of green plants are generating some O₂? I started to wonder a while back whether a possible benefit of meditation/deep breathing—aside from stress relief and just being calm—is actually giving the body more oxygen.  (I wonder the same thing about intense exercise: when you breathe more deeply, plus moving the body and potentially improving circulation, is this a way to get more oxygen to different tissues?) I could be completely wrong about this, which is why I’m asking. (And it’s totally okay for you to laugh at me! These might be really stupid ideas. I don't know, because I've never asked anyone.)  But this would help me understand whether mitochondria become damaged first, so cells & tissues don't need/use as much oxygen, or, is hypoxia, itself, one of the causes of mitochondrial dysfunction? (Meaning, if the cells/tissues have an insufficient oxygen supply, then the mitochondria start to malfunction, because they need a good supply of oxygen to work properly? If this is the case, then I see a role for activities that get more oxygen into the body being helpful, even though we have almost no control over where that oxygen goes inside us.)

A: Again, great question. I hope so! I think it’s a mix of things…I think good breathing is a marker for good health (mental & physical). Being an asthmatic (or I was an asthmatic) I can attest to how important good breathing is to anxiety, strength, mood etc. Any technique that teaches one to correctly pay attention to good breathing is well worth a try in my opinion. Going outdoors in nature is an added, important, benefit for a whole host of reasons. Now, to be concrete: will it prevent, or cure cancer? Hell no :( ….but can or should it be integrated as part of a larger prevention, management or palliative strategy? Hell YES :)

Nice! So my thinking isn’t completely off the mark there. (Or if it is, I’ve got at least one really intelligent person thinking the same way.) Do you understand my logic? This is sort of predicated on two things: keeping mitochondria in working order, and making sure they have enough oxygen. Oxygen comes from green plants. It comes from photosynthesis. I don’t spend anywhere near as much time as I’d like in green, woodsy spaces, but I try to get out on a nearby trail a couple times a week, or at least go for a walk outdoors in my suburban neighborhood. I can tell you without a doubt that I always, always feel better after being out on that trail. I usually feel good coming back from a walk in the neighborhood, but nowhere near as good as I feel after the trail, which is near a lake and is just absolutely verdant. There are a number of reasons why I feel better, but I have to believe one of them is just being outdoors, in what is likely an immediate environment that is richer in oxygen than my house, the library, the gym, the black pit of despair, or other places I spend any time. Way back in my post about "vitamin J," I wrote about the importance of spending time in natural settings. Perhaps fresh, clean air, and more oxygen is part of why I always feel better in green spaces. (Mark Sisson has written about this as well, here and here, and I wrote about it for Designs for Health here. There is a surprisingly robust body of scientific literature that backs up the importance of spending time in green spaces. None of it says outright, nor even suggests, that it is a surefire cancer prevention strategy, but for overall physical and mental wellbeing? Jackpot! More good stuff here.)

Don’t get me wrong. I’m no dummy. I understand that even indoors, there’s plenty of oxygen to go around. I’m just speculating wildly (like I said I would) that maybe there’s more when you’re surrounded by dense greenery that is literally creating oxygen all around you.

Another way to get more oxygen is to—shocker—breathe more deeply. I was happy Raphi didn’t laugh at me for this one. I meant what I said in my question to him: think about how deeply you breathe while engaged in your normal activities—reading, studying, working, watching TV. You probably don’t breathe deeply at all. Shallow city. And sure, you’re getting enough oxygen to keep you alive, but if you spend most of your life taking those short little shallow breaths, could some parts of you eventually become hypoxic? I don’t know; it’s just something to think about.

