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Alcohol and Cancer

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A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: closed (30 September 2017) | Viewed by 83900

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Prof. Dr. Helmut K. Seitz

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Guest Editor

Centre of Liver- and Alcohol Diseases, Ethianum Clinic Heidelberg, Germany
Interests: alcohol metabolism and toxicity; carcinogenesis; liver disease;
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Sebastian Mueller

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Guest Editor

Professor of Medicine, University of Heidelberg, Heidelberg, Germany

Special Issue Information

Dear Colleagues,

Chronic alcohol consumption is responsible for more than 200 diseases or symptoms. One of the most severe diseases associated with chronic alcohol abuse is cancer. Epidemiologists and clinicians have known this for more than hundred years. However, in the last three decades, countless epidemiological data from cohort and case control studies have accumulated that identify alcohol as a major risk factor for various cancer sites, including the upper aerodigestive tract (oral cavity, pharynx, larynx, esophagus) the liver (mostly in the presence of cirrhosis), the colorectum, and the female breast. Especially, alcohol-mediated cancer of the large intestine and the breast are of major concern since, for the colorectum, the dosis associated with cancer risk seems to be significantly lower compared to the upper aerodigestive tract; no threshold dose exists for the breast.

Alcohol-mediated cancer increased within the last 15 years. In 2002, worldwide, a total of 3.6% of all cancers (5.2% in men and 1.7% in women) were derived from chronic alcohol consumption. In 2012, the total number of all alcohol-attributable cancer cases increased to 5.5% (7.2% in men and 3.5% in women). Responding figures for cancer deaths, attributable to alcohol, increased to 5.8%. Thus, undoubtedly, alcohol is an important cancer risk factor that can be completely avoided.

In 2007, the International Agency for Research in Cancer (IARC) published a paper in Lancet Oncology, as a result of a two-week expert panel discussion that alcoholic beverages are carcinogenic. Since then, alcohol and cancer became very important topics, and the National Institute of Alcohol and Alcohol Abuse (NIAAA), as well as the European Society for Biomedical Research on Alcoholism (ESBRA), increased their efforts to support research in this field over the last five years. The purpose of this Special Issue of Cancers is to summarize the present knowledge regarding alcohol and cancer epidemiology and pathophysiology. The focus, however, is on mechanisms by which alcohol exerts its carcinogenic action. This up-to-date knowledge will be presented by a number of world-class experts in the field. It is our hope that the knowledge presented here may result in specific research that may contribute to the solving of many open question in the field of alcohol and cancer.

Prof. Dr. Helmut K. Seitz
Prof. Dr. Sebastian Mueller
Guest Editors

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Keywords

Acetaldehyde
cytochrome P4502E1
oxidative stress
etheno DNA-adducts
retinoic acid
alcohol dehydrogenase
acetaldehyde dehydrogenase
breast cancer
colorectal cancer
pharyngeal cancer
laryngeal cancer
esophageal cancer
estrogens

Published Papers (10 papers)

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Review

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17 pages, 1374 KiB

Open AccessReview

Molecular Mechanisms of Alcohol-Induced Colorectal Carcinogenesis

by Caroline H. Johnson, Jaya Prakash Golla, Evangelos Dioletis, Surendra Singh, Momoko Ishii, Georgia Charkoftaki, David C. Thompson and Vasilis Vasiliou

Cancers 2021, 13(17), 4404; https://doi.org/10.3390/cancers13174404 - 31 Aug 2021

