February 4, 2014

Preventing Chronic Disease

Is there a way to exploit the metabolic quirk of cancer?

Can we starve the disease?

Read Time 9 minutes

One night, as I alluded to in this post, Tim and I were having dinner and the topic of cancer came up.  Personally and professionally I have a great interest in cancer, so when Tim asked if I could write something about cancer that was: (i) interesting to a broad audience, (ii) not technically over the top, (iii) not my typical 5,000 word dissertation, (iv) yet nuanced enough for his readers, I agreed to give it a shot, in about 1,000 words.  (The content of this blog went up on Tim’s blog last week, but I’ve reproduced it here, less Tim’s commentary.)

Semantics and basics

Before jumping into this topic I want to be sure all readers — regardless of background — have a pretty good understanding of the ‘basics’ about cancer and metabolism.  In an effort to do this efficiently, I’ll list concepts here, such that folks can skip them if they want to, or refer back as necessary. This way, I don’t need to disrupt the ‘story’ with constant definitions. (Yes, I realize this is sort of cheating on my 1,000 word promise.)

Cancer – a collection of cells in our bodies that grow at roughly normal speeds, but that do not respond appropriately to cell signaling. In other words, while a collection of ‘normal’ cells will grow and stop growing in response to appropriate messages from hormones and signals, cancer cells have lost this property.  Contrary to popular misconception, cancers cells do not grow especially fast relative to non-cancer cells.  The problem is they don’t ‘know’ when to stop growing.

Metabolism – the process of converting the stored energy in food (chemical energy contained mostly within the bonds of carbon and hydrogen atoms) into usable energy for the body to carry out essential and non-essential work (e.g., ion transport, muscle contraction).

ATP – adenosine triphosphate, the ‘currency’ of energy used by the body.  As its name suggests, this molecule has three (tri) phosphates.  Energy is liberated for use when the body converts ATP to ADP (adenosine diphosphate), by cutting off one of the phosphate ions in exchange for energy.

Glucose – a very simple sugar which many carbohydrates ultimately get broken down into via digestion; glucose is a ring of 6-carbon molecules and has the potential to deliver a lot, or a little, ATP, depending on how it is metabolized.

Fatty acid – the breakdown product of fats (either those stored in the body or those ingested directly) which can be of various lengths (number of joined carbon atoms) and structures (doubled bonds between the carbon atoms or single bonds).

Aerobic metabolism – the process of extracting ATP from glucose or fatty acids when the demand for ATP is not too great, which permits the process to take place with sufficient oxygen in the cell.  This process is highly efficient and generates a lot of ATP (about 36 units, for example, from one molecule of glucose) and easy to manage waste products (oxygen and carbon dioxide).

The process of turning glucose and fatty acid into lots of ATP using oxygen is called ‘oxidative phosphorylation.’

Anaerobic metabolism – the process of extracting ATP from glucose (but not fatty acids) when the demand for ATP is so great that the body cannot deliver oxygen to cells quickly enough to accommodate the more efficient aerobic pathway. The good news is that we can do this (otherwise a brief sprint, or very difficult exertion would be impossible).  The bad news is this process generates much less ATP per carbon molecule (about 4 units of ATP per molecule of glucose), and it generates lactate, which is accompanied by hydrogen ions.  (Contrary to popular belief, it’s the latter that causes the burning in your muscles when you ask your body to do something very demanding, not the former).

Mitochondria – the part of the cell where aerobic metabolism takes place.  Think of a cell as a town and the mitochondria as the factory that converts the stored energy into usable energy.  If food is natural gas, and usable energy is electricity, the mitochondria are the power plants. But remember, mitochondria can only work when they have enough oxygen to process glucose or fatty acids. If they don’t, the folks outside of the factory have to make due with suboptimally broken down glucose and suboptimal byproducts.

DNA – deoxyribonucleic acid, to be exact, is the so-called “building block” of life. DNA is a collection of 4 subunits (called nucleotides) that, when strung together, create a code.  Think of nucleotides like letters of the alphabet. The letters can be rearranged to form words, and words can be strung together to make sentences.

