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In this review, we aim to summarise the epidemiological evidence on alcohol and cancer risk and the mechanistic evidence of alcohol-driven carcinogenesis. We searched the PubMed and Cochrane databases for reviews, umbrella reviews, meta-analyses, and Mendelian randomisation studies on total alcohol use and cancer risk and mechanisms of alcohol-related carcinogenesis published up until June 2021. We also searched the WCRF’s Continuous Update Project reports for meta-analyses on alcohol consumption and cancer risk. Continued research into the detrimental and beneficial effects how to store pee of alcohol in human cancer patients and animal models of cancer is a key factor to understanding the complex interactions that affect tumor progression and survival, particularly in the context of alcohol use.

The significantly greater risks seen in men carrying the low-alcohol tolerability ALDH2 gene variant who still drank regularly suggests that greater accumulation of acetaldehyde may directly increase cancer risk. Because these alleles are allocated at birth and are independent of other lifestyle factors (such as smoking), they can be used as a proxy for alcohol intake, to assess how alcohol consumption affects disease risks. With alcohol consumption rising, particularly in rapidly developing countries such as China, there is an urgent need to understand how alcohol affects disease risks in different populations. It is important to continue studying cancers linked to alcohol, as patterns of alcohol use continue to shift over time, Dr. Abnet said. For example, in many parts of the world, women have begun drinking more than they used to, he explained. And, he added, if drinking rises within a group, their cancer cases are eventually likely to rise as well.

3. Increased Inflammation

The overall percentage of all T cells, as well as of CD4+ T-, CD8+ T-, B-, and NK cells, in contrast, did not differ between cancer and control patients. However, this effect cannot be clearly attributed to alcohol because the patients also were heavy tobacco users. The study found that among healthy participants, those with high alcohol consumption or smoking had a pronounced decrease of antigen-specific antibody production in vitro. Cancer patients who were heavy drinkers, in contrast, did not show any antigen-specific antibody production in vitro.

Assuming that analyses are conducted appropriately, due to the random distribution of these genetic variants at birth, MR studies should be less prone to conventional confounding and reverse causality. “That’s similar in other high-income countries, and it’s probably even lower in other parts of the world.” The first mutation is a loss-of-function mutation in the gene for the enzyme aldehyde dehydrogenase 2 (ALDH2). These molecules can damage DNA, and the gene changes that result can lead to a cell turning cancerous. But much of the kind of work necessary to help people with substance abuse problems of any sort is beyond the realm of oncologists, he stressed.

Can people’s genes affect their risk of alcohol-related cancers?

In addition to its involvement in downstream ROS-producing pathways, it is hypothesised that IL-8 contributes to further accumulation of white blood cells (neutrophils, specifically) in the liver leading to acute inflammation. Elevated IL-8 levels have been found in patients with acute liver injury such as alcoholic hepatitis [34]. Additionally, the cytokine IL-6 stimulates production of the anti-apoptotic protein Mcl-1, thus avoiding cell death and exposing the cell to further DNA damage [35]. ROS can act as messengers in intracellular signalling pathways to activate the transcription factor nuclear factor κB (NF-κB).

Study Probes Awareness of Alcohol’s Link to Cancer

The study found that the ethanol group exhibited higher primary tumor growth rates, increased final tumor weights, and a twofold increase in lung metastases compared with the water-drinking control group. Immunohistochemical analyses of the mammary tumor tissues also showed a higher density of do you need to wean off prozac tiny blood vessels in the ethanol group, indicating that ethanol promoted tumor angiogenesis. MCP-1 plays an important role in suppressing antitumor immune functions and facilitating tumor metastasis (Kudo-Saito et al. 2013), indicating another mechanism through which alcohol could promote breast cancer progression. The association between alcohol drinking and risk of other cancer types has been studied but without sufficient evidence to be classified in the IARC monographs or WCRF Continuous Update Project. Positive associations have been reported in some meta-analyses; for example, a 3% increase in lung cancer risk was observed per 10 g alcohol per day in the WCRF meta-analysis based on 28 studies (RR 1.03 (95% CI 1.01–1.04)) after excluding studies which did not control for smoking [7]. A positive association with lung cancer was only found for heavy drinkers in Bagnardi and colleagues’ meta-analysis, but this was probably due to residual confounding from smoking because alcohol use did not increase the risk of lung cancer among non-smokers [8].

