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Tuesday, August 30, 2011

Ketones Fuel Cancer?!

Ketones and lactate “fuel” tumor growth and metastasis

Previously, we proposed a new model for understanding the “Warburg effect” in tumor metabolism. In this scheme, cancer-associated fibroblasts undergo aerobic glycolysis and the resulting energy-rich metabolites are then transferred to epithelial cancer cells, where they enter the TCA cycle, resulting in high ATP production via oxidative phosphorylation. We have termed this new paradigm “the Reverse Warburg effect.” 
Here, we directly evaluate whether the end-products of aerobic glycolysis (3-hydroxy-butyrate and L-lactate) can stimulate tumor growth and metastasis, using MDA-MB-231 breast cancer xenografts as a model system. More specifically, we show that administration of 3-hydroxy-butyrate (a ketone body) increases tumor growth by ~2.5-fold, without any measurable increases in tumor vascularization/angiogenesis. Both 3-hydroxy-butyrate and L-lactate functioned as chemo-attractants, stimulating the migration of epithelial cancer cells.  Although L-lactate did not increase primary tumor growth, it stimulated the formation of lung metastases by ~10-fold.  thus, we conclude that ketones and lactate fuel tumor growth and metastasis, providing functional evidence to support the “reverse Warburg effect.” 
Moreover, we discuss the possibility that it may be unwise to use lactate-containing i.v. solutions (such as lactated Ringer’s or Hartmann’s solution) in cancer patients, given the dramatic metastasis-promoting properties of L-lactate. Also, we provide evidence for the upregulation of oxidative mitochondrial metabolism and the TCA cycle in human breast cancer cells in vivo, via an informatics analysis of the existing raw transcriptional profiles of epithelial breast cancer cells and adjacent stromal cells. 
Lastly, our findings may explain why diabetic patients have an increased incidence of cancer, due to increased ketone production, and a tendency towards autophagy/mitophagy in their adipose tissue.

A friend sent me this one recently.  I'm mostly passing it along as a PSA of sorts as I'm busy with other interests at the moment.  However there have been many blogs and threads on discussion boards discussing the role of glucose and carbs in general in cancer.  Also, around a year ago headlines splashed across the web such as Fructose can trigger cancer cells to grow faster, study finds, Cancer cells slurp up fructose, US study finds, and 'Fructose-Slurping' Cancer Could Sour the Soda Business.  These sparked innumerable blogs and disco board threads in LC/Paleo/Anti-Sugar-warrior arenas.  

Now ketones and lactate aren't dietary agents, let alone the easily demonized HFCS, so it's no mystery why this paper didn't spawn a similar flurry.   The metastasis part of this really gives me pause.  


Quarrel said...

Might be interesting to some. Particularly Dr Seyfried's response.

There are bad studies on every side of every fence I suspect :/


Evelyn aka CarbSane said...

Hi Quarrel! Welcome!! I missed this one. I don't bother much with Jimmy's blog anymore, except like with a big wreck on the highway, I can't stop rubbernecking every now and again.

I just read through it. I have to say Seyfried's response is disappointing. And a long term low carber included amongst "experts"?

I was also disappointed in the Ottobonis who say: "First, the biochemical logic: Cancer cells require glucose as their source of energy. As far as is known, glucose is their only energy source. Cancer cells cannot survive, grow, and metastasize without energy." And later: "Ketone bodies produced in humans as a result of β-oxidation of fatty acids ... have been shown to be an excellent source of energy for all normal tissues and organs, except the liver." Umm... what do they think cancer cells are? Alien explants? No ... they are human cells gone awry.

Quarrel said...

I must admit, I saw first saw this and thought it was hardly surprising. Ketone bodies are a known good source of energy - it hardly seems a stretch that a mutation (cancer) could use them as a source if they're freely available in the right body.

I think its more an argument for the evolutionary process than against a diet choice though :)

I'm sure if I was a cancer researcher though, and discovered a new, unknown, source of energy for cancer it'd be worth writing a paper about...

I agree about the lame "long term low carber" bit...


psychic24 said...

What I find super interesting is the possibility for ketones to part in parcel of some of the longevity found on various tropical islands; these locations (kitava, okinawa..etc) are the places which use coconut oil and limit their protein intake, allowing for a more ketogenic environment. These are also the populations which make great use of starches. Maybe concomitant use of ketogenic promoting foods and starches are necessary for optimal health...