Gene – if nucleotides are the letters of the alphabet, and DNA is the words and sentences, genes are the books – a collection of words strung together to tell a story.  Genes tell our body what to build and how to build it, among other things.  In recent years, scientists have come to identify all human genes, though we still have very little idea what most genes ‘code’ for.  It’s sort of like saying we’ve read all of War and Peace, but we don’t yet understand most of it.

FDG-PET – a type of ‘functional’ radiographic study, often called a ‘pet scan’ for short, used to detect cancer in patients with a suspected tumor burden (this test can’t effectively detect small amounts of cancer and only works for ‘established’ cancers). F18 is substituted for -OH on glucose molecules, making something called 2-fluoro-2-deoxy-D-glucose (FDG), an analog of glucose. This molecule is detectable by PET scanners (because of the F18) and shows which parts of the body are most preferentially using glucose.

Phosphoinositide 3-kinase – commonly called PI3K (pronounced “pee-eye-three-kay”), is an enzyme (technically, a family of enzymes) involved in cell growth and proliferation.  Not surprisingly, these enzymes play an important role in cancer growth and survival, and cancer cells often have mutations in the gene encoding PI3K, which render PI3K even more active. PI3Ks are very important in insulin signaling, which may in part explain their role in cancer growth, as you’ll see below.

The story (in about 1,000 words, as promised)

In 1924 a scientist named Otto Warburg happened upon a counterintuitive finding. Cancer cells, even in the presence of sufficient oxygen, underwent a type of metabolism cells reserved for rapid energy demand – anaerobic metabolism.  In fact, even when cancer cells were given additional oxygen, they still almost uniformly defaulted into using only glucose to make ATP via the anaerobic pathway. This is counterintuitive because this way of making ATP is typically a last resort for cells, not a default, due to the very poor yield of ATP.

This observation begs a logical question? Do cancer cells do this because it’s all they can do? Or do they deliberately ‘choose’ to do this?  I’m not sure the answer is entirely clear or even required to answer the macro question I’ve posed in this post. However, being curious people we like answers, right?

The first place to look is at the mitochondria of the cancer cells.  Though not uniformly the case, most cancers do indeed appear to have defects in their mitochondria that prevent them from carrying out oxidative phosphorylation.

Explanation 1

Cancer cells, like any cells undergoing constant proliferation (recall: cancer cells don’t stop proliferating when told to do so), may be optimizing for something other than energy generation.  They may be optimizing for abundant access to cellular building blocks necessary to support near-endless growth.  In this scenario, a cancer would prefer to rapidly shuttle glucose through itself. In the process, it generates the energy it needs, but more importantly, it gains access to lots of carbon, hydrogen, and oxygen atoms (from the breakdown of glucose).  The atoms serve as the necessary input to the rate-limiting step of their survival — growth.  The selection of cancer cells is based on this ability to preferentially grow by accessing as much cellular substrate as possible.

Explanation 2

Cells become cancerous because they undergo some form of genetic insult.  This insult – damage to their DNA – has been shown to result in the turning off of some genes (those that suppress tumor growth) and/or the activation of other genes (those that promote cell growth unresponsive to normal cell-signaling).  Among other things, this damage to their DNA also damages their mitochondria, rendering cancer cells unable to carry out oxidative phosphorylation.  So, to survive they must undergo anaerobic metabolism to make ATP.

Whichever of these is more accurate, the end result appears the same – cancer cells almost exclusively utilize glucose to make ATP without the use of their mitochondria.  A detailed discussion of which explanation is better is beyond the scope of my word allotment, and it’s not really the point I want to make.  The point is, cancer cells have a metabolic quirk.  Regardless of how much oxygen and fatty acid they have access to, they preferentially use glucose to make ATP, and they do it without their mitochondria and oxygen.

So, can this be exploited to treat or even prevent cancer?

One way this quirk has been exploited for many years is in medical imaging.  FDG-PET scans are a useful tool for non-invasively detecting cancer in people.  By exploiting the obligate glucose consumption of cancer cells, the FDG-PET scan is a powerful way to locate cancer (see figure).