Tumor metastasis is the ability of tumor cells to spread from their original site to other sites in the body and to re-establish growth, a new blood supply, and tumor colonies at the new location. (1) Cells that escape from a primary solid tumor invade into the surrounding normal tissue by passing through the basement membrane and extracellular matrix (ECM). Several factors are involved in the invasion process, including the ability to activate enzymes called matrix metalloproteinases (MMP), which are important for the tumor cells to degrade basement membranes and underlying stroma. (2) The escaped cells reach the blood either directly by actively passing through endothelial cells that line the blood vessels or passively through the lymphatic system, which ultimately carries the tumor cells to the blood. (3) Once in the blood, the tumor cells exit into tissues at the secondary site from small capillaries by passing through endothelial cells and then invading the basement membrane of the ECM. Dormant cells also can proliferate at a future date and ultimately establish a new metastatic tumor.

9. Liver Cirrhosis

However, this association was restricted to light and moderate drinking in Bagnardi and colleagues’ meta-analysis (RR 0.92 (95% CI 0.86–0.99) and 0.79 (95% CI 0.72–0.86), respectively) [8]. The same meta-analysis also found significant inverse associations for the risk of thyroid cancer, Hodgkin lymphoma and non-Hodgkin lymphoma [8]. For people being treated for cancer, regularly consuming a few beers or cocktails also has other potentially harmful consequences, including making their treatments less effective. And for longer-term cancer survivors, there is some evidence that regular alcohol use may increase the chances of their cancer returning. There is strong and consistent evidence that drinking alcohol increases your risk of developing a cancer, based on a growing body of research.

1. For example, instead of including all types of liver cancer, “they focused on hepatocellular carcinoma, the type of liver cancer that’s linked to alcohol,” he said.
2. “It’s pretty clear there are no health benefits [from heavy drinking], and there’s lots of risk to health overall,” she said.
3. According to the study, cancers of the esophagus (189,700 cases), liver (154,700 cases), and breast (98,300 cases) “contributed the most cases.”
4. A large body of literature indicates that alcohol consumption modulates many aspects of the innate and adaptive immune systems.
5. These increased risks are seen only among people who carry the ALDH2 variant and drink alcohol—they are not observed in people who carry the variant but do not drink alcohol.

I think there is a chunk of society that, if they knew [about the risk], would drink differently,” she said. Breast cancer in women came in third place for number of cases, with almost 100,000 cases (about 4% worldwide) attributable to alcohol use. “The breast cancer numbers are pretty high, just because breast cancer is so common,” Dr. LoConte explained. Cancers of the esophagus and liver accounted for more than 340,000 alcohol-attributable cancers diagnosed in 2020. The researchers estimated that, overall, about 17% of liver cancer cases and 32% of esophageal cancer cases diagnosed in 2020 were attributable to alcohol use. Dr. LoConte said that she has direct conversations with her patients about drinking and other behaviors that could affect their treatment.

Sex hormone levels may be increased by alcohol through oxidative stress and through inhibition of the steroid degradation enzymes sulfotransferase and 2-hydroxylase [39]. Heavy use of alcohol has also been linked with increased circulating levels of oestrone and oestradiol as well as dehydroepiandrosterone sulphate (DHEAS) [39]. DHEAS is metabolised to oestrogen by aromatase, the activity of which is also increased in chronic alcohol consumers [40]. A large cohort study found DHEAS levels 25% higher molly mdma wikipedia among women consuming at least 20 g alcohol per day compared with non-drinkers [41].

Inflammation is a key pathway to cancer progression at several sites and is enhanced by alcohol use. Chronic alcohol consumption can recruit specific white blood cells (monocytes and macrophages) to the tumour microenvironment. These white blood cells produce pro-inflammatory cytokines, such as tumour necrosis factor α (TNF-α) and the interleukins IL-1, IL-6, and IL-8 [31,33], which activate oxidant-generating enzymes leading to downstream formation of ROS [30]. Following epidemiological evidence of the link between alcohol use and risk of cancer at multiple sites, several pathways have been investigated to explain the carcinogenic effects of alcohol. Here, we discuss the key mechanisms linking alcohol consumption to carcinogenesis, which are depicted in Figure 4.

Increased ethanol consumption can induce microbial dysbiosis and bacterial overgrowth in the intestine [20]. This heightened bacterial presence may compromise the intestinal barrier resulting in ”gut leakiness” where the permeability of the intestinal lumen is high enough such that bacterial products including lipopolysaccharides and peptidoglycan move from the intestine into the blood [20,45]. Once in the blood these bacterial products easily reach the liver where a variety of cells are activated (endothelial cells, liver macrophages, stellate cells and hepatocytes) producing a chronic inflammatory environment [33], which may confer an increased risk of liver cancer [46]. In addition to associations from epidemiological studies, multiple mechanistic pathways through which alcohol can cause cancer have been proposed.

