Omega-3s, Angiogenesis and Cancer: Part II

Posted by on April 29, 2011 62 comments

On Tuesday (Omega-3 Fats, Angiogenesis, and Cancer: Part I, April 26, 2011) I introduced the issue of possible relationships between omega-3 fatty acids, their lipid peroxidation products, and diseases of angiogenesis such as cancer, and promised to discuss a possible mechanism today.

It may be well, however, to start by saying a little bit more about the Brasky paper [1] linking prostate cancer to DHA.

Denise Minger’s Commentary on the Brasky Paper

Denise Minger wrote a commentary on this paper for Mark’s Daily Apple, which is excellent. Her conclusion – “given the oxidation-prone nature of all polyunsaturated fats, a massive intake of omega-3’s – despite their brilliance in moderation – could potentially do more harm than good” – is the proper one.

A few of Denise’s observations, however, could stand elaboration.

The study measured the fraction of serum phospholipid fatty acids in various polyunsaturated and trans-fat species, not dietary intake. This is the right parameter to measure, as fatty acid profiles can be measured precisely while dietary intakes assessed through questionnaires are notoriously unreliable. Also, phospholipids are the fats in cell membranes, and these are the ones involved in the inflammatory signaling pathways long thought to drive cancer risk. So cell membrane lipid measurements have the best chance to demonstrate a link to cancer risk.

Denise makes the important point, however, that the connection between dietary fish oil intake and serum fatty acid profile is not simple. Higher DHA intake raises phospholipid DHA levels, but lower intake of non-omega-3 fats also raises the DHA fraction. She points to a study [2] comparing a low-fat diet (20% fat, 6.7% PUFA, n-6:n-3 ratio 11.1) to a high-fat diet (45% fat, 15% PUFA, n-6:n-3 ratio 12.3).  The low-fat diet had more of its fat in the form of long-chain omega-3s, but the specific DHA intake on the diets was not reported. Membrane DHA ended up 28% higher on the low-fat diet.

So if DHA is dangerous, low-fat dieters will be in the most trouble. Another reason to eat a high-fat diet!

Does this affect our interpretation of the Brasky study? I don’t think it affects it much, because study participants were healthy at the start of the study with no history of cancer and macronutrient intakes don’t vary a lot among the general public. Americans vary surprisingly little from the median of about 50% carbs, 15% protein, and 35% fat – so it’s likely that the quartile with high tissue DHA levels were also high fish oil consumers.

However, study participants were followed for 7 years, at which point their prostate cancer status was assessed. Incidence of low-grade prostate cancers had no association with start-of-the-study DHA intake, but incidence of high-grade prostate cancers was strongly associated.

Here are a couple of possible explanations for this pattern:

  1. DHA is bad: DHA doesn’t drive early cancer development but does drive late-stage cancer growth – i.e. the transition from low-grade to high-grade cancer. So the DHA consumers got the high-grade cancers. Angiogenesis does, in fact, drive the shift from low-grade to high-grade cancer, so a DHA-angiogenesis association would be consistent with this explanation.
  2. Hospital diet advice is bad: DHA was a marker at the start of the study for conscientious, educated, disciplined persons who followed health advice and ate fish oil. When these people were diagnosed with low-grade cancer, they followed the dietary advice of their cancer dietitian. The dietitian’s advice?  Eat lots of wheat, whole grains, legumes, and vegetable oils. It could be the conscientious folks who followed bad diet advice from the hospital dietitian who got the high-grade cancers.

So there is a possible confounding effect.

Another of Denise’s assertions is that there is an “otherwise consistent train of research showing that DHA seems protective at best (and neutral at worst).” Now it is true that there are more studies showing DHA to have benefits against cancer than harm. But this trend is hardly consistent, and the vast majority of studies have failed to detect a relationship.

In the comments to Tuesday’s post, eric linked to a 2005 meta-review of studies on omega-3 fats and cancer. [3] The reviewers looked at 1,210 journal articles and found a mixed bag of mostly insignificant evidence:

Significant associations between omega-3 consumption and cancer risk were reported for lung cancer in two studies; for breast cancer in one; for prostate cancer in one; and for skin cancer in one. However, for lung cancer, one of the significant associations was for increased cancer risk and the other was for decreased risk (four other risk ratios were not significant for lung cancer). For breast cancer, five other estimates did not show a significant association. Only one study assessed skin cancer risk. No effects were reported for cancers of the aerodigestive tract, bladder cancer, colorectal cancer, lymphoma, ovarian cancer, pancreatic cancer, or stomach cancer. Thus, omega-3 fatty acids do not appear to decrease overall cancer risk.