Cited by 16 | Viewed by 4019

Abstract

The etiology of colorectal cancer (CRC) is complex. Approximately, 10% of individuals with CRC have predisposing germline mutations that lead to familial cancer syndromes, whereas most CRC patients have sporadic cancer resulting from a combination of environmental and genetic risk factors. It has become increasingly clear that chronic alcohol consumption is associated with the development of sporadic CRC; however, the exact mechanisms by which alcohol contributes to colorectal carcinogenesis are largely unknown. Several proposed mechanisms from studies in CRC models suggest that alcohol metabolites and/or enzymes associated with alcohol metabolism alter cellular redox balance, cause DNA damage, and epigenetic dysregulation. In addition, alcohol metabolites can cause a dysbiotic colorectal microbiome and intestinal permeability, resulting in bacterial translocation, inflammation, and immunosuppression. All of these effects can increase the risk of developing CRC. This review aims to outline some of the most significant and recent findings on the mechanisms of alcohol in colorectal carcinogenesis. We examine the effect of alcohol on the generation of reactive oxygen species, the development of genotoxic stress, modulation of one-carbon metabolism, disruption of the microbiome, and immunosuppression. Full article

(This article belongs to the Special Issue Alcohol and Cancer)

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27 pages, 1583 KiB

Open AccessReview

Epidemiology of Moderate Alcohol Consumption and Breast Cancer: Association or Causation?

by Samir Zakhari and Jan B. Hoek

Cancers 2018, 10(10), 349; https://doi.org/10.3390/cancers10100349 - 22 Sep 2018

Cited by 16 | Viewed by 7712

Abstract

Epidemiological studies have been used to show associations between modifiable lifestyle habits and the incidence of breast cancer. Among such factors, a history of alcohol use has been reported in multiple studies and meta-analyses over the past decades. However, associative epidemiological studies that were interpreted as evidence that even moderate alcohol consumption increases breast cancer incidence have been controversial. In this review, we consider the literature on the relationship between moderate or heavy alcohol use, both in possible biological mechanisms and in variations in susceptibility due to genetic or epigenetic factors. We argue that there is a need to incorporate additional approaches to move beyond the associations that are reported in traditional epidemiological analyses and incorporate information on molecular pathologic signatures as a requirement to posit causal inferences. In particular, we point to the efforts of the transdisciplinary field of molecular pathological epidemiology (MPE) to evaluate possible causal relationships, if any, of alcohol consumption and breast cancer. A wider application of the principles of MPE to this field would constitute a giant step that could enhance our understanding of breast cancer and multiple modifiable risk factors, a step that would be particularly suited to the era of “personalized medicine”. Full article

(This article belongs to the Special Issue Alcohol and Cancer)

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16 pages, 238 KiB

Open AccessFeature PaperReview

Liver Transplantation for Alcoholic Liver Disease and Hepatocellular Carcinoma

by Patrizia Burra, Alberto Zanetto and Giacomo Germani

Cancers 2018, 10(2), 46; https://doi.org/10.3390/cancers10020046 - 09 Feb 2018

Cited by 26 | Viewed by 4560

Abstract

Hepatocellular carcinoma is one of the main important causes of cancer-related death and its mortality is increasingly worldwide. In Europe, alcohol abuse accounts for approximately half of all liver cancer cases and it will become the leading cause of hepatocellular carcinoma in the next future with the sharp decline of chronic viral hepatitis. The pathophysiology of alcohol-induced carcinogenesis involves acetaldehyde catabolism, oxidative stress and chronic liver inflammation. Genetic background plays also a significant role and specific patterns of gene mutations in alcohol-related hepatocellular carcinoma have been characterized. Survival is higher in patients who undergo specific surveillance programmes than in patients who do not. However, patients with alcohol cirrhosis present a significantly greater risk of liver decompensation than those with cirrhosis due to other aetiologies. Furthermore, the adherence to screening program can be suboptimal. Liver transplant for patients with Milan-in hepatocellular carcinoma represents the best possible treatment in case of tumour recurrence/progression despite loco-regional or surgical treatments. Long-term result after liver transplantation for alcohol related liver disease is good. However, cardiovascular disease and de novo malignancies can significantly hamper patients’ survival and should be carefully considered by transplant team. In this review, we have focused on the evolution of alcohol-related hepatocellular carcinoma epidemiology and risk factors as well as on liver transplantation in alcoholic patients with and without hepatocellular carcinoma. Full article

(This article belongs to the Special Issue Alcohol and Cancer)

