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).
- 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).
- 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.
- 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).
- Clearly, more mechanistic research is needed to define the complex interactions between cancer and alcohol.
- Moreover, conversion from estrogen receptor alpha positive to estrogen receptor alpha negative can occur (Hoefnagel et al. 2010).
- 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.