June 18, 2020

expert reaction to ICR study in lab tissue and in mice looking at cancer’s reliance on fat

A study, conducted in lab tissue and mice and published in Cell, has looked at cancer’s reliance on fat.

Prof Tom Sanders, Professor Emeritus of Nutrition and Dietetics, King’s College London, said:

“This report is a complex study using state of the art cell culture and mice experiments which has identified certain breast cancer tumours as sensitive to metabolites of arachidonic acid (AA), a omega-6 polyunsaturated fatty acid made predominantly in the body from the essential fatty acid linoleic acid (LA), which is derived plants (mainly seeds and vegetable oils) but not made in our bodies.  While the study has been meticulously conducted and may give some insight in to how to develop drugs to target specific tumours, it is quite wrong to interpret this study as providing evidence that diets free of a fat  or devoid of omega-6 fatty acids could be used to treat or prevent breast cancer.

“It has been known for decades that increasing the intake of linoleic acid promotes mammary tumour in mice but that the effect can be abrogated by restricting calorie intake.  It is uncertain in this study how well calorie intake was matched.  AA is involved in regulating multiple metabolic processes some of the effects may be harmful such as inflammation and cell proliferation, but others are beneficial such as its effects on cell mediated immunity and tissue repair.  Overall, it is difficult to predict what the net effect on risk of human breast cancer of restricting the dietary intake of omega-6 fatty acids.  The best evidence outside of randomised trials is to examine blood levels of LA and AA with disease risk.  This has already been done in huge study of US Nurses which found no relationship between levels of omega-6 fatty acids in blood cells and subsequent risk of breast cancer¹.

“My concern is that the authors have ventured beyond their expertise to speculate on the impact of extreme dietary fat restriction on human breast cancer.  The authors are mistaken in suggesting that levels of AA in tissues are dependent on the dietary intake of AA from meat and dairy products.  Meat and milk from ruminants (cows, sheep, goats) are poor sources of omega-6 fatty acid because the LA provided by oils from grass and seeds is hydrogenated by rumen bacteria.  The trace amounts of AA found in milk and meat have a negligible effect on tissue levels.  This is well illustrated by the fact that tissue levels of AA are similar in vegans compared to meat-eaters despite the lack of AA in vegan diets.  The levels of AA in tissues are dependent on the intake of LA in the diet but this plateau and at relatively low intakes (1-2% of the energy intake) which is close to the dietary requirement for LA.  The authors’ narrative that western diets contain a huge excess of omega-6 fatty acids is wrong.  Intakes are comparable in China, Japan, South East Asia to those in Europe and North America and are typically in the range of 3.5 – 8% of the dietary energy and are unlikely to lead to significant variations in tissue levels of AA.”

1 Hirko, K.A., Chai, B., Spiegelman, D., Campos, H., Farvid, M.S., Hankinson, S.E., Willett, W.C. and Eliassen, A.H. (2018), Erythrocyte membrane fatty acids and breast cancer risk: a prospective analysis in the nurses’ health study II. Int. J. Cancer, 142: 1116-1129. doi:10.1002/ijc.31133

Prof Paul Pharoah, Professor of Cancer Epidemiology, University of Cambridge, said:

“This paper reports some careful molecular biology investigating the biochemical profile of breast cancer tissue.  A large number of complex experiments are described, some of which have been carried out on samples of cancer tissue in a laboratory and some of which have been carried out in mice.

“The authors have used a technique called REIMS (which is referred to as the iKnife in the press release) to measure the fat content of the tissues.  REIMS involves the rapid heating of tissue and analysis of the gaseous vapours produced.

“The key findings were: 1. that the profile of fats varies in different breast cancers and that the metabolism of breast cancers that have a mutation in the gene PIK3CA have a particular reliance on fats; and 2. that a drug that alters the metabolism of some fats can slow the growth of tumours in mice if the mice are on a fat free diet.

“The press release says “Analysing cancer’s metabolism with a surgical ‘iKnife’ detects tumours with heavy reliance on fats”.  None of the experiments described have used the iKnife to perform surgery.  The REIMS/iKnife was used to analyse tissue that had already been obtained from conventional surgery.

