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Molecular mechanisms of alcohol-mediated carcinogenesis

Key Points

  • Together with tobacco, alcohol is the most abundantly consumed noxious compound worldwide. Within the last decade, much knowledge about the pathophysiology of alcohol-related organ damage has been gathered that draws a much clearer picture of its potential dangers.

  • There is a clear association between chronic alcohol consumption and the development of cancers of the upper gastrointestinal tract, the liver, the colorectum and the female breast.

  • There is convincing evidence that acetaldehyde, the first metabolite produced during alcohol degradation, is responsible for the carcinogenic effect of ethanol on the upper aerodigestive tract owing to its multiple mutagenic effects on DNA.

  • Mechanisms of ethanol-induced hepatocarcinogenesis include the induction of cirrhosis of the liver, ethanol-related increase of oxidative stress, altered methylation and a reduction of retinoic acid.

  • An increase in oestradiols due to alcohol may contribute to breast cancer.

  • Patients with chronic hepatitis B and C; hereditary haemochromatosis and non-alcoholic fatty liver disease owing to insulin resistance; gastroesophageal reflux disease (GERD); and colorectal polyps are more susceptible to the carcinogenic properties of ethanol.

  • Carriers of the inactive aldehyde dehydrogenase 2*2 (ALDH 2*2) allele are at increased risk for alcohol-related oesophageal cancer. Carriers of other genetic variants, such as alcohol dehydrogenase 1C*1 (ADH1C*1) homozygotes and methylenetetrahydrofolate reductase (MTHFR) 677CT variants, should also be considered at higher risk for alcohol-related cancers.

  • Lifestyle factors such as smoking, poor oral hygiene, and certain dietary deficiencies (folate, vitamin B6, methyl donors) or an excess of others (vitamin A/β-carotene), owing to unevenly composed diets or self-medication, also increase the risk for alcohol-associated tumours.

Abstract

Approximately 3.6% of cancers worldwide derive from chronic alcohol drinking, including those of the upper aerodigestive tract, the liver, the colorectum and the breast. Although the mechanisms for alcohol-associated carcinogenesis are not completely understood, most recent research has focused on acetaldehyde, the first and most toxic ethanol metabolite, as a cancer-causing agent. Ethanol may also stimulate carcinogenesis by inhibiting DNA methylation and by interacting with retinoid metabolism. Alcohol-related carcinogenesis may interact with other factors such as smoking, diet and comorbidities, and depends on genetic susceptibility.

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Figure 1: Ethanol metabolism and its role in carcinogenesis.
Figure 2: Effect of CYP2E1 and acetaldehyde on DNA damage and repair.
Figure 3: Structures of acetaldehyde-derived DNA adducts and adducts from lipid peroxidation products61.
Figure 4: Effect of ethanol and acetaldehyde on methyl transfer.
Figure 5: A simplified scheme of the mechanisms by which alcohol may affect carcinogenesis.

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Acknowledgements

This paper is dedicated in gratitude and friendship to Charles S. Lieber, a pioneer in alcohol research. The authors wish to thank M. Schätzle and P. Winterbauer for valuable assistance in preparing the manuscript. Original research of H.K.S. is supported by a grant of the Dietmar Hopp Foundation and by the Heinz Götze Memorial Fellowship Program, and original research of F.S. is supported by a grant from the Novartis Foundation (06B53) and the Swiss Foundation of Liver Research.

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Glossary

Relative risk

(RR) The risk of developing a disease relative to exposure. Relative risk is a ratio of the probability of the event occurring in the exposed group versus the control (non-exposed) group. For example, if the probability of developing lung cancer was 20% among smokers and 1% among non-smokers, then the relative risk of cancer associated with smoking would be 20. Smokers would be 20 times as likely as non-smokers to develop lung cancer.