Both ethanol and acetaldehyde can disrupt DNA methylation by inhibiting S-adenosyl-L-methionine (SAMe) synthesis and DNA methyltransferase (DNMT) activity, and ethanol can impair one-carbon metabolism. Cytochrome P-450 2E1 (CYP2E1) activity produces reactive oxygen species (ROS) leading to lipid peroxidation, metastasis, angiogenesis, and further formation of DNA adducts. Retinoid metabolism and the normal function of the immune system are both impaired by ethanol, while ethanol may lead to increases in sex hormone levels, as well as dysbiosis of the microbiome and liver cirrhosis. More than 30 years ago, in 1988, the International Agency for Research on Cancer (IARC) classified alcoholic beverages as a group 1 carcinogen, the most severe classification [4]. The IARC Monographs program aims to classify cancerous agents according to the strength of the available epidemiological and experimental evidence. Ethanol–the principal form of alcohol in alcoholic beverages–is a widely-used, psychoactive, and dependence-producing substance.

Defining the epigenetic mechanisms that modulate cancer progression also has great potential for the development of new treatment options not only for treating alcoholics with cancer but also for treating other alcohol-induced diseases. If human tumor cells are introduced (i.e., inoculated) into animals with functioning immune systems, they do not form tumors because they are recognized as foreign by the animal’s immune system. However, human tumors often grow in animals with compromised immune systems, and such animals can be used as models for a variety of research questions, including studies regarding the roles of various immune cells in controlling cancer and the impact of alcohol on this process. One such study specifically examined the role of CD4+ T cells in regulating tumor growth by implanting cells from a human lung cancer (i.e., the 201T human lung adenocarcinoma cell line) into the lungs of a strain of mice called BALB/c (Hunt et al. 2000). In this study, the mice were administered alcohol chronically for 8 weeks and then were injected with an anti-CD4 monoclonal antibody to deplete CD4+ T cells. To examine the effect of alcohol, the mice were administered ethanol in their food5 as well as 10 percent in their drinking water throughout the experimental period.

Drinking Alcohol, Often Heavily, Common among People with Cancer and Long-Term Survivors

Several studies using animal cancer models indicate tumor specific differences in the effect of alcohol on tumor growth and metastasis. These models included various types of breast cancer, melanoma, lung cancer, colon cancer, and hepatocellular carcinoma (For more information, see the sidebar “Effects of Alcohol on Tumor Growth, Invasion, Metastasis, and Survival 2c b fly in Animal Models”). Taken together, these studies and animal models did not allow for general conclusions regarding the impact of alcohol on tumor growth, metastasis formation, and disease progression, as findings differed significantly depending on tumor type. The alcohol model used as well as the duration of alcohol administration also are important variables and can affect the overall outcome (D’Souza El-Guindy et al. 2010), as is the amount of alcohol administered. Several mechanisms have been suggested as to how acute alcohol may enhance metastasis formation, including alcohol-induced formation of as well as inhibition of various signaling molecules (i.e., cytokines and chemokines). However, although both of these mechanisms seem to contribute to the increase of metastases after acute administration, they do not account for the entirety of alcohol’s effects.

For cancer specifically, an estimated 4.1% of all new cases globally in 2020 (3), and from 2013 through 2016, 4.8% of all cases annually in the U.S., were attributable to alcohol consumption (4). Current evidence suggests that “[t]here is no threshold of alcohol consumption below which cancer risk does not increase, at least for some cancers ” (5), and cancer prevention guidelines indicate that it is best not to drink alcohol (5, 6). Despite the large body of scientific evidence on the topic, the full cancer burden due to alcohol remains uncertain because for many cancer (sub)types associations with risk and survivorship are inconsistent or there are few studies.

The breakdown of ethanol in the body can also create high levels of acetaldehyde, which can damage DNA and cause liver, head and neck, and esophageal cancers. One of the ways in which the body defends itself against tumor cells involves their destruction by NK cells. The investigators also analyzed alcohol’s effects on NK-cell activity, finding that neither acute injection nor dietary administration of ethanol in these experiments affected NK-cell activity against MADB106 cells when determined in an in vitro assay (Yirmiya et al. 1992). When MADB106 and CRNK-16 cells were incubated with ethanol in vitro, the numbers of these cells were reduced after 5 days. These effects were significant for MADB106 cells at ethanol concentrations of 0.2 percent, 0.5 percent, and 1.0 percent ethanol and for CRNK-16 cells at 0.5 percent and 1.0 percent ethanol. Ethanol had no effect in rats that were depleted of NK cells, and metastasis was not affected do alcoholics have big noses after injection of the NK-insensitive C4047 rat colon cancer cell line (Ben-Eliyahu et al. 1996).