Data were insufficient to permit assessment of a temporal or dose-response relationship. [3]

So the score was 4 studies finding that DHA is associated with less cancer, 1 that it is associated with more, and a boatload that it had no association.

Now there are two ways of interpreting this general insignificance of DHA against cancer. One is to note that there are slightly more studies showing DHA to have benefits than harm, and therefore to judge that DHA might be helpful against cancer.

But another, equally plausible, interpretation is this. Most Americans eat far too much omega-6, and their omega-6 to omega-3 tissue ratio is too high, which is pro-inflammatory via the COX-2 pathway. Eating omega-3s including DHA reduces inflammation by downregulating the COX-2 pathway. This accounts for the well-attested benefits of DHA against cardiovascular disease. Now, cancer is promoted by COX-2 pathway inflammation, which is why COX-2 inhibitors such as aspirin and ibuprofen are protective against cancer. [4] DHA’s action to downregulate this pathway must generate an anti-cancer effect. But, unlike aspirin and ibuprofen, DHA has no observable effect on overall cancer risk. This suggests that DHA has other effects, unrelated to its anti-inflammatory activity, that are cancer promoting. These counterbalance the benefits from its anti-inflammatory effect. If DHA has pro-angiogenic effects that are independent of COX-2 mediated inflammation, then this could account for the observations.

One reason an association of DHA with high-grade cancer may have been missed is that it would be detected only in large studies able to segregate cancers by grade. Brasky et al note:

In the European Prospective Investigation into Cancer and Nutrition (EPIC) (12), the highest quintile of percent DHA was associated with elevated risks of both low-grade (relative risk (RR) = 1.53, 95% CI: 0.96, 2.44) and high-grade (RR = 1.41, 95% CI: 0.76, 2.62) prostate cancer. They also reported significant positive associations of the percent EPA with high-grade prostate cancer (RR = 2.00, 95% CI: 1.07, 3.76). Given that the Prostate Cancer Prevention Trial and the European Prospective Investigation into Cancer and Nutrition, the 2 largest studies of blood levels of phospholipid fatty acids, reported increased risks of high-grade prostate cancer with high levels of ω-3 fatty acids, it remains a possibility that these fatty acids promote tumorigenesis. [1]

If there were no other evidence linking DHA to angiogenesis, the Brasky and EPIC study associations would be interesting, but unlikely to change anyone’s mind. Denise points out the need for other evidence – especially, mechanistic evidence – to make the connection more plausible:

We haven’t sleuthed out any mechanism that could explain why DHA (but not other polyunsaturated fats) promotes rapid tumor growth.

And this is where today’s post comes in. In fact, there is a known mechanism by which DHA but not other polyunsaturated fats can promote rapid tumor growth. Shou-Ching told me about it a few months ago.

DHA and Angiogenesis in Macular Degeneration

Let’s start by going back to 2003 and a paper on the role of a compound called carboxyethylpyrrole (CEP) in age-related macular degeneration (AMD). [5] AMD is an eye disease caused by improper angiogenesis. Basically, malformed blood vessels overgrow the eye, causing retinal detachment and blindness. It afflicts 35% of those over age 75, and is the leading cause of blindness in developed countries. CEP? Well, the paper explains:

Free radical-induced oxidation of docosahexaenoate (DHA)-containing lipids generates ω-(2-carboxyethyl)pyrrole (CEP) protein adducts that are more abundant in ocular tissues from AMD than normal human donors…. The CEP adduct uniquely indicates oxidative modification from DHA derivatives because CEP protein modifications cannot arise from any other common polyunsaturated fatty acid. [5]

CEP is uniquely produced by oxidation of DHA, not other PUFAs. Its abundance depends on DHA abundance, availability of retinyl proteins, and the level of oxidative stress.

CEP is elevated in AMD. The correlation is strong: a person in whom the immune system is trying but failing to clear elevated CEP levels almost invariably has macular degeneration (AMD):

Of individuals (n = 13) exhibiting both antigen and autoantibody levels above the mean for non-AMD controls, 92% had AMD. [5]

So CEP is a great marker for AMD. Is it causal?

