Monday, December 15, 2014

Fish Oil: Prostate Cancer Risk and Benefits

Study confirms link between omega-3 fatty acids and increased prostate cancer risk

A second large, prospective study by scientists at Fred Hutchinson Cancer Research Center has confirmed the link between high blood concentrations of omega-3 fatty acids and an increased risk of prostate cancer.

Published July 11 in the online edition of the Journal of the National Cancer Institute, the latest findings indicate that high concentrations of EPA, DPA and DHA – the three anti-inflammatory and metabolically related fatty acids derived from fatty fish and fish-oil supplements – are associated with a 71 percent increased risk of high-grade prostate cancer. The study also found a 44 percent increase in the risk of low-grade prostate cancer and an overall 43 percent increase in risk for all prostate cancers.

The increase in risk for high-grade prostate cancer is important because those tumors are more likely to be fatal.

The findings confirm a 2011 study published by the same Fred Hutch scientific team that reported a similar link between high blood concentrations of DHA and a more than doubling of the risk for developing high-grade prostate cancer. The latest study also confirms results from a large European study.

"The consistency of these findings suggests that these fatty acids are involved in prostate tumorigenesis and recommendations to increase long-chain omega-3 fatty acid intake, in particular through supplementation, should consider its potential risks," the authors wrote.

"We've shown once again that use of nutritional supplements may be harmful," said Alan Kristal, Dr.P.H., the paper's senior author and member of the Fred Hutch Public Health Sciences Division. Kristal also noted a recent analysis published in the Journal of the American Medical Association that questioned the benefit of omega-3 supplementation for cardiovascular diseases. The analysis, which combined the data from 20 studies, found no reduction in all-cause mortality, heart attacks or strokes.

"What's important is that we have been able to replicate our findings from 2011 and we have confirmed that marine omega-3 fatty acids play a role in prostate cancer occurrence," said corresponding author Theodore Brasky, Ph.D., a research assistant professor at The Ohio State University Comprehensive Cancer Center who was a postdoctoral trainee at Fred Hutch when the research was conducted. "It's important to note, however, that these results do not address the question of whether omega-3's play a detrimental role in prostate cancer prognosis," he said.

Kristal said the findings in both Fred Hutch studies were surprising because omega-3 fatty acids are believed to have a host of positive health effects based on their anti-inflammatory properties. Inflammation plays a role in the development and growth of many cancers.

It is unclear from this study why high levels of omega-3 fatty acids would increase prostate cancer risk, according to the authors, however the replication of this finding in two large studies indicates the need for further research into possible mechanisms. One potentially harmful effect of omega-3 fatty acids is their conversion into compounds that can cause damage to cells and DNA, and their role in immunosuppression. Whether these effects impact cancer risk is not known.

The difference in blood concentrations of omega-3 fatty acids between the lowest and highest risk groups was about 2.5 percentage points (3.2 percent vs. 5.7 percent), which is somewhat larger than the effect of eating salmon twice a week, Kristal said.

The current study analyzed data and specimens collected from men who participated in the Selenium and Vitamin E Cancer Prevention Trial (SELECT), a large randomized, placebo-controlled trial to test whether selenium and vitamin E, either alone or combined, reduced prostate cancer risk. That study showed no benefit from selenium intake and an increase in prostate cancers in men who took vitamin E.

The group included in the this analysis consisted of 834 men who had been diagnosed with incident, primary prostate cancers (156 were high-grade cancer) along with a comparison group of 1,393 men selected randomly from the 35,500 participants in SELECT.

Omega-3s May Help Slow Prostate Cancer Growth
Research in mice suggests that a diet high in omega-3 fatty acids found in fish oil and certain types of fish could potentially improve the prognosis of men who are genetically prone to develop prostate cancer.

“This study clearly shows that diet can tip the balance toward a good or a bad outcome,” said senior researcher Yong Q. Chen, Ph.D., from Wake Forest University School of Medicine. “It’s possible that a change in diet could mean the difference between dying from the disease and surviving with it.”

In mice that were engineered with a genetic defect that caused prostate cancer, a diet high in omega-3 fatty acids beginning at birth reduced tumor growth, slowed disease progression and increased survival. The research is reported by the Journal of Clinical Investigation and in the July 2, 2007 issue.

Prostate cancer is the most frequently diagnosed cancer and is a leading cause of death in men in the United States. Population studies have suggested that consumption of fish or fish oil reduces prostate cancer incidence. However, these investigations have been hampered by the difficulty people have in accurately reporting their dietary intake.

The goal of the current study was to explore gene-diet interactions in prostate cancer. It involved mice that were engineered with a genetic defect – they lacked a tumor suppressor gene and spontaneously developed prostate cancer. This gene (Pten) is absent in 60 to 70 percent of metastatic cancers in humans.

The engineered mice and “wild-type” (or non-engineered) mice were fed varying levels of omega-3 and omega-6 polyunsaturated fatty acids (PUFAs). Both are “essential” fatty acids, which means the body needs them for proper cell function but cannot produce them. Many vegetable oils contain omega-6 PUFA. Fish like mackerel, lake trout, herring, sardines, albacore tuna and salmon are high in omega-3 fatty acids.

Nutritionists recommend that people consume equal proportions of omega-3 and omega-6 PUFA. However, in current western diets, the proportion of omega-6 to omega-3 is between 30 and 50 to one.

