Thursday, March 1, 2012

Arachidonic Acid and Breast, Prostate, and Colon Cancers

Arachidonic acid (AA) is a long-chain polyunsaturated omega-6 fat.  It does not occur in commonly consumed plant tissues, so animal foods supply dietary AA consumed by humans.  According to the National Cancer Institute, the top ten sources of arachidonic acid in U.S. diets include:

1. Chicken and chicken dishes (27%)
2. Eggs and egg dishes (18%)
3. Beef and beef dishes (7%)
4.  Sausage, franks, bacon, and ribs (7%)
5. Other fish and fish mixed dishes (6%)
6.  Burgers (5%)
7.  Cold cuts (3%)
8.  Pork and pork mixed dishes (3%)
9.  Mexican mixed dishes (3%)
10.  Pizza (3%)


Since AA is used in muscle cell membranes the AA (20:4 n-6) content (g/100 g edible) of lean flesh from grass-fed cattle may not differ significantly from the meat of corn-concentrate fed  cattle.  One study actually found that the highest AA level occurred in grazed (grass-fed) Scott cattle and the lowest level in Simmental cattle fed concentrate (corn) [1, full text]:



Both lean and fat from animals provides AA; lard may have the highest AA content of any animal fat: 

"The aim of this study was to accurately quantitate the AA content of visible fat and the lean portion of beef, lamb, pork, chicken, duck, and turkey. The visible fat of meat contained a significant quantity of AA, ranging from 20 to 180 mg/100 g fat, whereas the AA content of the lean portion of meat was lower, ranging from 30 to 99 mg/100 g lean meat. Beef and lamb meats contained lower levels of AA in both the visible fat and lean portion than that from the other species. The highest level of AA in lean meat was in duck (99 mg/100 g), whereas pork fat had the highest concentration for the visible fats (180 mg/100 g). The lean portions of beef and lamb contained the higher levels of n-3 polyunsaturated fatty acids (PUFA) compared with white meats which were high in AA and low in n-3 PUFA. The present data indicate that the visible meat fat can make a contribution to dietary intake of AA, particularly for consumers with high intakes of fat from pork or poultry meat." [2 ]

In the absence of AA intake, an intake of linoleic acid (LA, the omega-6 fat found in plants) up to four percent of calories either has no effect on AA or reduces AA levels, but an intake of twenty percent of calories might stimulate undesirable eicosanoid synthesis temporarily. [3, 4]  In one study, a liquid formula diet supplying twenty percent of calories as linoleic acid significantly reduced platelet aggregation (-25%) and thromboxane formation (-43%). Levels of some prostaglandin metabolites increased during the first 10 days, then declined to a level lower than the pre-experimental values at the end of the 3-week period. [4]  Thus, it appeared that a diet enriched in LA ultimately reduced tissue levels of AA metabolites.

A review of 36 high-quality reports of studies of the effect of dietary LA on AA levels found "Increasing LA by as much as 551% from baseline and reducing LA by as much as 90% from baseline failed to yield compelling evidence supporting the concept that any conversion of dietary LA to downstream metabolites results in tissue enrichment of AA, a notion commonly assumed." [26 full text]  

In contrast, increased dietary intake of AA (i.e. meat and animal fat) increases the production of pro-inflammatory eicosanoids in humans. [5, 6 ]

Probably the body regulates conversion of LA to AA according to need, the same way it regulates conversion of beta-carotene to retinol according to need.  Although it is possible to overdose on retinol (so-called vitamin A), humans can't get an overdose of retinol by route of eating carotenoids because the body will not convert carotenoids to retinol unless it has a retinol deficiency.  Similarly, it appears that the body does not convert LA to AA unless it has a deficiency of AA, but we can get an excess of AA by eating AA directly, just as we can get an excess of retinol by eating retinol directly.  This suggests that human metabolism is not well adapted to diets containing preformed retinol or AA.