0 pages, 1556 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Colorectal Cancer and Alcohol Consumption—Populations to Molecules

by Marco Rossi, Muhammad Jahanzaib Anwar, Ahmad Usman, Ali Keshavarzian and Faraz Bishehsari

Cancers 2018, 10(2), 38; https://doi.org/10.3390/cancers10020038 - 30 Jan 2018

Cited by 102 | Viewed by 15855

Abstract

Colorectal cancer (CRC) is a major cause of morbidity and mortality, being the third most common cancer diagnosed in both men and women in the world. Several environmental and habitual factors have been associated with the CRC risk. Alcohol intake, a common and rising habit of modern society, is one of the major risk factors for development of CRC. Here, we will summarize the evidence linking alcohol with colon carcinogenesis and possible underlying mechanisms. Some epidemiologic studies suggest that even moderate drinking increases the CRC risk. Metabolism of alcohol involves ethanol conversion to its metabolites that could exert carcinogenic effects in the colon. Production of ethanol metabolites can be affected by the colon microbiota, another recently recognized mediating factor to colon carcinogenesis. The generation of acetaldehyde and alcohol’s other metabolites leads to activation of cancer promoting cascades, such as DNA-adduct formation, oxidative stress and lipid peroxidation, epigenetic alterations, epithelial barrier dysfunction, and immune modulatory effects. Not only does alcohol induce its toxic effect through carcinogenic metabolites, but alcoholics themselves are predisposed to a poor diet, low in folate and fiber, and circadian disruption, which could further augment alcohol-induced colon carcinogenesis. Full article

(This article belongs to the Special Issue Alcohol and Cancer)

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27 pages, 959 KiB

Open AccessEditor’s ChoiceReview

Alcohol-Derived Acetaldehyde Exposure in the Oral Cavity

by Alessia Stornetta, Valeria Guidolin and Silvia Balbo

Cancers 2018, 10(1), 20; https://doi.org/10.3390/cancers10010020 - 14 Jan 2018

Cited by 64 | Viewed by 12387 | Correction

Abstract

Alcohol is classified by the International Agency for Research on Cancer (IARC) as a human carcinogen and its consumption has been associated to an increased risk of liver, breast, colorectum, and upper aerodigestive tract (UADT) cancers. Its mechanisms of carcinogenicity remain unclear and various hypotheses have been formulated depending on the target organ considered. In the case of UADT cancers, alcohol’s major metabolite acetaldehyde seems to play a crucial role. Acetaldehyde reacts with DNA inducing modifications, which, if not repaired, can result in mutations and lead to cancer development. Despite alcohol being mainly metabolized in the liver, several studies performed in humans found higher levels of acetaldehyde in saliva compared to those found in blood immediately after alcohol consumption. These results suggest that alcohol-derived acetaldehyde exposure may occur in the oral cavity independently from liver metabolism. This hypothesis is supported by our recent results showing the presence of acetaldehyde-related DNA modifications in oral cells of monkeys and humans exposed to alcohol, overall suggesting that the alcohol metabolism in the oral cavity is an independent cancer risk factor. This review article will focus on illustrating the factors modulating alcohol-derived acetaldehyde exposure and effects in the oral cavity. Full article

(This article belongs to the Special Issue Alcohol and Cancer)

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23 pages, 724 KiB

Open AccessFeature PaperReview

Local Acetaldehyde—An Essential Role in Alcohol-Related Upper Gastrointestinal Tract Carcinogenesis

