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Insight & Intelligence : Oct 26, 2011
Studies of Pathways Involved in Alcohol Metabolism Reveal Links to Cancer
Researchers are describing a role for ethanol metabolite acetaldehyde in alcohol-related cancer.!--h2>
About 3.6% of cancers worldwide are associated with chronic alcohol consumption, including upper digestive tract, liver, colorectal, and breast cancers. Evidence is also increasingly linking alcohol to pancreatic cancer. A recent epidemiological study showed that alcohol consumption, specifically three or more drinks per day, increases pancreatic cancer mortality independent of smoking.
Compared to the 10–15% of individuals who smoke that will develop lung cancer, the percentage of alcohol-related cancers may seem relatively low. But 15% of alcoholics eventually develop cirrhosis of the liver, and about 5% of people with cirrhosis eventually get liver cancer.
Among initial studies that recognized the effect of alcohol on cancer incidence evaluated the interaction of drinking and smoking on cancers of the upper digestive and respiratory tracts. One case-control study reported a 5.8-fold increased risk of mouth and pharynx cancer from drinking and a 7.4-fold increased risk from smoking. Both factors in combination, however, increased the risk 38-fold. This epidemiological evidence of the interaction between drinking and smoking led to the hypothesis that alcohol acts primarily as a co-carcinogen.
Two types of research link alcohol and cancer: epidemiologic studies and cellular/biochemical mechanistic studies. While the latter have been few and far between, researchers are now increasingly applying molecular biology tools and protein expression analysis to establish a direct connection between alcohol and carcinogenesis. Studies have elucidated, for example, mechanisms of how acetaldehyde, the first and most toxic ethanol metabolite, can promote cancer.
Linking Acetaldehyde to Cancer
Alcohol is eliminated from the body by various metabolic mechanisms. The primary enzymes involved are aldehyde dehydrogenase (ALDH), alcohol dehydrogenase (ADH), cytochrome P450 (CYP2E1), and catalase. Variations in the genes for these enzymes influence alcohol consumption, alcohol-related tissue damage, and alcohol dependence.
“In most people, acetaldehyde is quickly converted to acetate, a relatively harmless substance, by an enzyme called aldehyde dehydrogenase 2 (ALDH2),” said Philip J. Brooks, Ph.D., program director in the division of metabolism and health effects at the National Institute on Alcohol Abuse and Alcoholism (NIAAA). “However, approximately 30 percent of East Asians are unable to metabolize alcohol to acetate due to a genetic variant in the ALDH2 gene and have a greatly elevated risk of esophageal cancer from alcohol drinking. This helped researchers establish the carcinogenicity of acetaldehyde in humans and its role in alcohol-related esophageal cancer.”
In experimental animals, it has been shown that acetaldehyde reacts with DNA to form cancer-promoting compounds. Lately, experimental evidence has begun to define mechanisms by which this compound can directly cause certain human cancers.
In addition, highly reactive, oxygen-containing molecules that are generated in certain alcohol metabolism pathways can damage DNA, which can also induce tumor development. Sustained, repeated alcohol consumption or chronic alcohol abuse leads to the induction of CYP2E1, another enzyme normally active in the alcohol metabolic pathway.
Chronic alcohol abuse can increase the enzyme’s activity 10–20 fold over its normal, basal activity. In such a situation CYP2E1 becomes a primary pathway for alcohol metabolism. In conjunction with ADH-dependent alcohol metabolism, it contributes to increased hepatic acetaldehyde production.
CYP2E1-dependent alcohol metabolism also leads to increased hepatic oxidative stress due to the generation of reactive oxygen species (ROS) including hydroxyethyl radicals (HERs). Although ROS can form DNA and protein adducts directly, they can also react with lipid molecules in the cell membrane, leading to the formation of biologically reactive aldehyde molecules.
Scientists are beginning to describe the fundamental molecular mechanisms of how various changes may directly impact the induction of cancer-promoting cellular pathways. Dr. Brooks’ team reported on research establishing a link between alcohol metabolism and acetaldehyde-induced DNA damage. The study will appear in the December 2011 issue of Alcoholism: Clinical & Experimental Research.
Dr. Brooks said that while the association between drinking alcohol and certain types of cancers was initially established in the 1980s, research has not established that alcohol itself caused the cancers. Recent evidence, however, more strongly suggests that alcohol—or specifically ethanol—is carcinogenic to humans at several sites in the body, he pointed out.