Well, first it’s worth noting that the retina is uniquely vulnerable to DHA oxidation:

Although rare in most human tissues, DHA is present in ~80 mol % of the polyunsaturated lipids in photoreceptor outer segments (13). The abundance of DHA in photoreceptors, the high photooxidative stress in retina, and the fact that DHA is the most oxidizable fatty acid in humans (13) suggests that DHA oxidation products may have possible utility as biomarkers for AMD susceptibility. [5]

Oxidation is linked to AMD, and antioxidants slow AMD progression:

Oxidative damage appears to contribute to the pathogenesis of AMD (4) based on epidemiological studies showing that smoking significantly increases the risk of AMD (1, 24). The molecular mechanism for how smoking enhances the risk for AMD is not known. We speculate that reactive oxygen and nitrogen species derived from tobacco smoke in the lungs leads to oxidative protein modifications in the blood that contribute to drusen formation and choroidal neovascularization. Results from a recent clinical trial (5) also demonstrate that the progression of AMD can be slowed in some individuals by high daily doses of antioxidant vitamins and zinc. Direct evidence of oxidative damage in AMD donor eye tissues include elevated levels of CEP adducts uniquely derived from the oxidative fragmentation of DHA (6). [5]

This is where things stood in 2003. By 2010 this group, led by Case Western Reserve University chemist Robert G. Salomon, had established that administering CEP to mice can cause AMD:

To test the hypothesis that this hapten is causally involved in initiating an inflammatory response in AMD, we immunized C57BL/6J mice with mouse serum albumin (MSA) adducted with CEP. Immunized mice develop antibodies to CEP, fix complement component-3 in Bruch’s membrane, accumulate drusen below the retinal pigment epithelium during aging, show decreased a- and b-wave amplitudes in response to light, and develop lesions in the retinal pigment epithelium mimicking geographic atrophy, the blinding end-stage condition characteristic of the dry form of AMD. Inflammatory cells are present in the region of lesions and may be actively involved in the pathology observed. [6]

This constitutes the first really good animal model for AMD. [6]

How does this relate to cancer? That leads us to a Nature paper from October 2010 [7], from the group of Tatiana Byzova at the Cleveland Clinic.

DHA, Immunity, and Angiogenesis

This is a rich paper. Briefly, CEP has a physiological function: it is transiently elevated in wounds and recruits immune cells from bone marrow to the site of the wound. These immune cells further increase oxidative stress and promote angiogenesis; CEP levels are highest at the time of peak angiogenesis. CEP is highly elevated in cancers. Unlike in wounds, where CEP is elevated for a few days, in cancers CEP elevation is chronic.

Here’s a staining comparing CEP in normal skin and in melanoma:

The CEP is co-localized with CD68, a glycoprotein which binds to LDL and is found on macrophages, and with CD31, a membrane marker of neutrophils, macrophages, and endothelial cells. CEP is marking endothelial cells and white blood cells in angiogenic vessels, and possibly LDL.

It turns out that CEP drives angiogenesis by attaching to an immune receptor, Toll-like receptor 2 (TLR2). There are two major pathways for angiogenesis: one driven by vascular endothelial growth factor (VEGF), which is dominant in conditions of hypoxia (oxygen starvation), and one by TLR2. Of these, the TLR2 pathway may in some contexts be more important. Here are pictures of wound healing in mice:

On the upper left is a normal mouse. On the upper right is a similar wound treated with the VEGF inhibitor AAL-993. This wound is rather like a cancer treated with the VEGF inhibitor Avastin. Wound healing is slightly impaired, but still works.

On the lower left is a similar wound with no VEGF inhibition, but the TLR2 pathway blocked by TLR2 knockout. The wound can’t scab and doesn’t heal successfully. If TLR2 is knocked out and VEGF inhibited, there is no wound healing at all (lower right).

You can accelerate angiogenesis and wound healing by adding CEP to the wound.

In the bottom row, CEP has been added. Left is without VEGF inhibition, right with.

If you administer CEP-neutralizing antibodies to a normal wound, wound healing takes more than twice as long. This confirms that angiogenesis driven specifically by CEP (and therefore by DHA oxidation) is part of healthy wound healing.

Tumors use these same pathways to generate vessels and feed their growth. As the paper notes:

[T]umors implanted in TLR2-/- mice exhibited dramatically decreased vascularization and increased areas of necrosis. [7]

Here’s the paper’s conclusion:

