Fatty acids and brain tumours

After a recent study came out suggesting that brain tumours can adapt and use fatty acids for energy I thought I would attempt to clear up a few things concisely and succinctly. I'm writing a research proposal at the moment that I'm very excited about if my plans ever come to fruition from sufficient funds but firstly I wanted to tackle this confusion over the fatty acid study that came out recently entitled; 

'Fatty acid oxidation is required for the respiration and proliferation
of malignant glioma cells.'

Firstly I would like to point out that the title is a misleading half truth which validates one very important point but does by no means conclude that all fats are created equal. I could point out several questionable aspects of the study design, however I cannot fault the actual investigation, more the application and the sweeping conclusions made that I find a little irresponsible and misleading. The conclusions by no way invalidate a ketogenic diet, but the findings definitely support a well structured ketogenic diet and validate the significant benefits that come with ensuring fatty acids are balanced appropriately.

I found some of the conclusions equally baffling, including this one. Also strangely no real mention of glutamine even though one of the study aims was to identify the metabolic fuel requirements of human glioma cells.:

They mention how the fatty acid binding drug etomoxir can be used therapeutically to inhibit fatty acid oxidation and reduce proliferation and viability of mouse glioma-initiating cells which is certainly an interesting finding and I applaud them for that, however I question the safety of this drug in terms of the detrimental effect is has on the liver over time and the possible depletion of DHA which I will explain has countless anti tumour benefits.

The drug could potentially be a useful strategy for late stage disease where there is little time to intervene without this pharmalogical approach. It would be wrong for me to disregard this approach completely as the findings to support use of this drug in vivo are certainly interesting despite my reservations.

In my opinion they should have renamed the study

'Fatty acid oxidation primarily via n-6 PUFAs such as linoleic acid can be required for the respiration and proliferation of malignant glioma cells.'

Let's explore some of these misleading statements about all fats through investigation of lipid distribution in both normal, and neoplasms of the brain:

- In the brain, lipids are major structural components with fatty acids making up about 50% of the total mass of neural membranes.

- Long chain PUFA (polyunsaturated fatty acid) such as docosahexaenoic acid (DHA, an omega 3 fatty acid) and arachidonic acid (AA, an omega 6 fatty acid) are abundant in the brain, constituting close to 20% of the dry weight of the brain, including 6% for AA and 8% for DHA. Just imagine, this doesn't even include the CFS (cerebro-spinal fluid) which probably contains quite a lot of DHA I would think.

IMG- http://www.slideshare.net/SpinalCordCom/infographic-17-interesting-facts-about-the-human-brain

The type of fat used in the study is linoleic acid, which is an omega 6 fatty acid that goes through conversion to arachidonic acid. An imbalance of docosahexaenoic acid (an omega 3 fatty acid) and arachidonic acid in favour of omega 6 is a huge problem for normal neurological functioning.

IMG- https://en.wikipedia.org/wiki/Linoleic_acid

IMG- http://www.ncbi.nlm.nih.gov/pubmed/23981365

- Brain turnover of AA and DHA is closely linked and maintenance of a favourable or homeostatic DHA:AA ratio is critical for normal brain function.

- Crucially, deprivation of omega 6 PUFAs is shown to increase brain DHA metabolism while maintaining AA levels by down-regulating enzymes involved in its metabolism.

- It is important to note here that in a standard UK diet (SUK!) that we have at least a 15-16:1 ratio in favour of omega 6 fatty acids, which are typically inflammatory (with omega 3 fatty acids being anti-inflammatory). This is far from ideal and contributory to many health problems, particularly for the brain and heart. The optimal ratio of 3:6 is said to be 3:1 in favour of omega 6 but I try and aim for as close to 1:1 as possible for brain cancer management.

You can read more here: http://www.ncbi.nlm.nih.gov/pubmed/12442909

IMPORTANT POINT!!!!- MALIGNANT GLIOMA IS CHARACTERISED BY LIPID METABOLISM IMBALANCE

IMG- http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4461378/

This is actually true of most, if not ALL brain tumours, as is explored further here: http://www.omicsgroup.org/journals/docosahexaenoic-acid-a-potential-modulator-of-brain-tumors-2167-7956.1000e119.php?aid=19902

How can we exploit this to our benefit and what does this mean?

Consider this:

- The omega 3 and 6 ratio is dramatically increased in malignant glioma, suggestion deregulation of fundamental lipid homeostasis in brain tumour tissue. - full paper available here, well worth a read: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4461378/



ALTERED LIPID METABOLISM IS ASSOCIATED WITH A WORSE PROGNOSIS IN THESE TUMOURS. WE CAN CHANGE THIS WITH THE FATS WE CONSUME!!!