 Cells supplied with exogenous AA show increased production of an eicosanoid, PGE2, which in turn decreases production of tumor necrosis factor (TNF), a type of cytokine that induces programmed cell death (apoptosis) in tumor cells. [7]   This becomes relevant to cancer promotion; less TNF means less immune system control over tumor cells.

Research seems to suggest that promotion of AA metabolism promotes breast, prostate, and colon cancer, while inhibition of AA metabolism, even using aspirin or other COX2 inhibitor NSAIDs, reduces occurrence of these, the most common cancers in the United States.

"Epidemiologic evidence suggests the incidence of breast, colon, and lung cancers is inversely related to the use of aspirin and nonsteroidal anti-inflammatory drugs, which are nonspecific inhibitors of COX. COX-1 and COX-2 are enzymes that generate prostaglandins and thromboxanes from free arachidonic acid." [8
Below I have quoted some relevant publications or abstracts (when I don't have access to the full document), showing that scientists doing basic research on the biochemistry involved in cancer growth have identified AA metabolism as a target for cancer prevention and therapy. 

If you search PubMed with "arachidonic acid and (insert name of cancer)" you will find many more like these.

Breast Cancer

"Arachidonic acid (AA) and its metabolites play critical role in the development of breast cancer, but the mechanisms through which AA promotes mammary tumorigenesis and progression are poorly understood." [9]

Arachidonic metabolism by LOX enzymes is involved in lymph node metastasis of breast cancer.  [10 full text ]

"Arachidonic acid, a dietary cis-polyunsaturated fatty acid, stimulates adhesion and migration of human cancer cells on the extracellular matrix by activation of intracellular signaling pathways."[11 full text ]

"In our previous work, we utilized a highly metastatic human [breast] cancer cell line, MDA-MB-435, and demonstrated that arachidonic acid induced cellular adhesion to collagen type IV in an integrin-dependent manner requiring the activation of multiple signal transduction proteins." [12 full text ]

"The estrogen independent MDA-MB-435 cell line has the advantage that it metastasizes consistently to the lungs and forms quantifiable secondary nodules when injected into the mammary fat pads. With these breast cancer cells, the stimulating effects of polyunsaturated omega-6 fatty acids on both primary tumor growth and metastasis were demonstrated; in contrast, the long-chain omega-3 fatty acids were inhibitory. The model can also be adapted to examine dietary fatty acids, and inhibitors of their metabolism, as experimental adjuvant therapy after surgical excision of the primary tumors. ..The results obtained by these several approaches have demonstrated distinct roles for the cyclooxygenase and lipoxygenase-mediated products of omega-6 fatty acid metabolism, and suggest new approaches to experimental breast cancer therapy. " [13 ]

"15(S)-Lipoxygenase-2 Mediates Arachidonic Acid-stimulated Adhesion of Human Breast Carcinoma Cells through the Activation of TAK1, MKK6, and p38 MAPK....The cis-polyunsaturated fatty acid arachidonic acid and its many metabolites are important mediators of cell signaling with roles in inflammation, platelet aggregation, tissue development, and carcinogenesis (15). The cis-polyunsaturated fatty acids have been implicated in a number of in vivo and in vitro rodent studies that link fat intake and cellular fatty acid levels with carcinogenesis, tumor development, and metastasis (68)."  [14 full text ]

Prostate Cancer

"The target of arachidonic acid pathway is a new anticancer strategy for human prostate cancer." [15 ]

"Herein we provide evidence that fatty acids (FA) can trigger androgen synthesis within steroid starved prostate cancer (CaP) tumor cells..... We propose that this characterized arachidonic acid induced steroidogenesis mechanism significantly contributes to the activation of AR in CRPC progression and therefore recommend that fatty acid pathways be targeted therapeutically in progressing CaP." [16]