by Mikko T. Nieminen and Mikko Salaspuro

Cancers 2018, 10(1), 11; https://doi.org/10.3390/cancers10010011 - 05 Jan 2018

Cited by 53 | Viewed by 9104

Abstract

The resident microbiome plays a key role in exposure of the upper gastrointestinal (GI) tract mucosa to acetaldehyde (ACH), a carcinogenic metabolite of ethanol. Poor oral health is a significant risk factor for oral and esophageal carcinogenesis and is characterized by a dysbiotic microbiome. Dysbiosis leads to increased growth of opportunistic pathogens (such as Candida yeasts) and may cause an up to 100% increase in the local ACH production, which is further modified by organ-specific expression and gene polymorphisms of ethanol-metabolizing and ACH-metabolizing enzymes. A point mutation in the aldehyde dehydrogenase 2 gene has randomized millions of alcohol consumers to markedly increased local ACH exposure via saliva and gastric juice, which is associated with a manifold risk for upper GI tract cancers. This human cancer model proves conclusively the causal relationship between ACH and upper GI tract carcinogenesis and provides novel possibilities for the quantitative assessment of ACH carcinogenicity in the human oropharynx. ACH formed from ethanol present in “non-alcoholic” beverages, fermented food, or added during food preparation forms a significant epidemiologic bias in cancer epidemiology. The same also concerns “free” ACH present in mutagenic concentrations in multiple beverages and foodstuffs. Local exposure to ACH is cumulative and can be reduced markedly both at the population and individual level. At best, a person would never consume tobacco, alcohol, or both. However, even smoking cessation and moderation of alcohol consumption are associated with a marked decrease in local ACH exposure and cancer risk, especially among established risk groups. Full article

(This article belongs to the Special Issue Alcohol and Cancer)

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379 KiB

Open AccessReview

Alcohol and Cancer Stem Cells

by Mei Xu and Jia Luo

Cancers 2017, 9(11), 158; https://doi.org/10.3390/cancers9110158 - 20 Nov 2017

Cited by 18 | Viewed by 7192

Abstract

Heavy alcohol consumption has been associated with increased risk of several cancers, including cancer of the colon, rectum, female breast, oral cavity, pharynx, larynx, liver, and esophagus. It appears that alcohol exposure not only promotes carcinogenesis but also enhances the progression and aggressiveness of existing cancers. The molecular mechanisms underlying alcohol tumor promotion, however, remain unclear. Cancer stem cells (CSC), a subpopulation of cancer cells with self-renewal and differentiation capacity, play an important role in tumor initiation, progression, metastasis, recurrence, and therapy resistance. The recent research evidence suggests that alcohol increases the CSC population in cancers, which may underlie alcohol-induced tumor promotion. This review discusses the recent progress in the research of alcohol promotion of CSC and underlying cellular/molecular mechanisms. The review will further explore the therapeutic potential of CSC inhibition in treating alcohol-induced tumor promotion. Full article

(This article belongs to the Special Issue Alcohol and Cancer)

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1973 KiB

Open AccessReview

Does Hypoxia Cause Carcinogenic Iron Accumulation in Alcoholic Liver Disease (ALD)?

by Inês Silva, Vanessa Rausch, Helmut-Karl Seitz and Sebastian Mueller

Cancers 2017, 9(11), 145; https://doi.org/10.3390/cancers9110145 - 25 Oct 2017

Cited by 20 | Viewed by 7417

Abstract

Alcoholic liver disease (ALD) is a leading health risk worldwide. Hepatic iron overload is frequently observed in ALD patients and it is an important and independent factor for disease progression, survival, and the development of primary liver cancer (HCC). At a systemic level, iron homeostasis is controlled by the liver-secreted hormone hepcidin. Hepcidin regulation is complex and still not completely understood. It is modulated by many pathophysiological conditions associated with ALD, such as inflammation, anemia, oxidative stress/H₂O_2, or hypoxia. Namely, the data on hypoxia-signaling of hepcidin are conflicting, which seems to be mainly due to interpretational limitations of in vivo data and methodological challenges. Hence, it is often overlooked that hepcidin-secreting hepatocytes are physiologically exposed to 2–7% oxygen, and that key oxygen species such as H₂O₂ act as signaling messengers in such a hypoxic environment. Indeed, with the recently introduced glucose oxidase/catalase (GOX/CAT) system it has been possible to independently study hypoxia and H₂O₂ signaling. First preliminary data indicate that hypoxia enhances H₂O₂-mediated induction of hepcidin, pointing towards oxidases such as NADPH oxidase 4 (NOX4). We here review and discuss novel concepts of hypoxia signaling that could help to better understand hepcidin-associated iron overload in ALD. Full article