Think more oily fish, less bacon for a more favourable omega 3:6 ratio- IMG http://www.fourfourtwo.com/performance/nutrition/think-fast-and-fish-out-pass

Is this one potential contributory factor for the development of these tumours or a simple consequence? We may never know, but it is likely there is something we can do about this imbalance to put the odds back in our favour. I feel we are missing a trick if we do not scrutinise the fatty acid profile of ketogenic diets for the management of these tumours. If you eat nuts for example, maybe opt for walnuts that have a more favourable ratio of omega 3 and 6 compared to almonds. It would also be preferential to not cook them or to cook with olive oil as it can be oxidised. Some argue differently but I would err on the side of caution personally. For balance I will include this even though I don't necessarily agree:

Source- https://www.oliveoilsource.com/page/heating-olive-oil

It is well established that the essential fatty acids, cis-linoleic acid (LA, an omega 6 fatty acid), and a-linolenic acid (ALA, an omega 3 fatty acid), the pre-cursors of AA and DHA, respectively, have to be obtained from the diet because our bodies cannot synthesise them.

Accumulation of long chain fatty acid metabolites (like the linoleic acid used in this study) has been consistently associated with the worst survival in malignant glioma. This is nothing new, and certainly not a breakthrough, as has been suggested recently. Specifically, extensive research indicates that DHA levels are reduced by up to 50% in malignant glioma samples compared to normal brain tissue. Don't forget that some omega 6 is good and beneficial if it comes from the right sources like coconut oil for example where there are countless additional benefits. The key is the ratio and the quality of the source.

PUFA metabolism- https://openi.nlm.nih.gov/detailedresult.php?img=PMC3335257_JNUME2012-539426.001&req=4

With this in mind (linoleic acid), consider this fact:

'The decrease in DHA observed in malignant glioma was accompanied by unchanged AA levels AND A 4-FOLD INCREASE IN LINOLEIC ACID, RESULTING IN AN OVERALL INCREASE IN x-6/x-3 FATTY ACID RATIO COMPARED TO NORMAL BRAIN.

IMG- http://ebooks.cambridge.org/reading_experience.jsf?bid=CBO9781139680783&cid=CBO9781139680783d4e5810

The fatty acid composition of the diet will also have a clear effect on how the disease spreads within the brain.

'The migratory properties of malignant glioma cells can be modified by altering the ratio of AA:DHA in growth medium, with increased migration observed in AA-rich medium.'- http://www.ncbi.nlm.nih.gov/pubmed/23981365

IMG- https://commons.wikimedia.org/wiki/File:Glioblastoma_-_very_high_mag.jpg

It would be interesting therefore, if the study I am scrutinising used linoleic acid WITH a-linolenic acid (to have a balance of omega 3 and 6 fatty acids), to see how this changed cells in vitro. I predict their results would not have validated their hypothesis under these conditions. I am surprised the paper was accepted in light of this and flaws I have not even mentioned regarding flaws in their methods.

Source- http://www.fatsoflife.com/fats-and-health/fat-basics/

My next point involves what are called FATTY ACID BINDING PROTEINS- they are intracellular fatty acid binding proteins that have complex roles which I won't detail too much but I will just say for clarification that the protein involved specifically to the brain is called FABP7. It is also called B-FABP- Brain fatty acid binding protein.

'Altering the DHA:AA ratio in the culture medium affects cell migration in a FABP7 specific manner, with an increased DHA:AA ratio associated with reduced cell migration.'- HUGE POINT ONCE AGAIN!

In glioblastoma FABP7 is highly expressed at sites of infiltration and surrounding blood vessels.

IMG- http://www.jbc.org/content/285/47/37005.full

Closely observe this image and you will understand my argument completely. The whole paper is available to view so readers can dissect it thoroughly if they wish.

Is DHA (docosahexaenoic acid) the saviour for brain cancer sufferers? Well, it could certainly be part of the solution. Let's shed some light onto this...

We know that unlike the fat used in the fatty acid study appearing to lambast all fats and question the over-simplistic Warburg effect, DHA has inhibitory effects on pro-inflammatory pathways such as COX-2, which is believed to be important for cancer proliferation and invasion.