"The arachidonic acid pathway incorporates phospholipase, cyclooxygenase, lipoxygenase and epoxygenase enzymes. This pathway has been shown to have a major role in the development and progression of a number of cancers, including prostate cancer. We discuss the current status of research of this pathway in the area of prostate cancer, ranging from preclinical in vitro studies to human clinical trials....Evolving data suggest a significant role for some areas of the arachidonic acid pathway in prostate cancer. Inhibiting 1 or a number of these enzymes in combination may hold promise for future prostate cancer treatment." [17]

Colorectal Cancer

"Arachidonic acid metabolism through cyclooxygenase (COX), lipoxygenase (LOX) and cytochrome P-450 epoxygenase (EPOX) pathways leads to the generation of biologically active eicosanoids, including prostanoids, leukotrienes, hydroxyeicosatetraenoic acid, epoxyeicosatrienoic acid and hydroperoxyeicosatetraenoic acids. Eicosanoid expression levels vary during tumor development and progression of a range of malignancies, including colorectal cancer. The actions of these autocoids are also directly influenced by diet, as demonstrated by recent evidence for omega-3 fatty acids in colorectal cancer (CRC) prevention and/or treatment. Eicosanoids regulate CRC development and progression, while inhibition of these pathways has generally been shown to inhibit tumor growth/progression. A progressive sequence of colorectal cancer development has been identified, ranging from normal colon, to colitis, dysplasia, and carcinoma. ...Finally, novel approaches targeting these arachidonic acid-derived eicosanoids (using pharmacological or natural agents) for chemoprevention and/or treatment of colorectal cancer are outlined. "  [18]

Dietary Regulation of AA Metabolism

In the January 9, 1892 issue of Scientific American, an article stated that some members of the French  Society For The Advancement of Science believed already that "Reclus, the French Geographer, has proved that cancer is most frequent among those branches of the human race where carnivorous habits prevail."  This was before the widespread practice of raising animals on corn-based concentrated feed, suggesting that if diets rich in animal foods do increase the risk of cancer, they do so by components that occur in those foods regardless of the animal's diet, such as arachidonic acid.

More than 110 years later, scientists still find cancer risks elevated by consumption of various types of red meat [e.g. 20 full text] or poultry and eggs [e.g. 21].  Some data also suggests that fish oils may promote cancer metastases more potently than safflower oil:

"Rats were kept on either a low-fat diet or on a fish oil (omega-3 PUFAs) or safflower oil (omega-6 PUFAs) diet for 3 weeks before the administration of colon cancer cells to the portal vein, until they were sacrificed at 1 or 3 weeks after tumor transplantation. At 1 week after transplantation, the fish oil diet had induced 7-fold more metastases (in terms of number and size) than had the low-fat diet, whereas the safflower oil diet had not affected the number and total volume of metastases. At 3 weeks after tumor transplantation, the fish oil diet and the safflower oil diet had induced, respectively, 10- and 4-fold more metastases (number) and over 1000- and 500-fold more metastases (size) than were found in the livers of rats on the low-fat diet."[22 full text]
"PUFAs are incorporated into the membranes of both cancer cells and normal cells, altering their physical and functional properties (30, 39), which may interfere seriously with immunological surveillance against cancer cells. Furthermore, n-3 PUFA supplementation decreases cytokine production (40) and MHC class II expression on the cell surface of antigen-presenting macrophages (41, 42), thus interfering with the immune response (43, 44)."[22 full text]
In this study, "Fish oil and safflower oil were kept at 4°C under nitrogen to avoid autooxidation of PUFAs. Vitamin E levels in the food were kept at a minimum of 35 mg/kg of
the low-fat diet [5% (v/w) soybean oil] and at 75 mg/kg of the n-3 and n-6 PUFA diets [20% (v/w) fish oil or safflower oil. respectively] to avoid vitamin E deficiency."  Thus the ill effect of the oils in this study were not likely due to oxidation of the PUFAs.