You can probably tell where I’m leading you.  What happens if we reduce the amount of glucose in the body? Could such an intervention ‘starve’ cancer cells?  An insight into this came relatively recently from an unlikely place – the study of patients with type 2 diabetes.

In the past few years, three retrospective studies of patients taking a drug called metformin have shown that diabetic patients who take metformin, even when adjusted for other factors such as body weight and other medications, appear to get less cancer. And when they do get cancer, they appear to survive longer. Why? The answer may lie in what metformin does.  Metformin does many things, to be clear, but chief among them is activating an enzyme called AMP kinase, which is important in suppressing the production of glucose in the liver (the liver manufactures glucose from protein and glycerol and releases it to the rest of the body).  This drug is used in patients with diabetes to reduce glucose levels and thereby reduce insulin requirement.

So, the patients taking metformin may have better cancer outcomes because their glucose levels were lower, or because such patients needed less insulin. Insulin and insulin-like growth factor (IGF-1) also appear to play an integral role in cancer growth as recently demonstrated by the observation that people with defective IGF-1 receptors appear immune to cancer. Or, it may be that activation of AMP kinase in cancer cells harms them in some other way.  We don’t actually know why, but we do know that where there is smoke there is often fire. And the ‘smoke’ in this case is that a relatively innocuous drug that alters glucose levels in the body appears to interfere with cancer.

This may also explain why most animal models show that caloric restriction improves cancer outcomes.  Though historically, this observation has been interpreted through the lens of less ‘food’ for cancer. A more likely explanation is that caloric restriction is often synonymous with glucose reduction, and it may be the glucose restriction per se that is keeping the cancer at bay.

Fortunately this paradigm shift in oncology – exploiting the metabolic abnormality of cancer cells – is gaining traction, and doing so with many leaders in the field.

Over a dozen clinical trials are underway right now investigating this strategy in the cancers that appear most sensitive to this metabolic effect – breast, endometrial, cervical, prostate, pancreatic, colon, and others.  Some of these trials are simply trying to reproduce the metformin effect in a prospective, blinded fashion.  Other trials are looking at sophisticated ways to target cancer by exploiting this metabolic abnormality, such as targeting PI3K directly.

To date, no studies in humans are evaluating the therapeutic efficacy of glucose and/or insulin reduction via diet, though I suspect that will change in the coming year or two, pending outcomes of the metformin trials.

Last point (beyond my 1,000 word allotment)

Check out this blast from the past! Gary Taubes, who is currently working hard on his next book, came across the article the other day from 1887.

Influences

I’ve been absurdly blessed to study this topic at the feet of legends, and to be crystal clear, not one thought represented here is original work emanating from my brain.  I’m simply trying to reconstruct the story and make it more accessible to a broader audience.  Though I trained in oncology, my research at NIH/NCI focused on the role of the immune system in combating cancer. My education in the metabolism of cancer has been formed by the writings of those below, and from frequent discussions with a subset of them who have been more than generous with their time, especially Lewis Cantley (who led the team that discovered PI3K) and Dominic D’Agostino.

  • Otto Warburg
  • Lewis Cantley
  • Dominic D’Agostino
  • Craig Thompson
  • Thomas Seyfried
  • Eugene Fine
  • Richard Feinman (not to be confused with Richard Feynman)
  • Rainer Klement
  • Reuben Shaw
  • Matthew Vander Heiden
  • Valter Longo

Further reading

I do plan to continue exploring this topic, but for those of you who want to know more right now and/or for those of you with an appetite for depth, I recommend the following articles, some technical, some not, but all worth the time to read. This is the short list:

  1. Relatively non-technical review article on the Warburg Effect written by Vander Heiden, Thompson, and Cantley
  2. Science piece written about cancer (for non-technical audience) by Gary Taubes
  3. Non-technical talk by Craig Thompson
  4. Detailed review article by Tom Seyfried
  5. Review article on the role of carb restriction in the treatment and prevention of cancer
  6. Talk given by author of above paper for those who prefer video
  7. Moderately technical review article by Shaw and Cantley
  8. Clinical paper on the role of metformin in breast cancer by Ana Gonzalez-Angulo
  9. Mouse study by Dom D’Agostino’s group examining role of ketogenic diet and hyperbaric oxygen on a very aggressive tumor model
  10. Mechanistic study by Feinman and Fine assessing means by which acetoacetate (a ketone body) suppresses tumor growth in human cancer cell lines