“The key finding is that this biochemical analysis identifies some tumours that are particularly reliant on the metabolism of fats to grow.

“The press release says “Landmark study finds metabolic weakness could be targeted by combining new drugs with diet free of omega-6 fats, primarily found in grain-fed meat and dairy”.  The key work here is ‘could’.  The authors have shown that this treatment/diet has an effect in mice, but that is a very long way from demonstrating that such treatment would be safe, acceptable or effective in humans.  A small minority of treatments that have been shown to be effective in laboratory mice ever become used in the clinic.

“The press release says “iKnife has potential to identify tumours suitable for new metabolic treatment in real time during surgery”.  Given that we are far from having a new treatment, this is rather premature.  The real time concept is irrelevant.  The fact that one might be able to apply the method during surgery makes no difference as any decisions about drug treatment would be made some time after surgery.”

Prof Graham Burdge, Professor of Nutritional Biochemistry, University of Southampton, said:

“This is an intriguing study which is consistent with existing knowledge about breast cancer and fat metabolism, although caution must be exercised in extrapolating these cell culture and animal studies to women.

“There are, however, alternative explanations for the mechanism that links fat metabolism to cancer growth, and the relevance of the mouse dietary manipulation to breast cancer in humans is questionable.

“The potential for novel targets for drug treatments is exciting, although aspirin (which also blocks arachidonic acid metabolism) does not to reduce breast cancer risk in women (Yaghjyan et al. (2020) Cancer Causes & Control).”

* ‘Metabolic Fingerprinting Links Oncogenic PIK3CA with Enhanced Arachidonic Acid-Derived Eicosanoids’ by Nikos Koundouros et al. was published in Cell on Thursday 18 June 2020.

DOI: 10.1016/j.cell.2020.05.053

Declared interests

Prof Tom Sanders: “Tom has the following declarations:

• Honorary Nutritional Director HEART UK (unpaid).
• Scientific Governor of the British Nutrition Foundation (until November 2019).
• Wrote a briefing paper on nutritional and health benefits of apples for a PR company that represents the British Apple and Pears.
• Tom was a member of the FAO/WHO Joint Expert Committee that recommended that trans fatty acids be removed from the human food chain.
• Finished as a member of the scientific advisory committee of the Global Dairy Platform in 2013 (never been a consultant to the dairy industry).
• Was paid to chair a meeting by the Almond Board of California two years ago and was sponsored to speak at conference IUNS by Alpro in 2015.
• Member of the Programme Advisory Committee of the Malaysian Palm Oil Board.
• In the past Tom has acted as a consultant to Archer Daniel Midland Company and received honoraria for meetings sponsored by Unilever PLC.
• Tom’s research on fats was funded by Public Health England/Food Standards Agency.
• He is now emeritus but when he was doing research at King’s College London, the following applied:
• Tom does not hold any grants or have any consultancies with companies involved in the production or marketing of sugar-sweetened drinks.  In reference to previous funding to Tom’s institution: £4.5 million was donated to King’s College London by Tate & Lyle in 2006; this funding finished in 2011.  This money was given to the College and was in recognition of the discovery of the artificial sweetener sucralose by Prof Hough at the Queen Elizabeth College (QEC), which merged with King’s College London.  The Tate & Lyle grant paid for the Clinical Research Centre at St Thomas’ that is run by the Guy’s & St Thomas’ Trust, it was not used to fund research on sugar.  Tate & Lyle sold their sugar interests to American Sugar so the brand Tate & Lyle still exists but it is no longer linked to the company Tate & Lyle PLC, which gave the money to King’s College London in 2006.
• Tom also used to work for Ajinomoto on aspartame about 8 years ago.”

Prof Paul Pharoah: “I have no conflicts of interest to declare.”

Prof Graham Burdge: “I have received research funding from Nestle, Abbott Nutrition and Danone.  I have served as member of the Scientific Advisory Board of BASF AS and I am member of the BASF Asia-Pacific Grant Award Panel.  I am Editor in Chief of Lipids, member of the scientific advisory board of the Institute of Food Brain and Behaviour.”