Galina L. said...

It doesn't explain why most cancers are among "diseases of civilization" category. I understand that civilization is more than food, likely a lifestyle, but ketones are abandoned in starving people, who are not particularly prone to getting cancers compare to overfed ones(according to all that data about benefits of calorie restriction).
Also, the expression "administration of 3-hydroxy-butyrate " caught my attention. If ketones are not created in the body but artificially added in one form or another it may have different effect and create a diabetic-like environment with abandon nutrition for anything growing.

Diana said...

"It doesn't explain why most cancers are among "diseases of civilization" category."

I am no cancer expert but let me take a whack at this. Most cancers occur among older people. Not all, but most. Since aging is a "disease of civilization," wouldn't it make sense that cancer is more prevalent amongst a population where most people get to live their 3-score and ten?

Duffy Pratt said...

That would depend on how one did the comparison. If the comparison were simply of cancer rates across total populations, then the aging explanation might make some sense. If the comparison were based on cancer rates among particular age groups, that would take aging out of the basis for comparison. I don't know how people made these observations when they said that cancer doesn't appear among the primitive.

Evelyn aka CarbSane said...

Consider also that for some cancers, prostate comes to mind, most forms are very slow growing. With PSA, detection rates have gone up dramatically whereas just 20 years ago far more men died with cancer but not of cancer.

I have some thoughts on the other comments. Be back in a bit :)

SamAbroad said...

C'mon carbsane, you're better than this. An invitro study? Chris masterjohn did an excellent blog post demolished the usage of a sole inV study to hang any hypothesis on.

I'll see your invitro study and counter it with a (totally tiny) pilot study showing a keto diet reversing or slowing the growth of tumours. You know the study, why dismiss that even though it is a higher form of evidence than you have posted?

Evelyn aka CarbSane said...

Am I hanging a hypothesis? Was that fructose study heralded last year in vivo? Hint: nope. What makes you think I'm done yet Sam?

Got a link to the pilot study? I haven't really looked at this much either way.

Galina L. said...

Cancer mostly affect old ones, but not always. My main point is the difference between real body in ketosis and an artificial situation when ketones are introduced. Sounds too easy - want to be in ketosis - just get some medicine.

Sue said...

Doesn't it depend on the cells whether they do better or worse (can use as energy source)on ketones. Just like when you are trying to rid yourself of a pathogen - you need a ketone diet or more of a carb one.

OnePointFive said...

There is a more recent paper available in full.
Ketones and lactate increase cancer cell “stemness”, driving recurrence, metastasis and poor clinical outcome in breast cancer
There is a section on Metformin and cancer cells that concludes and might be relevent (really this is mostly beyond my comprehension far too specialised)

" Finally, it is quite ironic that such a promising anti-cancer drug (metformin) exerts its therapeutic effects by inducing a type of metabolism (aerobic glycolysis) that has been proposed to be the “root-cause” of cancer for the last 85 years. Thus, induction of aerobic glycolysis in cancer cells may not be the “cause of cancer,” but rather it may be the “cure for cancer.”

SamAbroad said...

Huh? Did I mention the fructose study?,8599,1662484,00.html

Not published yet as far as I can see, but still impressive results.

And a good ol' (published) mouse study for good measure:

Although, I don't really know if that tells us absolutely anything because I doubt the mice were eating anything akin to real food.

Paul Jaminet hypothesised that mucin deficiency could lead to gastric cancers in long term VLC, and I find the theory plausible long term but if I would be diagnosed tomorrow (touch wood) I'd hop on a VLC diet stat (I'd prob restrict protein too to be on the safe side re: glutamate issues.)

Evelyn aka CarbSane said...

Umm ... huh? Did you read my post?

SamAbroad said...

Yup, did you read my original post? I wasn't talking about the fructose paper. You should hold yourself to the same standard that you hold others you know. You might say you weren't hanging a hypothesis but look at your headline, all it's missing is an OMG!!!!!

Anti Carnist said...

Here's another study reporting the same thing; that cancer cells can utilize ketones:

Dr. Adrienne Scheck's studies reversing cancer on a ketogenic diet have received some attention from the low carb community. But she also used the ketogenic diet in conjunction with chemo and radiation therapy:

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