Figure of FDG-PET imaging showing no evidence of recurrent tumor after standard care treatment including a water-only fast and a ketogenic diet by Zuccoli et al., 2009 is licensed under CC by 2.0

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240 Comments

  1. I recently stumbled on an article written a couple years ago that says “…a study by a team of researchers at Johns Hopkins and elsewhere shows that lymph gland cancer cells…can use glutamine in the absence of glucose for cell replication and survival, particularly under low-oxygen conditions, which are common in tumors.”

    Would you expect that other cancer types would share this characteristic (using glutamine in the absence of glucose)?

    FWIW, the study found “When the investigators used a glutaminase inhibitor, cancerous growth of B cells was stopped in petri dishes.”

    • Hard to day, and it’s always dangerous to spend too much time looking at tumor lines vs. actual tumors. The mutations can have little resemblance to the clinical cancer.

  2. I wonder what your old biochem lab partner from Queen’s would have to say about this blog. You should get in touch with her to discuss. (seriously!)

  3. Apologase for sure. Anyway, I’m at U of Arizona now. Get in touch. Would be good to catch up…and talk science.

  4. sir,
    Thanks for the great info.
    1) Have you read law carb fraud and what do you think of it?

    2)I do not live in america. In my country , the whole wheat we get is most of time whole and real and is a staple food. Most of the people do not seem to have a problem eating it since many years. This is not the refined version. People eat less refined and there are no canned food here. I am wondering if all the wheat problems apply here?

    3) Secondly, there are studies that show the benefits of grains and legumes. Why cant a person pursue a balanced diet incorporating more of veggies, some fat, some protein (all from good sources) and some wholegrains /lentils etc. It almost seems going against nature to count carbs while having vegetables. I tried ketosis diet for 10 days and suffered constipation and had hypothyroid like symptoms. It might be great for others. Why do we have paleo, atkins, carb backloading and all these complications when we can just have a simple balanced diet with regular exercise?

    am sorry if these questions sound trivial to you but I really wanted to know your thoughts. thanks

    • unless ofcourse one is suffering from certain issues and need to follow a diet prescribed to help deal with the issue ( I am talking about life in general). I hope you find time to let me know what you think.

  5. Hi Peter,

    The new study about risks of high protein diet and its connection to cancer are all over the web. Do you have any insights into this issue? Please kindly comment. Here is what is says:

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  6. Dr. Attia – What’s your take on the Longo/Crimmins study out this week with the screaming headline that high protein (20%+) diets cause cancer and diabetes rates to rise in those of middle age?

  7. Why does the media insist on sensationalizing this stuff, let alone interpret findings as they see fit? [They] seem to always be one-sided about everything. What ever happened to impartial, objective journalism? I’m one to believe that the media is totally responsible for the obesity epidemic. The “Studies” and the “Media” feed off each other! When a journalist starts out a sentence with “A new study…”, my BP goes up 10 points!

    Every time something like this surfaces, doesn’t it damper the NuSi’s objective? – the one step forward, two steps back theory!

  8. I am an 18 year old male and have always been a pretty normal weight and never thinking much about diet. I picked up running and cycling about a year ago and was poorly misguided into eating a low protein, low fat, high carbohydrate diet with little meat. My weight got down to about 130 (I am 5’10”) and was looking rather gaunt. As a freshman in college majoring in science I was astounded at the complexity of your talk, An Advantaged Metabolic State: Human Performance, Resilience & Health. I began experimenting about three months ago reducing carbohydrates. To eliminate other variables in the experiment I pretty much ate identical foods as you did in What I actually eat, part II – “IFIK” (circa Q3 2012).
    Any-who, over the 3 months I have noticed a lot of changes. Overall I feel a lot better. I however immediately gained weight. I’ve gone from 130 to 150 pounds. Some of this is muscle, as I have also started rock climbing. Some is definitely fat. I can see and grab a little tire under my belly button and the love handles. Again I feel much better but I am not anywhere near as lean. Without getting into a ton more details, is there any quick reason you think I gained weight?
    P.S. My mom says I look healthier.