Haemochromatosis

A genetic disorder attributable to several mutations in the haemochromatosis gene (HFE) leading to excessive iron storage. Clinically, affected individuals may develop liver cirrhosis, diabetes, cardiomyopathy, arthropathy and a bronze colour of the skin, which is responsible for the lay term 'bronze diabetes'.

Non-alcoholic steatohepatitis

A feature of non-alcoholic fatty liver disease. In contrast to alcoholic steatohepatitis, the accumulation of fat in the liver is mostly due to hyperinsulinemia in obese individuals. There is no difference in histomorphology between the two types of liver disease. One feature is an increase in reactive oxygen species generation, which results in lipid peroxidation.

Anti-oxidative defence system

The sum of counteractive mechanisms directed to offset oxidative stress. Endogenous mechanisms include antioxidant enzymes in the cytosol and mitochondria such as glutathione peroxidase and superoxide dismutase, whereas exogenous antioxidants are usually derived from diets as antioxidant micronutrients such as tocopherol (vitamin E), ascorbic acid (vitamin C), β-carotene (provitamin A) and selenium.

Glutathione-S-transferase

(GST) A family of sulphur-containing enzymes deriving from four gene subfamilies (GSTA, GSTM, GSTT and GSTP), which inactivate ROS and many toxic and carcinogenic xenobiotics through conjugation with glutathione.

Hyper-regeneration

Cellular reaction of tissues with marked cell proliferation in response to a toxic or physical insult. Usually a repair mechanism, but may predispose hyperproliferating tissues to malignant transformation.

Nitrosamines

A group of chemicals with carcinogenic potential generated from nitrate and biogenic amines. Nitrosamines are contained in preserved food such as smoked ham, sausages, cheese, some alcoholic beverages such as beer, and tobacco smoke.

Linkage disequilibrium

When alleles at two distinctive loci occur in gametes more frequently than expected given the known allele frequencies and recombination fraction between the two loci, the alleles are said to be in linkage disequilibrium.

Microsomal mono-oxygenase system

An enzymatic system located in microsomes that depends on cytochrome P450s, and metabolizes drugs, xenobiotics (including toxins and carcinogens) and some intermediary metabolites, detoxifies them and makes them more hydrophilic. Further reactions (such as glucoronidation and sulphation) then render them water soluble.

Hydroxyethyl radicals

A radical generated through the CYP2E1-dependent microsomal ethanol oxidation. The radical also binds to proteins, resulting in a neo-antigen formation, which may induce an immune reaction.

Enzyme-altered foci

(EAF) Hepatocyte conglomerates with altered protein expression as reflected by immunohistochemistry, typically of glutathione-S-transferase P1 and transforming growth factor-β. EAF are typically found in chemically-induced hepatocarcinogenesis, and indicate early malignant transformation.

Hepatectomy

Partial or complete surgical removal of the liver. Usually performed to resect malignant or benign liver tumours.

Kupffer cells

These are specialized macrophages located in the liver. The activation of these cells by various insults (such as exposure to bacterial endotoxin) results in the release of various cytokines in the liver that might lead to hepatocyte death or damage.

Epithelial–mesenchymal transition

Conversion from an epithelial to a mesenchymal phenotype, which is a normal component of embryonic development. In carcinomas, this transformation results in altered cell morphology, the expression of mesenchymal proteins and increased invasiveness.

Mallory bodies

Mallory body inclusions are a characteristic feature of alcoholic and non-alcoholic steatohepatitis, but may also be found in chronic cholestatic and metabolic diseases and hepatocellular neoplasms, particularly hepatocellular carcinomas. Mallory bodies share similarities with cytoplasmic inclusions observed in neural diseases and myopathies, and primarily consist of cytokeratins.

β-carotene

Synonym for provitamin A. Results in the generation of retinoids after centric or excentric cleavage. Contained in carrots and other vegetables and has antioxidant activity.

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Seitz, H., Stickel, F. Molecular mechanisms of alcohol-mediated carcinogenesis. Nat Rev Cancer 7, 599–612 (2007). https://doi.org/10.1038/nrc2191

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