Preamble: There has been some puzzlement recently among the LC hard core about the main stream antagonism against LC as an approach to disease management. I share their puzzlement. Stan currently has a post here and Wooo has one here. Why do people have to fake data to support an incorrect idea or to abandon techniques which work? Weird. But that's their problem. What frightens me more is when people have an idea in serious science but are disturbing in the conclusions which they come to based on it (I don't usually doubt the data, I'm innocent that way). It particularly scares me when supportive citations are cherry picked while closely related contradictory citations are omitted. Especially when the omitted citations have enormous explanatory power. I came across this unpleasant clash of research thinking accidentally through ron's comment on a Protons post. I was unaware of Sauer's work but have been meaning to blog about cancer and metabolic coupling for some time. Finding that Sauer was in the citation list of Lisanti's coupling paper has pushed me enough to stick this post up. The refs (all free full text) you need to make up your own mind are in the text below. I'm not sure that "enjoy" is quite the correct word. Here we go.
Over in the comments to the Protons summary post ron linked to this paper showing, rather nicely, that sustained fasting markedly promotes cancer xenograft growth. Sauer comments in the paper that the group had noticed this previously and this study appears to be a formalisation of that observation. They had an "Oh, that's interesting" moment and, being scientists, investigated rather than burying it. Here is one of a choice of several graphs:
The bottom lines are the tumour weights, the top lines the animal weights.
Sooooooooo, living with normal-for-starvation levels of ketones and and free fatty acids promotes cancer growth in these particular models, like wildfire.
I have been heard to comment, on more than one occasion, that I have personally been "fasting" for the last 10 years. I just keep replenishing my fat loss using dietary butter. I have had elevated ketones and free fatty acids, 24/7, for much of the last 10 years, probably to starvation levels.
I sort of like Sauer. He wanted to know what happened in starvation to promote cancer growth. As a 1980s physiologist he then did lots of operations on lots of rats which we would rather not go in to in great detail. But he got results.
Amongst the things they did was to perfuse cancer xenografts in live rats with blood from non cancer bearing rats who were in the fed or fasted state. Joined the "donor" rats directly to the arterial supply to the tumour, using various bits of tubing, all very cunning. The cancers only grew rapidly when perfused with blood from starved rats.
They then took blood from fed rats and engineered it in to various reconstituted blood-like fluids resembling the blood from starved rats, by adding assorted fatty acids, and perfused the tumours to see what it was that made them grow.
Palmitic, stearic and oleic FFA supplementation was inactive in promoting tumour growth.
Linoleic and arachidonic promoted growth, really well. That is very scary.
Aside: When people come to look in earnest at ketogenic diets for cancer management the omega 6 content of adipocytes is going to be one hell of a confounder. You will almost need to eliminate weight loss in order to eliminate or at best reduce the release of omega 6 PUFA if the patient has been living on soy oil or Flora for a lifetime... Not easy. End aside.
Got high cholesterol? Want to lower it? Use polyunsaturated acid based margarine! Want to grow a cancer? Hmmmmmm.
Personally I'll settle for butter or 90% cocoa chocolate with palmitic or stearic acids. I suppose I ought to 'fess up about ketones. Well, no. There has to be a pause here.
If you had a concept which ought to show that ketones were a super-fuel for cancer (there are folks with this viewpoint) you might want to cite Sauer and the papers which show that something about fasting or ketosis promotes cancer growth. Which is exactly what this group did in this paper:
"Ketones and lactate “fuel” tumor growth and metastasis. Evidence that epithelial cancer cells use oxidative mitochondrial metabolism".
Nice title. These are the refs they used:
21. Sauer LA, Dauchy RT. Stimulation of tumor growth in
adult rats in vivo during acute streptozotocin-induced
diabetes. Cancer Res 1987; 47:1756-61.