  9. I just want to thank you for your amazing, inspiring and informative writings! I cannot express how interesting your blog is. Thanks for sharing your insights and research with all of us!!!

  10. I was obese and diabetic and not doing well at all, I saw myself spiraling into a bad place. I started the KD about ten months ago after watching your video on TED and feel amazingly better and have lost 65#!! I am 5’11” was 255# and now about 190# I thank you for all my success honestly you saved my life. I know this system works… I live it and I breathe it everyday, after the first month this was the easiest thing I have ever done to lose weight. This is my lifestyle now and I will remain in it……BUT BUT BUT, I am confused now after my husband has had testicular cancer five times since he was 17 and its back again I have been researching like crazy to try and help him. The confusing part is you read about KD sounds great I know it works then you read about a alkaline diet for cancer and all the meat and eggs are acidic so its bad. Then another cancer place sites that you should not eat cooked meat because its dead food. Some say protein some so absolutely not. Then the new study on Low Carb diets just came out to say it causes cancer…but they don’t site any stats just print it in the Huiffington Post! When I talk to his regular Dr.’s about this they are clueless and offer more surgery. What is your opinion on this issue? Meats are acidic and eggs and protein….so in the long run is it the sugar that hurts and feeds the cancer (as by any PET scan you can tell it does) or is it the acid foods from protein and or sugar?? We are juicing and supplementing and doing anything we can but I’m on info overload……HELP! Thank you!

  11. I’m just catching up to this, from earlier in the thread: “From a practical standpoint, outside of a calorie-restricted KD, the way to get to sustained level of BHB at 4 mM likely requires new foods that also provided exogenous BHB and/or AcAc.”
    Right. Kieran Clarke of Oxford U, and Richard Veech of NIH, are working on the butanediol ester with beta-hydroxybutyrate, for human consumption. Metabolizes promptly, basically you get two equivalents of ketone body from each molecule. Veech has published the safety studies. Their startup company is TdeltaS, there is a website. They’ve been working on this for years, I understand they have a biosynthetic synthesis method.

    D’Agostino, from your suggested readings, and others are working on glyceryl tri-hydroxybutyrate also aiming for a food supplement I believe.
    A triglyceride of a ketone body, very clever. This is mentioned in “Ketone Body Therapy: From ketogenic diet to oral administration of ketone ester. ” Hashim SA Md1, Vanitallie TB Md. – a recent paper, check PubMed, full text available.

  12. Possible new avenue to exploit:
    “The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth”
    http://www.nature.com/nature/journal/v452/n7184/abs/nature06734.html
    “This persistence of high lactate production by tumours in the presence of oxygen, known as aerobic glycolysis, was first noted by Otto Warburg more than 75 yr ago. How tumour cells establish this altered metabolic phenotype and whether it is essential for tumorigenesis is as yet unknown. Here we show that a single switch in a splice isoform of the glycolytic enzyme pyruvate kinase is necessary for the shift in cellular metabolism to aerobic glycolysis and that this promotes tumorigenesis.”

    Once researchers stop digging in the dry hole that is the somatic theory of cancer, they may rapidly find all sorts of exploitable things.