Altogether our results establish a novel mechanism of angiogenesis that is independent of hypoxia-triggered VEGF expression. The products of lipid oxidation are generated as a consequence of oxidative stress and are recognized by TLR2, possibly in a complex with TLR1 on ECs, and promote angiogenesis in vivo, thereby contributing to accelerated wound healing and tissue recovery. If high levels of CEP and its analogs accumulate in tissues, it may lead to excessive vascularization, e.g. in tumors. Contribution of the CEP/TLR2 axis to angiogenesis varies in different physiological settings possibly depending on the extent of oxidative stress. CEP-driven angiogenesis may be an attractive therapeutic target, especially in cancers resistant to anti-VEGF therapy. Inflammation and oxidation-driven angiogenesis may occur in other pathologies, for example atherosclerosis, where arterial thickening can depend on its microvasculature. In these settings, there is an extensive generation of oxidative products which might promote atherogenesis via TLR2. Indeed, it was shown that TLR2?/? mice are protected from atherosclerosis, and this effect could be mediated by cells other than bone marrow-derived29. Thus, along with pathogen- and danger-associated molecular patterns, TLR2 recognizes an oxidation-associated molecular pattern. This new function of TLR2 as a sensor of oxidative stress reveals the shortcut link between innate immunity, oxidation and angiogenesis. [7]

Connection to Vitamin A

DHA is oxidized to a compound called HOHA which then combines with a protein, generally a retinyl (vitamin A-derived) protein to form CEP.

Cancers generate lots of CEP from DHA, and perhaps one way they do that is by generating lots of retinyl proteins. Cancers are known to have disturbed vitamin A biology with lots of retinyl:

Disturbance in vitamin A metabolism seems to be an important attribute of cancer cells. Retinoids, particularly retinoic acid, have critical regulatory functions and appear to modulate tumor development and progression. The key step of vitamin A metabolism is the esterification of all-trans retinol, catalyzed by lecithin/retinol acyltransferase. In this work we show that malignant melanoma cells are able to esterify all-trans retinol and subsequently isomerise all-trans retinyl esters into 11-cis retinol, whereas their benign counterparts – melanocytes are not able to catalyze these reactions. Besides, melanoma cell lines express lecithin/retinol acyltranseferase both at the mRNA and protein levels. In contrast, melanocytes do not express this enzyme … [8]

I haven’t looked much into this literature but it may speak to higher cancer risk with excessive vitamin A intake. Thus high-vitamin A cod liver oil may be a double risk for cancer patients.

Conclusion

It looks like we have a recipe for angiogenesis:

DHA + retinyl + oxidative stress = angiogenesis

This recipe is invoked normally and properly during wound healing. But it is also invoked excessively in pathological contexts – notably in cancers and age-related macular degeneration, probably also in other angiogenesis-associated diseases such as arthritis, rosacea, obesity, psoriasis, endometriosis, dementia, and multiple sclerosis.

In the case of cancer, DHA oxidation to CEP might transform miniscule, harmless cancers to high-grade, life-threatening cancers.

Should this possibility affect our dietary omega-3 recommendations? Well, we need to know the relative importance of the three ingredients on the left side of the above equation in producing angiogenesis. Chris Kresser wondered in the comments Tuesday whether oxidation may be the key factor:

I question whether DHA supplementation would truly play a causative role in the absence of a *pro-oxidative environment*.

In other words, perhaps in someone eating a SAD, not exercising, under a lot of stress, etc. DHA is more easily oxidized and thus potentially carcinogenic.

But in someone that is keeping all other oxidative risk factors low (i.e. they’re avoiding n-6, exercising, managing stress, reducing exposure to chemical toxins, etc.) I tend to doubt that supplementing with DHA could cause significant harm.

That’s the last piece of the puzzle: how do we minimize the level of oxidized DHA?

As I replied to Chris in the comments, low-carb Paleo dieters are not out of the woods in regard to oxidative stress. Oxidative stress is generated normally during metabolism, immune function – and by cancers. If anti-oxidant minerals like zinc, copper, and selenium and vitamins like vitamin C are deficient, then oxidative stress can be very high on a low-carb Paleo diet.

At the moment, I think it’s prudent to eat no more than 1 pound of salmon or similar cold-water fish per week, to avoid further EPA/DHA supplements, and to avoid low-fat diets which tend to elevate membrane DHA levels. Moderate omega-3 consumption is especially important for those suffering from diseases of pathological angiogenesis – especially cancer. DHA is essential for good health – but in excess, it is probably dangerous.

References

[1] Brasky TM et al. Serum Phospholipid Fatty Acids and Prostate Cancer Risk: Results From the Prostate Cancer Prevention Trial. Am. J. Epidemiol. April 24, 2011 DOI: 10.1093/aje/kwr027 (Will be at http://pmid.us/21518693.)

[2] Raatz SK et al. Total fat intake modifies plasma fatty acid composition in humans. J Nutr. 2001 Feb;131(2):231-4. http://pmid.us/11160538.