The authors concluded that previous estimates of the association between alcohol and oral and oropharyngeal cancer from observational studies may have been underestimated [16]. Another MR study on UK Biobank data found that drinking alcohol, especially above the UK’s low-risk guideline of up to 14 units per week, was causally related with head and neck cancers, but not breast cancer [17]. A further updated MR study using UK Biobank data did not find an association between alcohol exposure and cancer of any site, though they noted limitations of a lack of precision in their analyses due to low variance explained by the single nucleotide polymorphisms [18]. An MR analysis by Ong and colleagues found no significant increase in breast cancer risk per genetically predicted drink per day (odds ratio 1.00 (95% CI 0.93–1.08)) [19]. Approximately 4% of cancers worldwide are caused by alcohol consumption, equating to more than 740,000 cases of cancer globally in 2020 [1]. The impact of alcohol consumption on cancer burden differs by cancer type, and cancers of the oesophagus, liver, and breast represent the most alcohol-attributable cases of cancer globally (Figure 1).

1. This has stimulated research directed toward developing effective immunotherapeutic approaches to treat cancer (for a review of the tumor immune response as well as approaches being taken to develop immunotherapeutics for cancer, see Harris and Drake 2013).
2. Retinoid metabolism and the normal function of the immune system are both impaired by ethanol, while ethanol may lead to increases in sex hormone levels, as well as dysbiosis of the microbiome and liver cirrhosis.
3. Current evidence suggests that “[t]here is no threshold of alcohol consumption below which cancer risk does not increase, at least for some cancers ” (5), and cancer prevention guidelines indicate that it is best not to drink alcohol (5, 6).
4. Clearly, more mechanistic research is needed to define the complex interactions between cancer and alcohol.
5. Moreover, conversion from estrogen receptor alpha positive to estrogen receptor alpha negative can occur (Hoefnagel et al. 2010).
6. Evidence from Western countries already strongly indicates that alcohol is a direct cause of cancer in the head, neck, oesophagus, liver, colon and breast.

That could mean teaching health care providers to talk with patients about alcohol use when discussing sleep or memory problems, or if they have the beginning signs of liver disease, she said. But studies have shown that people pouring their own wine or spirits at home tend to underestimate the amount they’re actually consuming. Overall, the team found that about 741,300 cancer cases in 2020, or 4.1% of the global total for that year, could be attributed to alcohol consumption. “The high prevalence of cancer survivors engaged in hazardous drinking highlights the need for immediate interventions,” they wrote.

The DNA adducts in question include N2-ethylidene-2′-deoxyguanosine, N2-ethyl-2′-deoxyguanosine, N2-propano-2′-deoxyguanosine (PdG), and N2-etheno-2′-deoxyguanosine [23]. The PdG adduct may form additional highly genotoxic structures such as DNA-protein cross-links and DNA interstrand cross-links which may confer carcinogenesis [24]. Once consumed, alcohol is metabolised by enzymes including alcohol dehydrogenase (ADH), cytochrome P-450 2E1 (CYP2E1) and bacterial catalase, producing acetaldehyde [20].

The effect of ethanol on mammary cancer growth has been studied in a number of animal models, using both rodent and human tumor cell lines. There is mounting evidence that alcohol can negatively affect one-carbon metabolism which is essential for DNA methylation and DNA synthesis [25]. Ethanol and acetaldehyde can reduce the activity of enzymes involved in one-carbon metabolism that regulate DNA methylation, namely methionine synthase, methionine adenosyl transferase and DNMT, thus dysregulating epigenetic patterns and resulting in DNA hypomethylation [20]. Both acetaldehyde and ethanol can impact DNA methylation which may lead to changes in the expression of oncogenes and tumour-suppressor genes [21].

Site-of-care shifts: Healthcare’s $50B opportunity

These researchers also examined the effect of ethanol in vitro on the migration of the estrogen receptor–positive T47D breast cancer cell line. The results showed that cells exposed to different concentrations of ethanol from 0.1 percent to 0.5 percent exhibited increased migration, as did cells exposed to estrogen (20 nM). The combination of estrogen and 0.5 percent resulted in higher migration than either treatment alone. Most research involving alcohol and cancer concerns the relationship between alcohol consumption and cancer risk and the mechanisms of carcinogenesis. This review relates the amount and duration of alcohol intake in humans and in animal models of cancer to tumor growth, angiogenesis, invasion, metastasis, immune response, and host survival in specific types and subtypes of cancer. More research is needed to define the mechanisms that underlie the role of alcohol on cancer progression in both animals and humans.