A correlation between COX-2 expression and glioma grades has been described, with one report indicating that 71% of glioblastoma tumours had >50% COX-2 positive cells compared to 44% of anapaplastic astrocytomas and 30% of low grade astrocytomas. This suggests to me that the higher grade tumours definitely need to ramp up the DHA and keep omega 6 fatty acids as low as they can safely in an attempt to correct this imbalance in order to maintain lipid homeostasis to reduce expression of COX-2.

The linoleic acid used in the study would cause a further decrease in DHA, remember that linoleic acid is actually important for tumour survival and infiltration. The study should have specifically stated that it is only certain omega 6 fatty acids in isolation, and not fatty acid oxidation in general that can drive tumour growth. I would even go as far as to say that such statements are not only misleading, but they are irresponsible and it is poor science when you do not consider your words and exclude such crucial variables.

Its all about achieving an appropriate balance of eicosanoids- http://www.nature.com/nchembio/journal/v6/n6/fig_tab/nchembio.375_F1.html

In summary:

- DHA levels are decreased in malignant glioma tumour samples resulting in a higher AA:DHA in tumour compared to normal brain tissue.

- The up-regulation of FABP7 combined with the higher relative availability of AA may thus favour tumour infiltration.

- It is conceivable that strategies aimed at correcting the DHA:AA ratio may result in the inhibition of tumour cell migration/infiltration and reduce tumour recurrence.

- The inhibitory effect of DHA on the migration of FABP7 positive malignant glioma cells in vitro lends further support to the idea that it may be possible to control malignant glioma infiltration through manipulation of the lipid environment.

- As glioblastoma tumour tissues also have elevated levels of the omega 6 PUFA linoleic acid it would be worthwhile to investigate the effect of linoleic acid on the migration of FABP7 positive and FABP7 negative malignant glioma cells.

Future proposals:

- A better understanding of the consequences of lipid alterations in malignant glioma may shed light on the mechanisms driving tumour recurrence thereby revealing new approaches for the treatment of malignant glioma.

- Neuroimaging of AA and DHA: potential for astrocytoma detection and grading.

- Analysis of the cerebrospinal fluid to determine concentration of DHA:AA

- Potential of an intravenous, balanced eicosanoid ketogenic diet with a therapeutic dose of DHA to replace chemotherapy. This may be ambitious, and may be seen as a wild claim, however I personally believe this could work as it has done for some children with drug resistant epilepsy as noted here:





http://www.sciencedirect.com/science/article/pii/S0887899414007656

and here:

http://www.epilepsy.com/article/2015/5/can-you-give-ketogenic-diet-intravenously

 So....

How do you effectively manage a brain tumour? A good start would likely be attempting to fix this clear imbalance of lipids in the brain by optimising your omega 3 and 6 ratio. The same goes for a host of neurodegenerative diseases that display similar characteristics. 

We now have already established that:

'An increase in the AA:DHA ratio has been consistently reported in malignant glioma, suggesting that tumorigenicity is associated with enhanced DHA loss/metabolism, http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4461378/

It has been suggested that this is...

'to the extent that brain DHA loss cannot be compensated by liver or diet.'


I would tend to disagree with that last statement, as I believe consistent monitoring via a blood spot test can help humans to replicate both the in vitro and in vivo models that have shown therapeutic benefit through dietary manipulation of eicosonoids (fatty acids). I also supplement with a high quality, high DHA fish oil when I need it at therapeutic doses and store it in a way that it is not oxidised. It is marketed at pregnant women as they typically need more DHA, like brain tumour patients!

I don't take it all the time as my diet is naturally very high in omega 3 fatty acids, but it seems to be efficacious. https://www.amazon.co.uk/Minami-Nutrition-MorDHA-Prenatal-Capsules/dp/B0041TRPLS 

Below is my latest blood test result from a recent fatty acid profile. Something is clearly working for me. You can get a comprehensive fatty acid profile yourself through www.omegaquant.com

I hope I have provided whoever reads this with a useful critique of this fatty acid study. It is important for me to stress that the study in no way invalidates a well structured ketogenic diet, quite the opposite actually. I may have seemed a little harsh, but this is more to do with the working than the study itself, which was actually fairly comprehensive and thorough despite my many misgivings about some of the methodology and claims. The study, perhaps without the researchers realising it,  underlines the importance of balancing eicosanoids on a ketogenic diet, which I couldn't agree more with. 

I wish you all good health and happiness in your lives. I have some important updates regarding my own research in the near future and I am hopeful I can continue to get more of the incredible support I have received so far. I make no money from this and I am going to be digging around for funding as I really believe in metabolic therapy and I desperately want to turn around these dysmal statistics. I'm writing up my research proposal and I will keep you updated on my progress here. Wish me luck!!