As the amount of animal flesh, fat, and eggs in the diet increases, so does the intake of AA, which could promote AA metabolism; the more AA present in cells, the more substrate for the COX (cycloxygenase), LOX (lipoxygenase), and EPOX (expoygenase) enzymes that metabolize AA; this would result in chronic increases in PGE2 and chronic reductions in production of TNF.  As noted above [22 full text], omega-3 PUFA supplementation also interferes with immune responses involved in controlling cancer. 

This provides a couple of possible mechanisms by which a diet rich in animal flesh or eggs could support cancer development.  Briefly, chronically eating more food rich in AA would result in greater production of PGE2, which would chronically decrease production of TNF, which could reduce the control that the body has over tumor cell lines.  Eating food rich in n-3 fats (fish oils) would also depress cytokine production and MHC class II expression on the cell surface of antigen-presenting macrophages, also reducing the effectiveness of immune-system control of malignant cells.

Cancerous tumors start as single cells, and progress to detectable tumors by cell-division over the course of six to ten years.  Dr. John McDougall M.D. explains:

"The doublings remain undetectable until the cancer reaches a size of 1 mm (period-size), which now contains a million cells, after about 6 years of growth. After 10 years of growth, the tumor is 1 cm in diameter (eraser-size) and contains one billion cells. At this point in its natural history the doublings become very apparent: one billion cancer cells divide into a mass containing two billion cells, and with the next doubling there are 4 billion cancer cells inside the patient’s body. Thus, cancer is undetectable by the patient and his physician for the first two-thirds of its natural history, and this leads to confusion." [23]
Recognizing that tumors start as single malignant cells, we can appreciate how only a seemingly minor depression of immune function, e.g. a small chronic decrease in TNF production, or other alteration in the cell's environment could favor the survival of just one malignant cell, allowing it to divide to produce two, then four, then eight cells, and so on, for years, until one has a detectable tumor.


Plants provide many compounds that inhibit the COX (cycloxygenase), LOX (lipoxygenase), and EPOX (epoxygenase) enzymes that metabolize AA to PGE2 and other compounds :


"In this review, we present evidence that numerous agents identified from fruits and vegetables can interfere with several cell-signaling pathways. The agents include curcumin (turmeric), resveratrol (red grapes, peanuts and berries), genistein (soybean), diallyl sulfide (allium), S-allyl cysteine (allium), allicin (garlic), lycopene (tomato), capsaicin (red chilli), diosgenin (fenugreek), 6-gingerol (ginger), ellagic acid (pomegranate), ursolic acid (apple, pears, prunes), silymarin (milk thistle), anethol (anise, camphor, and fennel), catechins (green tea), eugenol (cloves), indole-3-carbinol (cruciferous vegetables), limonene (citrus fruits), beta carotene (carrots), and dietary fiber. For instance, the cell-signaling pathways inhibited by curcumin alone include NF-kappaB, AP-1, STAT3, Akt, Bcl-2, Bcl-X(L), caspases, PARP, IKK, EGFR, HER2, JNK, MAPK, COX2, and 5-LOX. The active principle identified in fruit and vegetables and the molecular targets modulated may be the basis for how these dietary agents not only prevent but also treat cancer and other diseases. This work reaffirms what Hippocrates said 25 centuries ago, let food be thy medicine and medicine be thy food." [24 ]


Since plants provide no AA (nor long chain omega-3 fats) but many COX2, LOX, and EPOX inhibitors, we could consider them among the "novel approaches" for preventing overproduction of the arachidonic acid-derived eicosanoids and thus "for chemoprevention and/or treatment of" cancer suggested by  [18].

We can expect that diets high in plants and low in or absent animal products would reduce the risk or even stem the growth of cancers, the latter of which has some confirmation by research I discussed here.


