Alcohol, Carcinoembryonic Antigen Processing and Colorectal Liver Metastases

Abstract

It is well established that alcohol consumption is related to the development of alcoholic liver disease. Additionally, it is appreciated that other major health issues are associated with alcohol abuse, including colorectal cancer (CRC) and its metastatic growth to the liver. Although a correlation exists between alcohol use and the development of diseases, the search continues for a better understanding of specific mechanisms. Concerning the role of alcohol in CRC liver metastases, recent research is aimed at characterizing the processing of carcinoembryonic antigen (CEA), a glycoprotein that is associated with and secreted by CRC cells. A positive correlation exists between serum CEA levels, liver metastasis, and alcohol consumption in CRC patients, although the mechanism is not understood. It is known that circulating CEA is processed primarily by the liver, first by nonparenchymal Kupffer cells (KCs) and secondarily, by hepatocytes via the asialoglycoprotein receptor (ASGPR). Since both KCs and hepatocytes are known to be significantly impacted by alcohol, it is hypothesized that alcohol-related effects to these liver cells will lead to altered CEA processing, including impaired asialo-CEA degradation, resulting in changes to the liver microenvironment and the metastatic potential of CRC cells. Also, it is predicted that CEA processing will affect cytokine production in the alcohol-injured liver, resulting in pro-metastatic changes such as enhanced adhesion molecule expression on the hepatic sinusoidal endothelium. This chapter examines the potential role that alcohol-induced liver cell impairments can have in the processing of CEA and associated mechanisms involved in CEA-related colorectal cancer liver metastasis.

p38γ Activation and BGP (Biliary Glycoprotein) Induction in Primates at Risk for Inflammatory Bowel Disease and Colorectal Cancer—A Comparative Study with Humans

“…The role of CEA in metastasis is not fully characterized but implicated as a prometastatic adhesion and signaling molecule that interacts with cells in the hepatic microenvironment [ 52 , 53 ]. Moreover, the prometastatic effects of CEA are enhanced in the setting of pre-existing liver disease including alcoholic [ 5 , 54 ] and nonalcoholic liver disease [ 55 , 56 ]. Most recently, it was reported that NAFLD and CEA expression are associated with an increased incidence of liver metastasis in CRC patients [ 55 ].…”

IEO model: A novel concept describing the complete metastatic process in the liver microenvironment (Review)

“…non-alcoholic fatty liver disease (nAfLd) and alcoholic liver disease are major health issues associated with tumor cell metastasis to the liver (28). According to previous studies, high alcohol intake is associated with CRLM (29,30).…”

“…According to previous studies, high alcohol intake is associated with CRLM (29,30). Both KCs and hepatocytes are affected by alcohol, and high expression of lipopolysaccharides and pro-inflammatory cytokines, such as TNFα and IL-1β changes the hepatic niche and CRC metastasis (28). nAfLd has been used to demonstrate the higher metastatic burden in steatotic livers compared with that in normal livers.…”

“…nAfLd is characterized by fat accumulation, which alters the local hepatic niche by stimulating triglyceride, recruiting inflammatory cells, increasing Tnfα expression and disrupting the normal structure of ECM. These alterations of the liver microenvironment, including tumor-associated inflammatory cells and aberrant ecM structure may promote colonization of tumor cells and cancer progression with poor outcome (28)(29)(30). However, Karube et al (31) demonstrated that fat metabolism disorders inhibit tumor cell proliferation and angiogenesis to prevent tumor growth and reduce the likelihood of metastasis.…”

Ethanol promotes alcohol-related colorectal cancer metastasis via the TGF-β/RUNX3/Snail axis by inducing TGF-β1 upregulation and RUNX3 cytoplasmic mislocalization

“…Alcohol consumption is very common in developed countries and has been confirmed to be an important risk factor for CRC, and particularly strong associations have been obtained with chronic and moderate to heavy alcohol intake [4]. Moreover, increasing numbers of epidemiological studies have revealed that alcohol consumption is also closely related to metastasis in patients with CRC, and this association was identified as the primary reason for the poor outcomes observed in these patients [8,9]. Due to the difficulty in detecting CRC at an early stage [10], it was conceivable to conclude that most CRC patients would not change their lifestyles until obvious symptoms and/or signs were detected.…”