  13. Maybe I missed it, but I see nothing about Peter Pedersen and Young Hee Ko’ s work at Johns Hopkins. They discovered over 12 years ago that a small cheap molecule- 3 bromopyruvate- would bring both glycolytic and Krebs cycle synthesis of ATP to a total halt, killing any cancer cell that it entered. Just as important, it enters cancer cells at a substantial rate because only they possess abundant membrane transporter for small carboxylic acids, thus little or no toxicity to normal cells. Use of 3brpa has been held up over ten years for some really screwy reasons: 1) a patent squabble- one of the discoverers was actually fired from Johns Hopkins for asserting that the patent rights were hers and the university licensed the patent to another individual. This individual May in fact be starting clinical trials (PreScience Labs LLC) but the original discoverer continues to work independently and still submits new patents. The researchers were initially looking for inhibitors of cancer cell hexokinase II. This enzyme binds to a voltage dependent anion channel on the outer mito membrane, and they assert that this is the step that immortalizes the cell. Could there be a nicer tie in to the role of sugar in cancer? 2) Pharmaceutical companies aren’t interested be they can’t see a profit (the stuff is CHEAP!). In addition, the compound itself can’t be patented. I can provide citations or just search Young Hee Ko and Peter Pedersen. To see a one hour amazing lecture delivered at the NIH by Dr Pedersen, visit singlecausesinglecure.org and follow the links – I found it by accident and was STUNNED!

  14. Thanks for a great article. It actually reinforces my belief that the “job” of cancer cells is to reduce the amount of glucose in the blood. It would help explain why cancer cells use the least efficient means to convert glucose to ATP if the cells aren’t actually trying to produce energy- just clean up the glucose before it can make a mess in the body. I figure it was probably a way to deal with times when people had excess carbohydrates- eg. Feasting, times when fat wasn’t readily available, etc. We just overtax the system with our Western diet.

  15. Is the liver able to produce ketones when a person has liver cancer and thus fight the liver cancer this way?

    • I don’t know the answer the this, but my hunch is that it depends on the extent and severity of the disease and the amount of normal liver parenchyma that remains.

  16. Peter, great article and I believe you achieved your goals (or at least the targets set for you!). My wife and I have come to similar conclusions in our research on sugar and its relationship to cancer cell growth (or inhibition).

    With respect to why cancerous cells do not respond to hormonally-based signals telling them to stop growing, have you looked at the lack of presence of monosaccharide receptors on the cancerous cells as the cause?

    http://www.ncbi.nlm.nih.gov/pubmed/10756839

    Furthermore, could the lack of those receptors be caused by an insufficient dietary intake of proper nutrition so that those receptors are not created properly (or at all)?

    Thank you in advance for your thoughts and for all you have written!

  17. Thanks for putting this together – very helpful in understanding some of the background to this approach. Can metformin be taken concurrently with chemo, radiation and other standard-of-care treatments? The great thing about the Seyfried et al approach (restricted ketogenic diet) is that it can be done along with most conventional treatments so you don’t have to pull a Steve Jobs and forsake the standard treatments, which do sometimes work. I don’t currently have cancer but I did have a melanoma safely removed several years ago (I had just turned 30!) and cancer seems very prominent in my family, so I am watching the progress of this approach very closely.

    • Until proven otherwise, refraining from standard of care in cancer is not something I would ever advise. Think addition, not substitution.

  18. “Until proven otherwise, refraining from standard of care in cancer is not something I would ever advise.”

    I think I can appreciate why you may feel the need to say this, but much of the standard of care in oncology seems about as evidence based as current medical nutrition dogma. And in many cases perhaps as destructive.

    I suspect that what has been done to millions of breasts, prostates, and thyroids in the name of cancer treatment, for example, will ultimately be remembered in somewhat then same way as leeches and bloodletting. (Can’t help but recall the great line from the original Star Trek, when the crew goes back in time and Bones says something like, “Jim, we can’t leave him in the hands of 20th century medicine!”) And many of the chemo and radiation protocols seem to have very little supporting evidence, with any benefits marginal at best and adverse affects significant to say the least.

    From what I know about it, some oncology is absolutely fantastic, even curative, but far from all. Not an easy situation to navigate if you are sick and scared.

  19. I found that cancer is about stem-cell mediated immunity erroneously ignited in the body. It can be easily reversed. I had stage 4 ovarian cancer, spread to the uterus, cervix, colon and both lungs. And had type 2 diabetes at the same time. The doctors treated me for the diabetes but threw their hands up about the cancer. I went on to make my discoveries and reversed both. That was 20 years ago.
    Have a look here: http://www.kyrani99godnscience.wordpress.com/2013/09/20/the-big-c-cancer-explained/
    kyrani Eade

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