Other diseases linked to metabolites of AA include:


  • Inflammatory bowel disease [25 full text]
  • Alzheimer's disease [26]
  • Ischemic heart disease [27 full text]
  • Psoriasis and dermatitis [28, 29]
  • Rheumatoid arthritis [e.g. 30]
  • Osteoarthritis [31, 32, , 36] "Our results demonstrated that AA enhanced superoxide production in RA and OA cells..."[32]
  • Migraine headaches [33]
  • Dysmenorrhea (menstrual pain) and endometriosis [34]
  •  Cystic disease of the breast [35]
  • Osteoporosis [37]
That's just a quickly composed list.  The AA cascade drives inflammation, and chronic inflammation causes tissue damage and malfunction.

In Chinese medicine, we call inflammation pathological 'heat' (a term no less scientific than 'inflammation' which literally means 'in flames'), and land-animal meats and fats are considered common dietary promoters of conditions involving pathological heat, while many plant foods and herbs are considered 'cooling' by which we mean that they reduce or eliminate pathological heat.

Chinese physicians came to this information through logical deductions based on the yin-yang theory, combined with self-experimentation and extensive clinical experience and collaboration.  Plants have relatively yin (i.e. more water-like) characteristics like high water content, relative immobility, relative insentience, silence, low temperature, and dominance by the blue-green color spectrum, while animals generally exhibit relatively yang (i.e. more fire-like) characteristics like lower water content, mobility, greater sentience, loud sounds, inherent warmth, and dominance by the red-yellow color spectrum.

Further, the green parts of plants spend daylight hours in direct hot and drying (yang) sunlight, to which they must adapt by countermeasures that cool and moisten, so the green parts of plants must have cooling and moistening properties to survive; but animals live by burning up (oxidizing) foods, the way a fire burns up (oxidizes) fuel, so animal tissues must have fire-like oxidizing and heating properties in order to survive.

Since animals generally are more like fire (with some exceptions), and plants generally more like water, yin-yang theory predicts that many foods from animals will probably generate more heat and dryness in varying degrees (relative to plants), while many foods from plants will generally reduce heat and generate moisture.  Chinese medicine applies yin-yang theory empirically and flexibly, not dogmatically, and recognizes, for example, that some animal foods have many relatively yin characteristics (e.g. milk, mussels) while some plant foods have yang characteristics (e.g. garlic, cinnamon, chili peppers).  Thus, yin-yang theory also predicts that if a plant or animal food has atypical characteristics, like chili peppers or cinnamon bark (both red, dry, and hot), it will have corresponding effects (e.g. cinnamon will have a warming effect).  Chinese physicians tested this hypothesis with self-experimentation and then clinical application, eventually producing the current Chinese materia medica which categorizes items (mineral, vegetable, and animal) according to thermal and other effects.

The information in this article indicates that Western science supports this point of view, providing some partial biochemical explanations for the traditional Chinese medical view, i.e. arachidonic acid as a promoter of inflammation, and various anti-inflammatory plant compounds as inhibitors of inflammation.

8 comments:

LeonRover said...

Nice article, Don.

Excess exogenous AA as inflammation promoter - a better dietary explanation than Barry Sears' ideas of some 15 years ago.

The ingestion of more "green & coloured" plant foods as practiced by Dr Terry Wahl's to the improvement of her MS outcomes is added information to the idea promoted by Gerson many years ago. My (then) wife used extensive juicing for a period of 2-3 years, and to it she ascribed remission if her diagnosed breast cancer.

Peter said...

Don,

have you seen this? You could blog about this upcoming study. The press release came yesterday.

Study shows how high-fat diets increase colon cancer risk (Public release date: 7-Mar-2012)

http://www.eurekalert.org/pub_releases/2012-03/tu-ssh030712.php

WoLong said...

This paper looks interesting, talks out PUFA on intestinal cancers. http://jn.nutrition.org/content/134/12/3421S.full

Bryan - oz4caster said...