Awareness varies by beverage type

Epidemiologic studies have shown that such individuals have a higher risk of alcohol-related esophageal cancer, as well as of head and neck cancers, than individuals with the fully active enzyme who drink comparable amounts of alcohol (31). These increased risks are seen only among people who carry the ALDH2 variant and drink alcohol—they are not observed in people who carry the variant but do not drink alcohol. In one of the first experiments conducted in melanoma, 6- to 8-week-old female CDBA/2F1 mice consumed water or 20 percent alcohol for 52 weeks before being inoculated in a leg with the Cloudman 8-91 melanoma tumor (Ketcham et al. 1963). When the tumors reached a size of 1.5 to 2.0 cm (about 28 days after tumor inoculation), the groups were divided in half, and half of each group had the primary tumor-bearing leg amputated.

Tumor growth was greatly inhibited in the mice receiving a high-fat diet as well as estrogen supplements. The calorie-restricted diet also inhibited tumor growth independent of the effects of alcohol and estrogen supplementation. One early study (Capel et al. 1978) investigated the effect of alcohol exposure on the growth and metastasis of Lewis lung carcinoma. Male animals from a type of mouse strain called C57BL/6 were exposed to 10 percent ethanol in their drinking water for 2, 4, 5, or 8 weeks before tumor cells were implanted into their thighs.

Moreover, most U.S. adults are unaware of the alcohol-cancer link (7), and the interrelationships of alcohol control regulations and cancer risk is unclear. These experiments showed that 10 percent w/v ethanol did not affect metastasis after intravenous tumor inoculation in female C57BL/6 mice consuming alcohol for 2 weeks or spontaneous metastasis in mice injected 1 week after initiating ethanol feeding. However, lung metastasis was inhibited if intravenous injection of tumor cells occurred at 4, 6.5, 7, and 12 weeks after initiation of 20 percent w/v ethanol. Similarly, spontaneous metastasis to the lung was significantly inhibited in mice injected with melanoma at 1, 4, 6.5, and 10 weeks of consuming 20 percent ethanol.

This research has a strong potential to discover new immunotherapy and epigenetic approaches to cancer treatment as well as treatment of other alcohol-induced diseases. This response is characterized by inflammatory reactions involving various mediators, including chemokines and cytokines that how long does cymbalta withdrawal last are produced by a variety of immune cells, such as macrophages, neutrophils, NK cells, and dendritic cells. Macrophages and neutrophils can exhibit antitumor activity as well as suppress immune response against tumor cells (i.e., have immunosuppressive activity).

How does alcohol affect the risk of cancer?

Similarly, incubation for 48 hours in 0.1 percent and 0.2 percent w/v ethanol stimulated invasion of estrogen receptor–negative SKBR3 and estrogen receptor–positive BT474 breast cancer cells. In contrast, ethanol exposure did not affect invasion of HB2, an immortalized normal human breast tissue cell line, or estrogen receptor–negative BT20 breast cancer cells. The effects of ethanol may depend not only on the specific cell line examined but also on the ethanol concentration used. Thus, studies from another laboratory demonstrated that exposure to 0.1 percent, 0.2 percent, and 0.5 percent w/v ethanol enhanced invasion of T47D, MCF-7, and MDA-MB231 cells in a dose-dependent manner (Wong et al. 2011). Similarly, Aye and colleagues (2004) examined the effects of exposure for 48 hours to different ethanol concentrations on estrogen receptor–negative SKBR3 and estrogen receptor–positive BT474 breast cancer cells. For both SKBR3 and BT474 cells exposure to 0.1 percent and 0.2 percent w/v ethanol stimulated invasion.

NK cells can destroy tumors on contact, and their antitumor function can be further stimulated by cytokines. Dendritic cells are important in presenting molecules that identify a cell as harmful or foreign (i.e., antigens) to other immune cells and are a bridge between the innate immune response and the B-cell and T-cell responses that characterize the adaptive immune system. Alcohol regulations are designed to ensure an orderly marketplace, and to minimize or reduce the health, social, and economic harms due to consumption. The U.S. Community Preventive Services Task Force’s (CPSTF) Guide to Community Preventive Services (54), and WHO’s 2010 Global Strategy to Reduce the Harmful Use of Alcohol(8) describe a range of evidence-based alcohol control policies. Evidence from Western countries already strongly indicates that alcohol is a direct cause of cancer in the head, neck, oesophagus, liver, colon and breast. But it has been difficult to establish whether alcohol directly causes cancer, or if it is linked to possible confounding factors (such as smoking and diet) that could generate biased results.