Pathogenetic mechanisms of upper aerodigestive tract cancer in alcoholics

Abstract

Chronic excessive alcohol consumption is the strongest risk factor for upper aerodigestive tract (UADT) cancer (oral cavity, pharynx, hypopharynx, larynx, esophagus). 1 In addition, alcohol also increases the risk for cancer of the liver, colorectum and breast. 1 A great number of epidemiological studies have demonstrated a correlation between alcohol ingestion and the occurrence of cancer in these organs. [1][2][3][4][5][6][7][8][9] These studies clearly show that the ingestion of all types of alcoholic beverages is associated with an increased cancer risk that suggests that ethanol itself is the crucial compound that causes that effect. The exact mechanism(s) of ethanol-associated carcinogenesis has remained obscure because ethanol by itself when given to animals is not carcinogenic. 10 Multiple mechanisms are involved in alcohol-associated cancer development of the UADT including the effect of acetaldehyde (AA), the first metabolite of ethanol oxidation, induction of cytochrome P-4502E1 (CYP2E1) leading to the generation of reactive oxygen species (ROS) and enhanced procarcinogen activation, modulation of cellular regeneration and nutritional deficiencies.In our minireview, major emphasis is laid on more recent developments including genetic aspects of ethanol metabolism, bacterial alcohol oxidation and nutritional deficiencies. EPIDEMIOLOGYAs early as at the beginning of the last century, Lamu noticed an increased incidence of esophageal cancer in absinth drinkers. 11 Meanwhile, an extensive body of epidemiologic data has accumulated that identified alcohol as a major risk factor for UADT cancer. [1][2][3][4][5][6] In a carefully designed French study, Tuyns 2 was able to demonstrate that alcohol consumption of more than 80 g/day (ϳ1 bottle of wine) increases the relative risk (RR) of esophageal cancer by a factor of 18, whereas smoking only (more than 20 cigarettes) leads to an increased RR of 5. Both factors act synergistically, resulting in an increased RR of 44. 2 More recently, an epidemiologic study by Maier et al. 3 showed that 90% of all patients with head and neck cancer consumed alcohol regularly in quantities twice the amount of a control group with a significant dose-response relationship. If the RR for an individual with a daily alcohol consumption of 25 g was assumed to be 1, this figure rose to 32 if alcohol consumption exceeded 100 g. Bruguere et al. 5 found RR values of 13.5 for oral cancer, 15.2 for oropharyngeal carcinoma, and of 28.6 for hypopharyngeal carcinoma when 100 -159 g of alcohol were consumed daily. It is noteworthy that even with these high daily alcohol dosages, the alcohol-associated cancer risk is not saturable. Alcohol consumption exceeding 1.5 bottles of wine daily results in a 100-fold increased risk for esophageal cancer. 4 In an epidemiologic study of the American Cancer Society on more than 750,000 individuals, Bofetta and Garfinkel 12 found an increased risk for esophageal cancer already at a dose of 12 g alcohol daily (RR ϭ 1.37) rising to an RR ϭ 5.8 after 72 g al...

Estimating dose‐response relationship between ethanol and risk of cancer using regression spline models

“…25 Thus, very high ethanol intakes (i.e., Ͼ200 g/day) was not considered in our study, allowing us to rule out most of the possible misclassifications and the effect of confounding factors connected with severe alcoholism (i.e., nutritional deficiencies, metabolic modifications, impairment of immune system, etc). 30 Depending on the exposure distribution, it might sometimes happen that spline models produce odd behaviour on the part of the fitted curve in the last exposure category, such as sudden and unexpected changes in trend. When this happens, further constraints can be easily introduced by restricting the fitted curve to be linear in the upper category.…”

Alcohol and gastrointestinal oncology

“…The mechanisms underlying alcohol-related cancers are unclear but several factors have been suggested to play a role [10][11][12] : local effect of ethanol, acetaldehyde (isoenzymes polymorphism), induction of cytochrome P450 2E1 (CY-P2E1) (conversion of various xenobiotics), nutritional deficiencies, interactions with retinoids, changes in the degree of methylation, immune surveillance, angiogenesis.…”

“…The activity of ADH in cancer cells is much higher than the activity of ALDH. This suggests that cancer cells have a greater capability for ethanol oxidation but less ability to remove acetaldehyde than normal tissues [11,13,14] . ADH and ALDH are encoded by multiple genes.…”

Carcinogenesis and alcohol

“…Seitz et al [4] affirm that CYP2E1 activity occurs at relatively low levels of alcohol (40 g/day) and at these levels of intake induction is already apparent after one week, although the extent varies interindividually. Some individuals exhibit a very low extent of induction of CYP2E1 activity, whereas others show a high extent of induction.…”

“…This increased retinoic acid metabolism decreases retinoic acid, which by itself results in an increased expression of the AP1 gene associated with an increase in their proteins c-jun and c-fos, finally leading to an increase in cycline D1, which is associated with hyperproliferation, at least in liver. Thus, retinoic acid deficiency is associated with acceleration of carcinogenesis [4,5].…”