The liver is the terminal site of metastatic disease of colorectal cancer (CRC), that without intervention usually heralds death. The liver is also the main organ affected by alcohol consumption. Interestingly, alcohol use has been identified as a significant risk factor for colorectal liver metastasis (CRLM), yet contributing mechanisms remain undefined. Although alcohol-related CRLM is a serious health concern for the general population, the Veteran population is especially vulnerable because of service-connected trauma and injuries that significantly contribute to alcohol use disorders and liver disease. Considering this, it is clinically important to determine mechanisms and potential therapeutic targets for colorectal metastasis in the alcohol-affected liver. The goal of this work is to determine how the alcoholic liver facilitates the colonization of metastatic CRC cells that express carcinoembryonic antigen (CEA). The CEA tumor glycoprotein is overexpressed in metastatic cancer cells and correlates with the development of CRLM. It is believed that CEA stimulates cells of the host microenvironment to produce inflammatory responses and factors that promote metastatic disease. Specifically, it is hypothesized that alcohol sensitizes hepatic macrophages to the effects of CEA resulting in the accelerated growth of CRC tumors in the liver. To investigate this, three specific aims are proposed to determine the role of alcohol- sensitized macrophages (Kupffer cells, infiltrating monocytes, and peritoneal cells) in CEA signaling and development of CRLM. In the first studies, the role of CEA as a key factor in the promotion of metastases will be established using a recently developed preclinical model of alcoholic liver injury and CRLM. In the second aim, the critical role of macrophage phenotype, activation, and related production of prometastatic factors will be determined in response to CEA-expressing cancer cells. In the last aim, key experiments will define the effectiveness of targeting CEA-mediated events to reduce the burden of colorectal liver metastasis. Macrophage inactivation and anti-CEA therapy will be tested alone or in combination with intestinal alkaline phosphatase supplementation to inhibit alcohol-related effects of gut-derived endotoxin. The successful completion of these studies will contribute to the field by defining targetable mechanisms involved in the alcohol-mediated exacerbation of CEA signaling and the associated development of CRLM. Moreover, this work will provide useful information for future therapeutic strategies aimed at reducing or eliminating liver metastases of colorectal cancer. This is a clinically relevant topic which has the potential to significantly impact healthcare for Veterans, especially those who are at a high risk for alcohol use disorders and the associated development colorectal liver tumors.

Public Health Relevance

Colorectal cancer (CRC) is a common cancer in the Veteran population. Unfortunately, CRC will metastasize to the liver in over half of patients resulting in more complications, need of advanced treatments, and death. Alcohol consumption has been identified as a significant risk factor for CRC as well as colorectal liver metastasis (CRLM), yet it is not known whether underlying alcoholic disease affects cancer spread to the liver. This research will determine alcohol's impact on the severity of CRLM and the related mechanistic interplay between alcohol-sensitized macrophages and CRC cells that express carcinoembryonic antigen. Also, potential therapeutic targets will be tested in efforts to reduce the burden of CRLM. This evaluation is clinically relevant since post-traumatic stress and related alcohol abuse affects Veterans disproportionately to the general population. Overall, this study can contribute to better therapeutic options for CRLM and improvements in healthcare for Veterans, especially those suffering from alcohol abuse disorders and cancer.

National Institute of Health (NIH)
Veterans Affairs (VA)
Non-HHS Research Projects (I01)
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Special Emphasis Panel (ZRD1)
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Omaha VA Medical Center
United States
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