[3] MacLean CH, Newberry SJ, Mojica WA, et al. Effects of Omega-3 Fatty Acids on Cancer. Summary, Evidence Report/Technology Assessment: Number 113. AHRQ Publication Number 05-E010-1, February 2005. Agency for Healthcare Research and Quality, Rockville, MD. http://www.ahrq.gov/clinic/epcsums/o3cansum.htm.

[4] Harris RE. Cyclooxygenase-2 (cox-2) and the inflammogenesis of cancer. Subcell Biochem. 2007;42:93-126. http://pmid.us/17612047.

[5] Gu X et al. Carboxyethylpyrrole protein adducts and autoantibodies, biomarkers for age-related macular degeneration. J Biol Chem. 2003 Oct 24;278(43):42027-35. http://pmid.us/12923198.

[6] Hollyfield JG et al. A hapten generated from an oxidation fragment of docosahexaenoic acid is sufficient to initiate age-related macular degeneration. Mol Neurobiol. 2010 Jun;41(2-3):290-8. http://pmid.us/20221855.

[7] West XZ et al. Oxidative stress induces angiogenesis by activating TLR2 with novel endogenous ligands. Nature. 2010 Oct 21;467(7318):972-6. http://pmid.us/20927103.

[8] Amann PM et al. Vitamin A metabolism in benign and malignant melanocytic skin cells: Importance of lecithin/retinol acyltransferase and RPE65. J Cell Physiol. 2011 Apr 4. doi: 10.1002/jcp.22779. [Epub ahead of print] http://pmid.us/21465477.

Omega-3 Fats, Angiogenesis, and Cancer: Part I

Posted by on April 26, 2011 69 comments

In the book we discuss the issue of omega-3 toxicity (pp 56-58, 71-72), why it is most dangerous when omega-3 fats are combined with alcohol or fructose, and why fish oil capsules are particularly dangerous (see Fish, Not Fish Oil Capsules, June 16, 2010).

We recommend eating about 1 pound per week of omega-3 rich marine fish, like salmon, sardines, or herring, but taking no omega-3 supplements. This amount is sufficient to optimize the tissue omega-6 to omega-3 ratio for cardiovascular health, and is not so great as to raise great risks of toxicity. We also recommend avoiding mixing omega-3 fats with sugar or alcohol – a point I reiterated in last week’s post (How to Raise HDL, April 20, 2011):

Drink alcoholic beverages – but only when consuming meals low in polyunsaturated fats. Drink up when you eat beef, but be cautious when the entrée is salmon.

Some new papers have recently come out on the subject of omega-3 toxicity, and may lead some in the Paleo community, possibly including us, to reconsider our advice about omega-3 fats.

High Omega-3 Intakes in the Paleo Community

Our 1 pound fish per week recommendation works out to about 1.5 g omega-3 fats per day. But some Paleo authorities recommend much higher intakes.

Various emailers and commenters have mentioned Robb Wolf’s recommendations. Beth summarized Robb’s advice:

Robb Wolf promotes a short period of hefty omega 3 supplementation for unhealthy folks — on the order of 1g/10lbs of body weight per day.

Which would work out to 18 g/day for me, about 12-fold more than we recommend. Of course, if this is only for a short period, it may not be a big deal. However, I know from emails that some people take large doses continuously. Here’s one of my emailers:

Supplements are 10g of fishoil – 3.5g of epa/dha …

Bit surprised about [recommendation to reduce] the Fish oil, since i’m on the very low end of what other people are recommending, for fat loss as well, ie. robb wolf, poliquin etc.

The Whole9 folks host a Robb Wolf fish oil calculator which recommends that a 180-pound man take 4.5 g EPA+DHA per day. Depending on whether it is accompanied by other omega-3 fats in fish oil, this could be anywhere from 3 to 10 times our recommended intake, and is in line with what my emailer was taking.

Some Known Consequences of Omega-3 Excess

What are the likely consequences of omega-3 toxicity?

The obvious dangers are those related to oxidative stress from lipid peroxidation. The concern with omega-3 fats is not direct toxicity, but toxicity from their oxidation products. Omega-3 fats have a lot of fragile carbon double bonds which are easily oxidized: EPA has 5 double bonds and DHA 6. These are therefore among the most fragile lipids in the human body.

We would expect such problems to show up primarily in the liver and in the nervous system, where EPA and DHA levels are highest.