I’m not saying we should all start breathing super-deeply all the time. First, that would be pretty ridiculous, and second, you might have to devote a lot of conscious effort to get yourself to breathe deeply all the time, and it would distract from actually getting anything else done. So we don’t have to do it all the time, but maybe—just maybe—there’s a place for all that woo-woo therapeutic deep breathing and meditation and whatever. Like I said when I asked Raphi, maybe that’s even part of why so many people report feeling better after meditating or deep breathing. Could it just be getting more oxygen? And maybe not just the brain, but the whole body, and perhaps an increase in whole-body oxygenation is one of the benefits of meditation/deep breathing, and why it’s been practiced by so many cultures throughout history. (And maybe we don’t even need to “meditate,” since I sort of hate meditation. Maybe we could just take a few minutes here and there to focus on breathing deeply, whether or not our minds are clear. Frankly, I love to cook, and I think of cooking as my “meditation”/happy place. I could certainly breathe more deeply while I do it. In fact, I've been trying to do this lately -- just be more aware of my breathing, and every now and then, just take a few slow, deep breaths. Will it do anything to truly improve my health? Who knows. But it does make me feel a tiny bit better, just remembering to fill my lungs more than usual.)

Something else that might help increase body oxygenation—plus improve circulation, plus improve mitochondrial/metabolic flexibility—is exercise. I could list many reasons why exercise makes me, personally, feel better, but perhaps one of them is increased body oxygenation. (I have no idea if this is true, but just follow me here.) One of the things that happens when I exercise is deep breathing. Not slow deep breathing, but I’m certainly breathing more deeply than when I’m hunched over my laptop writing blog posts. So maybe it’s even better if you exercise outdoors, preferably in a green space. (If you’re going to exercise in Los Angeles smog or NYC bus fumes, you’re probably better off indoors.) And when your heart rate gets up there, you know you’re certainly delivering a lot of blood (and oxygen) to the working muscles. But maybe this is a really dumb way to look at it, because 1) oxygen gets to the whole body all the time, as long as your heart is beating and you have good venous return; and 2) Nobody ever gets cancer in a muscle. You’ve never heard of “biceps cancer” or “cancer of the trapezius,” right? We get colon cancer, breast cancer, prostate cancer, liver cancer, pancreatic cancer, leukemia. So maybe improved circulation doesn’t have a damn thing to do with cancer. Like I said: wild speculation. Also: we have to keep in mind that cancerous tissue isn’t always hypoxic. There is sufficient oxygen; it’s just that the mitochondria can’t use it, so getting more oxygen won’t necessarily help.

Now, all that being said, we have to address something that I have no clue about:

What about babies?

What about babies & toddlers who get cancer? Do they get cancer because they don’t do sprints in the forest, and they breathe too shallowly while napping in their cribs? Um, NO. So adults probably don’t, either. (Plus, let's remember, hypoxia is only one teeny, tiny factor among zillions of others in cancer.) I’m pointing this out because one thing I like to do on my blog is bring us back to reality when we veer a little too far into “blame the victim” territory. It might be one thing to look at an older person who was sedentary their entire life and preferred to be indoors as much as possible and think, “Well, if only you had done x, y, and z, you wouldn’t have gotten cancer.” But we can’t really do that. Not with adults, and certainly not with children. (And I hope we can all agree that, even though we have some ideas about what's going on in cancer, what the initial triggering events and factors are are mostly not completely understood, and if any of us did engage in "blame the victim" shenanigans, it would make us ginormous, first-order black-hearted *ssholes. And I know that description doesn't fit anyone reading my blog, right?) Lest we forget: cancer strikes all ages. All genders, all races, all weights, all economic strata, everything. It gets athletes and couch potatoes. Geniuses and dullards. It is an equal opportunity killer. So I don’t think any of this oxygen stuff outright causes cancer. I’m just trying to point out some interesting stuff. Even if you take “cancer prevention” off the list of benefits, exercise, deep breathing, and spending time outdoors are still pretty good things to do for other reasons.