(This article belongs to the Special Issue Alcohol and Cancer)

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1416 KiB

Open AccessFeature PaperReview

Alcohol and Hepatocellular Carcinoma: Adding Fuel to the Flame

by Pierluigi Ramadori, Francisco Javier Cubero, Christian Liedtke, Christian Trautwein and Yulia A. Nevzorova

Cancers 2017, 9(10), 130; https://doi.org/10.3390/cancers9100130 - 25 Sep 2017

Cited by 45 | Viewed by 9805

Abstract

Primary tumors of the liver represent the fifth most common type of cancer in the world and the third leading cause of cancer-related death. Case-control studies from different countries report that chronic ethanol consumption is associated with an approximately 2-fold increased odds ratio for hepatocellular carcinoma (HCC). Despite the substantial epidemiologic data in humans demonstrating that chronic alcohol consumption is a major risk factor for HCC development, the pathways causing alcohol-induced liver cancer are poorly understood. In this overview, we summarize the epidemiological evidence for the association between alcohol and liver cancer, review the genetic, oncogenic, and epigenetic factors that drive HCC development synergistically with ethanol intake and discuss the essential molecular and metabolic pathways involved in alcohol-induced liver tumorigenesis. Full article

(This article belongs to the Special Issue Alcohol and Cancer)

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Open AccessCase Report

Alcohol Misuse Link to POEMS Syndrome in a Patient

by John Neary, Susan E. Goodwin, Lawrence B. Cohen and Manuela G. Neuman

Cancers 2017, 9(10), 129; https://doi.org/10.3390/cancers9100129 - 23 Sep 2017

Cited by 3 | Viewed by 4809

Abstract

Previously called Crow–Fukase syndrome, POEMS syndrome is characterized by poly-neuropathy, osteo-sclerotic myeloma, organomegaly, endocrinopathy, monoclonal plasma cell disorder, and skin changes. Extremely elevated levels of serum vascular endothelial growth factor (VEGF) are characteristic of the syndrome. Chronic hepatitis B (HBV) and C (HCV) infections can also be present in POEMS. The pathogenesis of the syndrome is not well understood. The link between chronic alcohol consumption and this malignant condition has not been reported until now. In addition, no previous study has evaluated the influence of cytokine and chemokines or viruses in the severity and evolution of POEMS. Objectives: (1) to describe a heavy-alcohol user, who was diagnosed with POEMS; (2) to demonstrate the utility of quantitative measurement of serum levels of VEGF in the diagnosis of POEMS and the monitoring of therapeutic interventions; (3) to demonstrate that overproduction of pro-inflammatory cytokines is a characteristic of POEMS. Methods: We describe a case of a POEMS patient presenting HCV and who is a heavy drinker; we compare the serum levels of cytokines and chemokines between the POEMS patient with 80 patients with HCV, 12 healthy controls, and 80 individuals with alcoholic liver disease (ALD). We quantified (ELISA pg/mL) the levels of VEGF, Interferon gamma (IFN-γ), Tumor Necrosis Factor alpha (TNF-α), Regulated-upon-Activation Normal-T-cell-Expressed and presumably-Secreted (RANTES), and Nuclear Factor kappa-B (NFκB). Results: In POEMS patients, VEGF levels were elevated versus control or other diseases, TNFα levels were higher versus control, but lower when compared with HCV or ALD patients. VEGF levels in POEMS patients decreased with therapeutic intervention. Conclusions: Chronic alcohol misuse can be a strong risk factor to rare malignancies such as POEMS syndrome. Extreme elevation of VEGF levels is diagnostic for POEMS syndrome, and should be followed to assess response to therapy. In addition, other comorbidities should be considered individually to ensure personalized therapeutic intervention. Full article

(This article belongs to the Special Issue Alcohol and Cancer)

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