To directly examine whether intracellular generation of acetaldehyde from ethanol metabolism might activate cancer-related cellular pathways, Dr. Brooks and colleagues used HeLa cells engineered to metabolize alcohol into acetaldehyde by ADH1B, which is expressed in human liver and breast tissue. “We found that the cells converted the alcohol into acetaldehyde and that this resulted in increased levels of acetaldehyde-DNA damage,” Dr. Brooks noted.
“In addition, the cells responded by activating the Fanconi anemia-breast cancer (FA-BRCA) network,” Dr. Brooks reported. “The Fanconi anemia-breast cancer network is a collection of proteins that responds to DNA damage by coordinating DNA repair or helping the replication machinery to bypass the DNA damage, thereby allowing replication to continue. In the human body, the FA-BRCA network seems to be particularly important in protecting against breast cancer.”
Dr. Brooks stressed that because all the studies were performed in cell culture, the investigators used alcohol concentrations that would correspond to blood alcohol levels attained during social drinking. He also cautioned that while the study results were consistent with a role for acetaldehyde in alcohol-related liver and breast cancers, more studies in animals and humans will be required to unequivocally establish a role for alcohol.
Researchers have also focused on the effects of alcohol on other molecular mechanisms impacting cancer. In 2009, Christopher Forsyth, Ph.D., assistant professor of medicine and biochemistry at Rush University Medical Center, and colleagues reported that alcohol stimulates epithelial-to-mesenchymal (EMT) transition, which is associated with the progression of cancer cells into a more aggressive form.
Dr. Forsyth told GEN that his idea for looking at alcohol’s effect on Snail proteins came from observations that these factors are critical to the process of embryogenesis. “If you block Snail when the nervous system is forming, you don’t get a nervous system because epithelial cells can’t migrate to form one.”
He credited Angela Nieto, Ph.D., currently professor and head of the developmental neurobiology unit at the Instituto de Neurociencias, with the original insight on Snail proteins. It has been shown that when the Snail gene is overexpressed in mice, it induces formation of multiple tumors.
To assess the effects of alcohol exposure on biochemical markers for EMT, Dr. Forsyth’s research group compared the in vitro effects of alcohol on colon and breast cancer cell lines, a normal intestinal epithelial cell line, and colonic mucosal biopsy samples from alcoholics.
The study results indicated that alcohol upregulated the signature EMT phenotypic marker vimentin as well as matrix metalloprotease (MMP)-2, MMP-7, and MMP-9. It also increased cell migration in colon and breast cancer cells, another characteristic of EMT.
Additionally, alcohol stimulated the expression and activity of Snail. In vivo, Snail expression was significantly elevated in colonic mucosal biopsies from alcoholics. Furthermore, Snail siRNA knockdown was shown to prevent alcohol-stimulated vimentin expression.
The investigators also found that alcohol stimulated activation of epidermal growth factor receptor (EGFR) signaling, and an EGFR inhibitor blocked alcohol-induced cell migration and Snail mRNA expression.
Dr. Forsyth said that this data was the first to show that alcohol turns on certain intracellular signals involved in EMT via an EGFR-Snail mediated pathway. “Our hope,” Dr. Forsyth told GEN, “is that we understand signaling pathways affected by alcohol in human cells so we can also understand how alcohol promotes disease.”
Abstinence Not an Option
The Cancer Council of Australia put out a statement conceding that alcohol has a dominant role in defining that country’s culture over the past 200 years. The council estimates that 5,070 cases of cancer, or 5% of all cancers in that country each year, are attributable to long-term chronic use of alcohol. This estimate only includes cancers for which there is convincing evidence that alcohol increases the risk of the disease. When cancers for which the risk is probably increased by alcohol use are included, the tally rises to 5,663, or 5.6% of all cancers.
“Alcoholic drinks and ethanol are carcinogenic to humans,” the Cancer Council of Australia has stated. “There is no evidence that there is a safe threshold of alcohol consumption for avoiding cancer or that cancer risk varies between the type of alcoholic beverage consumed.”
It is improbable that citizens of the many countries in which alcohol forms part of the social fabric will give it up, though. Dr. Forsyth pointed out that alcohol use provides a great opportunity to find out more about cellular regulatory mechanisms in general. “The great thing about alcohol is that there aren’t that many drugs that are widely used—it’s an ongoing human experiment. It’s been around for a long time.”
Basic research is certainly now revealing details of molecular pathways for alcohol-mediated promotion of cancer. Besides providing mechanistic insights into the process of carcinogenesis itself, it is also hoped that it will lead to treatments or preventions for alcohol-related cancers.
Patricia F. Dimond, Ph.D. ([email protected]), is a principal at BioInsight Consulting.
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