22. Goodstein ML, Richtsmeier WJ, Sauer LA. The effect
of an acute fast on human head and neck carcinoma
xenograft. Growth effects on an ‘isolated tumor vascular
pedicle’ in the nude rat. Arch Otolaryngol Head
Neck Surg 1993; 119:897-902.
Now, this group is very, very good. They have this concept that fibroblasts are enslaved by cancer cells and forced to perform glycolysis but then abort their own TCA and ox phos, supplying lactate and ketones, both derived from pyruvate, to the cancer cells which then use their own mitochondria to fuel cancer cell growth. It's probably correct.
In support of this concept they injected, intraperitoneally, half a gram per kg of lactate or half a gram per kg of beta hydroxybutyrate daily and got increased metastasis with lactate and increase cancer growth with beta hydroxybutyrate. Probably this really happens.
But there are some holes in this study. The ketones supplied to the mice carrying the cancer xeonografts were given by intraperitoneal injection and no one knows what blood levels were reached. Possibly quite high for a while. They never measured them, that I can see. Even well funded dieters measure their ketones.... Let's assume they go so high, whole body, as to actually mimic the sort of levels produced in the minute extracellular gap between a slave fibroblast converting glucose to ketones and pumping them directly on to the surface of an adjacent master cancer cell. We don't know what that level is either, but both get the desired effect on cancer growth to support the paradigm.
BTW, another complete aside, the locally-supplied, fibroblast-generated ketones and lactate are UTTERLY glycolysis dependent. If the Warburg effect is not happening in cancer cells, the reverse Warburg effect looks to be VERY susceptible to sudden onset normoglycaemia affecting the fibroblasts in metabolically coupled systems. The ketones/lactate come from glucose in this set up, not from lipolysis or anaerobic exercise! End aside.
So the question is, when comparing Sauer and Lisanti, what happens when you feed an in-vivo cancer xenograft with PHYSIOLOGICAL doses of ketones by continuous perfusion, using starvation levels?
Sauer of course, did check this. He took blood from fed rats, added ketones to it without omega 6 FFAs and used the blood to directly perfuse a series of cancer xenografts. He doesn't actually give us a concentration for the ketones he used (Edit; without looking up ref 10: OK, I checked ref 10, 4-ish mmol/l in the control rats, just about where I live) but he does appear to be a very interested in teasing out the cause of the effect, so I'll buy that he used the concentration he had measured in the blood of starved rats, which supported cancer growth so well.
When he had finished with the neutral effects of palmitic, stearic and oleic acids and the growth promoting effects of linoleic and arachidonic acids, this is what he has to say about ketones:
"Finally, perfusion of normolipemic blood enriched in the ketone bodies (10) had no effect on [3H]thymidine incorporation in tumors growing in fed adult rats (data not shown)."
Doesn't bode too well for therapies based on the Reverse Warburg effect from Lisanti's group targeting mitochondria. Did they not read all of Sauer's papers? Or did they really read them all and cherry picked the ones they wanted? Which idea scares you most? The cancers grow under the influence of omega 6 PUFA derivatives, NOT ketones. Sauer says so. Believe which ever group you like. I'm biased and I rather like Sauer.
It is very simple to fit omega 6 PUFA FFAs in to the Protons concept of cancer fuelling. I'm still working at why omega 3 fatty acids are protective in these models, they shouldn't be. In cirrhosis models they behave exactly as they should do, promoting cirrhosis as the omega 6s do, but more so. There is a link missing here somewhere. Sigh! I hate "higher level signalling" as an explanation, always seems like a cop out to me. What happens at basic energy metabolism level should give the answer...
Also Sauer specifically looked at cancer utilisation of ketones, lactate and assorted other fuels in some detail here. Some cancers can and do use ketones, but I don't see plasma ketones or lactate as superfuels for cancers in the real world. They get used, but I still see local glycolysis in fibroblasts as the major pathway supplying them. I'm fine with the Reverse Warburg effect. Targeting mitochondria will be a booboo.