Indeed, they do. In mice, high dietary omega-3, in conjunction with alcohol or sugar, induces fatty liver disease. [1] In pregnant rats, excessive doses of omega-3 fats cause offspring to have shortened life span and neural degeneration. The authors concluded, “both over- and under-supplementation with omega-3 FA can harm offspring development.” [2]

However, there are associations of high omega-3 intake with disease in other tissues. In particular, emerging work is linking high omega-3 intake to diseases of pathological angiogenesis.

Angiogenesis is the creation of new blood vessels in mature tissue. (Vasculogenesis is the creation of vessels in a developing embryo.) It is a normal part of wound healing, but over a dozen diseases feature inappropriate angiogenesis.

Omega-3 Intake Is Usually Anti-Angiogenic

Before I go further, let me emphasize that nothing I am saying here repudiates the idea that it is desirable to bring tissue omega-6 and omega-3 fats into proper balance.

There are many studies showing that when tissue omega-6 to omega-3 ratios are too high, as on the standard American diet (SAD), additional omega-3 DHA and EPA can improve the omega-6 to omega-3 balance, reduce inflammatory signaling, and through reduced inflammation exercise an anti-angiogenic effect.

The mechanisms linking the anti-angiogenic effects of omega-3 to a condition of omega-6 excess are fairly well understood. Here is one description of the mechanism:

Here, we demonstrate that omega-6 PUFAs stimulate and omega-3 PUFAs inhibit major proangiogenic processes in human endothelial cells, including the induction of angiopoietin-2 (Ang2) and matrix metalloprotease-9, endothelial invasion, and tube formation, that are usually activated by the major omega-6 PUFA arachidonic acid. The cyclooxygenase (COX)-mediated conversion of PUFAs to prostanoid derivatives participated in modulation of the expression of Ang2. Thus, the omega-6 PUFA-derived prostaglandin E2 augmented, whereas the omega-3 PUFA-derived prostaglandin E3 suppressed the induction of Ang2 by growth factors. Our findings are consistent with the suggestion that PUFAs undergo biotransformation by COX-2 to lipid mediators that modulate tumor angiogenesis, which provides new insight into the beneficial effects of omega-3 PUFAs. [3]

So the question at issue is not whether omega-6 and omega-3 balance needs to be achieved. Rather, two points are at issue:

(a)  At what level of polyunsaturated (and omega-3) fat intake should balance be achieved – high or low?

(b)  Does overshooting toward an omega-3 excess generate significant or insignificant dangers?

If omega-3 toxicity is significant, then it will be important to achieve balance at low intakes of both omega-6 and omega-3, and to be careful to avoid overshooting to an omega-3 excess.

New Paper: DHA Linked to Cancer Progression

A new paper, just published yesterday, from “the largest study ever to examine the association of dietary fats and prostate cancer risk” has linked blood DHA levels to cancer risk. Specifically:

Docosahexaenoic acid was positively associated with high-grade disease (quartile 4 vs. 1: odds ratio (OR) = 2.50, 95% confidence interval (CI): 1.34, 4.65) … [4]

This is a large effect: the highest quartile had 2.5-fold higher risk than the lowest-quartile.

That it was the omega-3 DHA specifically, and not polyunsaturated fats generally, that caused the problem, is supported by the fact that (note: edited to correct error in original post – PJ) omega-6 linoleic acid had no effect, and 18:1 and 18:2 trans-fats which are mostly obtained from partially hydrogenated vegetable oils were associated with protection against cancer:

TFA 18:1 and TFA 18:2 were linearly and inversely associated with risk of high-grade prostate cancer (quartile 4 vs. 1: TFA 18:1, OR = 0.55, 95% CI: 0.30, 0.98; TFA 18:2, OR = 0.48, 95% CI: 0.27, 0.84). [4]

People in the top trans-fat quartile had only half the risk of people in the lowest omega-6 quartile. This makes it looks like omega-6-derived trans-fats were protective.

This result conflicts with the idea that the only influence of omega-3 fats is through regulation of inflammation; if so the anti-inflammatory omega-3 would have suppressed cancer. As lead study author Theodore Brasky said in the press release:

“We were stunned to see these results and we spent a lot of time making sure the analyses were correct,” said Brasky, a postdoctoral research fellow in the Hutchinson Center’s Cancer Prevention Program. “Our findings turn what we know — or rather what we think we know — about diet, inflammation and the development of prostate cancer on its head and shine a light on the complexity of studying the association between nutrition and the risk of various chronic diseases.”

Angiogenesis A Possible Pathway

Angiogenesis is very important for cancer progression. Cancers need to form angiogenic vessels if the tumor is to be able to grow beyond about 0.5 mm (0.02 inch) in diameter.