Hyperbaric Oxygen Therapy

“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. Similarly, HBOT increases oxygen diffusion into cells in culture and thus its effects can be readily evaluated in the in vitro environment. HBOT has been shown to inhibit angiogenesis and tumor growth and increase survival time as a stand-alone or adjuvant therapy to standard care in a variety of cell, animal, and human studies.” (Poff, Ward, Seyfried, et al., 2015)

“The targeting of HIFs represents an attractive adjuvant cancer therapy to simultaneously eradicate cancer cells and induce anti-angiogenic effects in highly hypoxic tumours.” (Mimeault & Batra, 2013)

We’ll look just a little at hyperbaric oxygen therapy (HBOT) here. We’ll go into more detail after we tackle the role of the ketogenic diet, because they go hand-in-hand. Evidence suggests that the combination of a ketogenic diet and HBOT (with possible addition of ketone esters) is a one-two punch that kicks cancer cells in the jimmies. Neither of these approaches, whether alone or together, is a cure BY ANY MEANS. But they do seem to have some very impressive potential, and since every single one of us is or will be affected by cancer in some way (either personally, or via someone we love), we owe our gratitude to the researchers who are doing work in these areas.

Okay, back on message.

If mitochondria in cancer cells can’t use oxygen, then what’s the point of bombarding them with even more oxygen? That’s like what they say about yelling at a deaf person to get them to understand you: maybe if you just shout loudly enough, they’ll hear you. It doesn’t work that way. But in cancer cells, “talking louder” does seem to work. Well, if by “work,” we mean kill cancer cells. It’s not that bombarding cancer cell mitochondria with oxygen magically repairs them so that they can use it. It’s the opposite, actually: it ruins them. 

From Raphi: “Cancer cells are clever, yes, but actually quite fragile contrary to what many oncologists will tell you. They’re less ADAPTABLE. There’s more to it than the answer I’m going to give you but basically… You stress them more than normal cells when force-feeding them oxygen (at a higher pressure) given that their mitochondrial machinery used to process the oxygen is dysfunctional. You’re making their environment less friendly.”

I’m not clear on the specific mechanisms of how HBOT affects cancer cells, but this is one aspect I sort of understand:

HBOT helps increase free radicals (reactive oxygen species, or ROS). As we discussed way back in the first post about mitochondrial dysfunction, ROS are a normal byproduct of cellular energy generation. But sometimes, the amount of ROS produced overwhelms a cell’s capacity to quench them (with antioxidants), and all sorts of damage can occur—such as damage to the inner and outer mitochondrial membranes. Damage from ROS can cause malfunctioning mitochondria. When they’re malfunctioning just a little, the cell stays alive by reverting to the glycolytic phenotype and becoming cancerous. But HBOT slams the cells with oxygen. Under that “supraphysiologic” amount of oxygen, more ROS are produced than normal. And enough damage might occur that the cells actually die.

Something you might be wondering now is: what protects healthy cells from all that oxygen and ROS damage intended to kill cancer cells? EXCELLENT QUESTION. And such a great segue to our next topic, the one we’ve all been waiting for (me included!) – THE KETOGENIC DIET.

Preview:

There is “a synergistic interaction between the KD and hyperbaric oxygen therapy (HBO₂T). … HBO₂T will increase ROS in the tumor cells while the ketones protect normal cells against ROS damage and from potential oxygen toxicity…In contrast to radiation therapy, which also kills tumor cells through ROS production, the KD + HBO₂T will kill tumor cells without causing toxic collateral damage to normal cells.” (Seyfried, Flores, Poff, et al., 2015)

So, you see, the ketogenic diet for cancer is not just about reducing blood glucose and insulin (fuel supply and growth signal, respectively), though those are huge things in its favor. There’s a whole lot more to it. 

Coming soon!

P.S. Fascinatingly, what originally set Dr. D’Agostino on his path to studying the ketogenic diet was its use in protecting Naval Special Warfare divers (SEALs) from oxygen toxicity seizures. So he knew about these effects long before he learned about the myriad other benefits of ketogenic diets. I bet he never imagined he’d end up studying cancer! (Or using the same dietary approach to aid in his own personal bodybuilding efforts. The world is a magical, mysterious, beautiful place, eh?) 

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.