The mice were fed either a diet high in omega-3 (ratio of omega-6 to omega-3 was 1:1) a diet low in omega 3 (ratio omega-6 to omega-3 was 20:1), or a diet high in omega-6 (ratio of omega-6 to omega-3 was 40:1). The scientists compared survival rates and weighed the animals’ prostates to measure tumor progression.

Mice with the tumor suppressor gene remained free of tumors and had 100 percent survival, regardless of diet. In mice with the gene defect, survival was 60 percent in animals on the high omega-3 diet, 10 percent in those on the low omega-3 diet and 0 percent in those on the high omega-6 diet.

“This suggests that if you have good genes, it may not matter too much what you eat,” said Chen, a professor of cancer biology. “But if you have a gene that makes you susceptible to prostate cancer, your diet can tip the balance. Our data demonstrate the importance of gene-diet interactions, and that genetic cancer risk can be modified favorable by omega-3 PUFA.”

Chen said dietary changes may be particularly beneficial in people prone to prostate cancer because the disease is usually diagnosed in older men and the tumors are slow-growing. It’s possible that eating a high omega-3 diet could delay tumor development or progression long enough for the man to live out his natural lifespan with prostate cancer.

“Our data imply a beneficial effect of omega-3 PUFA on delaying the onset of human prostate cancer,” Chen said.

He noted that the mice got lifetime exposure of omega-3 and that some people may not be willing to change their diets until they develop cancer. He hopes to study whether there would be beneficial effects of adding omega-3 PUFA to the diet after tumors have developed.

He cautioned that the effects were obtained with the omega-3s found in fish oil and that omega-3s from flaxseed oil and other plants may not provide the same results.

Low-fat fish oil diet protects men with prostate cancer
Men with prostate cancer who ate a low-fat diet and took fish oil supplements had lower levels of pro-inflammatory substances in their blood and a lower cell cycle progression score, a measure used to predict cancer recurrence, than men who ate a typical Western diet, UCLA researchers found.

The findings are important because lowering the cell cycle progression (CCP) score may help prevent prostate cancers from becoming more aggressive, said study lead author William Aronson, a clinical professor of urology at UCLA and chief of urologic oncology at the West Los Angeles Veterans Affairs Medical Center.

"We found that CCP scores were significantly lower in the prostate cancer in men who consumed the low-fat fish oil diet as compare to men who followed a higher fat Western diet," Aronson said. "We also found that men on the low-fat fish oil diet had reduced blood levels of pro-inflammatory substances that have been associated with cancer."

This study appears in Cancer Prevention Research, a peer-reviewed journal of the American Association for Cancer Research.

This study is a follow-up to a 2011 study by Aronson and his team that found a low-fat diet with fish oil supplements eaten for four to six weeks prior to prostate removal slowed the growth of cancer cells in human prostate cancer tissue compared to a traditional, high-fat Western diet.

That short-term study also found that the men on the low-fat fish oil diet were able to change the composition of their cell membranes in both the healthy cells and the cancer cells in the prostate. They had increased levels of omega-3 fatty acids from fish oil and decreased levels of the more pro-inflammatory omega-6 fatty acids from corn oil in the cell membranes, which may directly affect the biology of the cells, Aronson said.

"These studies are showing that, in men with prostate cancer, you really are what you eat," Aronson said. "The studies suggest that by altering the diet, we may favorably affect the biology of prostate cancer."

The men in the previous study were placed into one of two groups, the low-fat fish oil diet or the Western diet. The Western diet consisted of 40 percent of calories from fat, generally equivalent to what many Americans consume today. The fat sources also were typical of the American diet and included high levels of omega-6 fatty acids from corn oil and low levels of fish oil that provide omega-3 fatty acids.

The low-fat diet consisted of 15 percent of calories from fat. Additionally, the men on this diet took five grams of fish oil per day in five capsules, three with breakfast and two with dinner, to provide omega-3 fatty acids. Omega-3 fatty acids have been found to reduce inflammation, and may be protective for other malignancies.

For this study, Aronson wanted to look at the potential biological mechanisms at work in the low-fat fish oil diet that may be providing protection against cancer growth and spread. They measured levels of the pro-inflammatory substances in the blood and examined the prostate cancer tissue to determine the CCP score.

"This is of great interest, as the CCP score in prostate cancer is known to be associated with more aggressive disease and can help predict which patients will recur and potentially die from their cancer," Aronson said.

Further, Aronson and his team analyzed one pro-inflammatory substance called leukotriene B4 (LTB4) and found that men with lower blood levels of LTB4 after the diet also had lower CCP scores.

"Given this finding, we went on to explore how the LTB4 might potentially affect prostate cancer cells and discovered a completely novel finding that one of the receptors for LTB4 is found on the surface of prostate cancer cells," Aronson said.

Further studies are planned to determine the importance of this novel receptor in prostate cancer progression, Aronson said.

Based on the results of his research, Aronson has been funded to start a prospective, randomized trial at UCLA next year studying 100 men who have elected to join the active surveillance program, which monitors slow-growing prostate cancer using imaging and biopsy instead of treating the disease. Study volunteers will receive a prostate biopsy at the beginning of the trial and again at one year. The men will be randomized into a group that eats their usual diet or to a low-fat fish oil diet group. Aronson will measure markers in the prostate biopsy tissue to check for cell growth and CCP score.

Prostate cancer is a leading cause of death among men in the United States. It's estimated that more than 230,000 American men will be diagnosed with prostate cancer this year alone, with more than 29,000 dying from their disease.

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