Indeed, angiogenesis seems to be a controlling factor for cancer mortality risk. It is believed that 50% of adults over age 40, and 100% of adults over age 70, have microscopic cancers. However, most tumors never develop an ability to induce angiogenesis and thus the tumors never grow beyond 0.5 mm and cause no observable disease.

Dietary factors that promote angiogenesis favor cancer progression, and anti-angiogenic factors tend to prevent cancer progression. Diet seems to be crucial for cancer prevention. Here is a TED video by Dr. William Li discussing the link between angiogenesis, dietary influences upon angiogenesis, and cancer.

Conclusion

So far, we’ve set the stage. On Thursday I’ll discuss a mechanism by which excessive DHA intake may promote angiogenesis. If this mechanism is important, then excessive fish oil or DHA supplementation may act as a major cancer-promoting food.

UPDATE: The next post in this series: Omega-3s, Angiogenesis and Cancer: Part II

References

[1] Nanji AA et al. Dietary saturated fatty acids: a novel treatment for alcoholic liver disease. Gastroenterology. 1995 Aug;109(2):547-54. http://pmid.us/7615205.

[2] Church MW et al. Excess omega-3 fatty acid consumption by mothers during pregnancy and lactation caused shorter life span and abnormal ABRs in old adult offspring. Neurotoxicol Teratol. 2010 March – April;32(2):171-181. http://pmid.us/19818397.

[3] Szymczak M et al. Modulation of angiogenesis by omega-3 polyunsaturated fatty acids is mediated by cyclooxygenases. Blood. 2008 Apr 1;111(7):3514-21. http://pmid.us/18216296.

[4] Brasky TM et al. Serum Phospholipid Fatty Acids and Prostate Cancer Risk: Results From the Prostate Cancer Prevention Trial. Am. J. Epidemiol. April 24, 2011 DOI: 10.1093/aje/kwr027 (Will be at http://pmid.us/21518693.)

Thank You From Shou-Ching

Posted by on April 24, 2011 29 comments

I would like to thank all of you who wished me well on my baptism.

Ten years ago, in a time of difficulty, Paul told me that “Love conquers everything.”

I have been attending church ever since. It took a long time for my perspective to change: to shift from a reductionist perspective I thought of as “scientific” toward a fuller view of living, dying, and spirit. Only after this was I ready to enter the church.

I am still in search of wisdom, but now I am persuaded: true wisdom is found through love.

I would like to share with you a few paintings in which I’ve tried to express the spirit of love. This is a pastel I started the day after Paul and I met:

This is an oil painting:

This is an oil pastel of the first dance at our wedding:

God bless all of you and Happy Easter!

Around the Web, Easter Vigil Edition

Posted by on April 23, 2011 34 comments

Today is Holy Saturday, the day when Jesus joined the dead; a day of sorrow as we await Easter and rebirth. Tonight, at the Easter Vigil mass at St Paul’s Church in Harvard Square, Shou-Ching will be baptized and received into the Roman Catholic Church.

[1] Interesting posts this week: Bix at Fanatic Cook finds another study showing that calcium supplements increase risk of heart attack and stroke. Ned Kock discusses why older Inuit had lower bone mineral density. Stan the Heretic links to a study showing that if you have heart disease and want to eat a BIG meal, you should make it fatty. Jimmy Moore discusses the rising cost of coconut oil. Jimmy recounts his 7 day fast here. Jamie Scott provides background on the epigenetics of obesity, and a recipe for shrinking pig brains. Mark Sisson explains how to breathe. CarbSane finds that exercise is highly under-rated for fat (not weight) loss. Earlier, CarbSane engaged her critics on insulin. From Kit Perkins, a correspondent of Richard Nikoley, comes a good line indicating the link between hunger and fat regulation:  “for me and a lot of others, we felt the most hungry when gaining fat and the most satiated while losing fat.”

The New York Times “Think Like a Doctor” series is getting to be like an episode of House. Test your analytical skills: The puzzle. The solution.

Finally, Don Matesz gives us more evidence from the China Study. Rice, fish, meat, and green vegetables are good. Wheat, other grains including corn, legumes, and light-colored vegetables are bad.

[2] Aw Maa!:

Via Yves Smith.

[3] Autism and Diet: “Best of Emily” continues at Psychology Today with two posts on the links between opioid peptides, leaky gut, and autism, and evidence in support of two possible fixes:  a gluten-free casein-free diet and low dose naltrexone.