Don, from what you are reporting it seems to me that the SAD diet is the worst possible diet because it is high in both AA and n-6 PUFA, not to mention high amounts of fructose. I'm skeptical that AA in a paleo diet that is primarily meat and vegetables would be very detrimental. From what I remember reading, even the Inuit and Masai when eating their native diets which are very high in animal foods had little or no cancer. If that's true, then perhaps another unaccounted factor mediated the AA effects in those diets.

Don said...

Bryan,

It is very difficult to know whether precontact Inuit or Masai had cancer before White contact. The small size of their populations and high mortality before old age reduced the number of people who reached the age range in which most cancers occur. When 30-40% of the population fails to make it to age 50 because of infant mortality, accidents, and infections, this greatly reduces the number of people who can develop cancer, a disease associated with aging.

But it seems likely that the Inuit did have a problem with cancer, since modern studies show they have rates equal to or higher than industrialized nations.

"The authors collected and analyzed cancer incidence data for Alaska Natives (Indians, Eskimos, and Aleuts) for the 15-year period 1969-83 by ethnic and linguistic groups. Compared with U.S. whites, observed-to-expected ratios are high in more than one ethnic group for cancer of the nasopharynx, salivary gland, liver, gallbladder, and cervix. Low ratios were found for cancer of the breast, uterus, bladder, and melanoma."

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1580163/

Also, I seem to recall seeing some early reports of Inuit mummies showing extensive malignancies, but don't have the reference.

Nevertheless, the epidemiological data points clearly at meat consumption increasing the risk of cancer in modern populations, of which you and I are a part. Further, besides AA there are many other mechanisms by which meat consumption may promote cancer, which I will discuss here in the future.

I won't take my chances with excess AA. Any dietary AA is excess, unless you have absolutely no LA in your diet, which with whole foods is virtually impossible (since meat also contains LA n-6).

Don said...

"When 30-40% of the population fails to make it to age 50 because of infant mortality, accidents, and infections, this greatly reduces the number of people who can develop cancer, a disease associated with aging."

This reduces the risk of cancer in the primitive population (e.g. the Inuit) but not for the individual. Since within a primitive population a relatively low percentage of individuals reach an age at which cancer can appear (because typically cancer is a long-latency, slow-to-manifest disease), cancer will appear to rarely occur among them, even if their diet does promote cancer.

This is why we need to use studies of modern, large populations, with high proportions of elders, not guesses about past populations, with low proportions of elders, to study the incidence of chronic degenerative diseases like cancer.

In other words, small primitive populations like the Inuit and Masai can't tell us much, if anything, about how diet affects cancer risk, until you get most of their individuals to live to age 50 and beyond.

gwarm said...

DrG's latest volume is out
http://tinyurl.com/drgvolume8
-
Older volume 6 and 7 and all vol 1-5
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And McEwen mentioned you around 50min in recently.

Jennifer Vajda said...

It's wonderful to see this information in one article, Don. However unless you already have prostate or colon cancer moderate use of food sources of lecithin/AA or LA is probably fine.

AA is part of membranes under normal conditions. AA can be converted from lecithin and combined with ethanolamine to become anandamide, an eCB. Lab tests are finding free AA once it has been broken down from eCBs in response to inflammatory signals. The eCBs in times of health are part of the membrane structure and there would be no free AA.

Linolenic acid and omega 6's may have gotten a bad name partially because larger research studies may not have excluded people with undiagnosed prostate or breast cancer. Their negative responses to a diet high in LA may have skewed the results of other people with normal tolerance for foods with LA or animal products with lecithin/AA.

Regarding the native peoples study: "In other words, small primitive populations like the Inuit and Masai can't tell us much, if anything, about how the diet affects cancer risk ..."
It is informative that both native and white groups got cancer but they got it in different types of organs. So they both had something in common in their diet or environment that promoted development of cancer but they also had differences in the different types of cancer.
This link is the fourth in a series that I wrote regarding the First Nations report on cancer. http://gingerjens.blogspot.com/2012/05/cancer-iodine-and-selenium-deficiency.html