LDN enhances bacterial and viral immunity, and there are links between autism and viral infection, so we consider LDN as a highly plausible frontline therapy for autism.

Emily has a third post that mentions evidence that maternal malnutrition contributes to autism. In it she links to a free review of maternal nutrition and birth outcomes.

[4] 10 Years of Weight Loss: My favorite post this week was from Seth Roberts, reporting 10 years of weight measurements from one of his readers:

Low-carb dieting worked great for a time – Alex lost 50 pounds in his first year on low-carb – but over the second year his weight bottomed at 200 pounds and went back up to 220, at which point he gave up on low-carb.

Alex went to the opposite extreme, vegetarian and vegan dieting, but gained more weight.

Then he began walking. As with the low-carb diet, he lost weight rapidly for a time and then regained some of it.

Finally, on Seth’s Shangri-La Diet he lost weight rapidly for a time, then plateaued in the 190s.

A long data series like this is instructive on the difficulties of returning to slenderness; and the tendency for weight – yes, even on low-carb low-insulin diets – to reach a plateau and then rebound.

[5] Fraud revisited: Last week (#13) I mentioned the arrest of a leading autism researcher for stealing research funds, and problems with research fraud.

This week John Hawks hints at another fraud problem in biomedical science: dishonest grant applications. This is a problem two ways:  (1) Only 15% of grants are funded, so even if a small fraction of the proposals are fraudulent, frauds may get most of the money if the “best” (read: too good to be true) proposals are funded. (2) Reviewers defend against fraud by awarding money only to people they know – their friends and the “big name” groups. So the field becomes inbred and un-innovative.

The best solution, I argued last week, would be to decentralize funding to patients and taxpayers. An Amazon-like system letting people rate researcher performance and review public records of proposals and results would be enough, I think, to guide funds to productive groups and institutions such as hospitals and universities, while enabling innovators and outsiders to get a share of funds.

[6] Preserving the Serengeti: JS Stanton has an appeal to protect migration ways of Serengeti wildlife by stopping construction of a highway through the park. (Depressing and covering the highway would be another solution.)

He provides some video as well as photos from a Guardian picture gallery:

[7] Do you know your bug type?: The New York Times reports that humans have four blood types, but only three “enterotypes” – gut microbial ecosystems. The story is based on this Nature article.

[8]  Dr Steve Parker unearths a good line:

Diet has always generated passion, and passion in science is an infallible marker of lack of evidence.

That sentence is from a review of diabetic diet cycles over the last 150 years, published in Diabetologia (2009, vol. 52, pages 1-7).

[9] The key to healthy shoulders: The Boston Globe reports that the leading cause of shoulder injuries may be misaligned shoulder blades.

This doesn’t surprise me, as the two things that most helped my shoulders were:

  1. Strengthening exercises, such as push-ups and the reverse fly, that promote shoulder blade retraction.
  2. Mobility exercises for the shoulder which retract the scapula. I like the following, which someone dubbed “shoulder dislocations”:

[10] REMOVED DUE TO DISGUST BY CO-AUTHOR. Do not watch the video linked by Stabby here.

[11] I hate when that happens: A bank in India opened a vault to find termites had eaten through millions of rupees.

[12] Beth Mazur is giddy: Beth points out a new way high-carb, high-vegetable-oil diets may promote obesity.

It turns out that insulin upregulates an enzyme that turns omega-6 fatty acids into an appetite stimulating hormone called anandamide, “which is a chemical that affects the same receptor in the brain that THC does … you know THC, it’s the active ingredient in pot. And when people smoke pot they often get … the munchies.”

Beth goes on to give a reason why American food works better than pot at causing obesity.

[13] Pesticides impact IQ: The most pesticides in the mother, the lower the IQ of the child, says The Scientist reporting on new research in Environmental Health Perspectives.

[14] Mozart: Two guys, one guitar:

[15] Another upright blogger: Emily Deans has a fancy new (hardwood!) standing desk.

[16] Ooh! Ooh! Can I have one?: If Jamie Scott’s walking desk doesn’t raise your HDL enough, consider a Dutch HDL-raising closet:

[17] Weekly video: Director Krzysztof Kie?lowski produced for Polish television a magnificent, dark but moving and inspirational, series called The Decalogue , consisting of 10 hour-long dramas each dealing with one of the Ten Commandments. The videos are on Youtube with English subtitles.

For those who have an hour to spare, in honor of Passion Week, here is Dekalog I part I:

The remainder of Dekalog I: Part 2, Part 3, Part 4, Part 5, and Part 6.