Enhanced colorectal cancer metastases in the alcohol-injured liver.
Metastatic liver disease is a major cause of mortality in colorectal cancer (CRC) patients. Alcohol consumption is a noted risk factor for secondary cancers yet the role of alcoholic liver disease (ALD) in colorectal liver metastases (CRLM) is not defined. This work evaluated tumor cell colonization in the alcoholic host liver using a novel preclinical model of human CRC liver metastases. Immunocompromised Rag1-deficient mice were fed either ethanol (E) or isocaloric control (C) diets for 4 weeks prior to intrasplenic injection of LS174T human CRC cells. ALD and CRLM were evaluated 3 or 5 weeks post-LS174T cell injection with continued C/E diet administration. ALD was confirmed by increased serum transaminases, hepatic steatosis and expression of cytochrome P4502E1, a major ethanol-metabolizing enzyme. Alcohol-mediated liver dysfunction was validated by impaired endocytosis of asialoorosomucoid and carcinoembryonic antigen (CEA), indicators of hepatocellular injury and progressive CRC disease, respectively. Strikingly, the rate and burden of CRLM was distinctly enhanced in alcoholic livers with metastases observed earlier and more severely in E-fed mice. Further, alcohol-related increases (1.5-3.0 fold) were observed in the expression of hepatic cytokines (TNF-α, IL-1 beta, IL-6, IL-10) and other factors noted to be involved in the colonization of CRC cells including ICAM-1, CCL-2, CCL-7, MMP-2, and MMP-9. Also, alcoholic liver injury was associated with altered hepatic localization as well as increased circulating levels of CEA released from CRC cells. Altogether, these findings indicate that the alcoholic liver provides a permissive environment for the establishment of CRLM, possibly through CEA-related inflammatory mechanisms.
Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA.
Ashley M
AM
Mohr
Research Service, VA Nebraska-Western Iowa Health Care System, Omaha, NE, USA.
John J
JJ
Gould
Research Service, VA Nebraska-Western Iowa Health Care System, Omaha, NE, USA.|Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, USA.
Jacy L
JL
Kubik
Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA.
Geoffrey A
GA
Talmon
Research Service, VA Nebraska-Western Iowa Health Care System, Omaha, NE, USA.|Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, USA.
Carol A
CA
Casey
Department of Surgery and Biomedical Sciences, Creighton University, Omaha, NE, USA.
Peter
P
Thomas
Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, USA.
Dean J
DJ
Tuma
Research Service, VA Nebraska-Western Iowa Health Care System, Omaha, NE, USA. bmcvicker@unmc.edu.|Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, USA. bmcvicker@unmc.edu.
Benita L
BL
McVicker
D000818:Animals; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000473:pathology*; D019392:Cytochrome P-450 CYP2E1 / Q000096:biosynthesis / Q000235:genetics; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D004705:Endocytosis; D004790:Enzyme Induction; D000431:Ethanol / Q000633:toxicity; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology; D064593:Heterografts; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D016867:Immunocompromised Host; D008108:Liver Diseases, Alcoholic / Q000150:complications*; D008114:Liver Neoplasms, Experimental / Q000209:etiology / Q000556:secondary*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics; D009368:Neoplasm Transplantation
D016207:Cytokines; D018398:Homeodomain Proteins; D009363:Neoplasm Proteins; C064658:RAG-1 protein; D000431:Ethanol; D019392:Cytochrome P-450 CYP2E1
Alcoholic liver disease (ALD); Asialoglycoprotein receptor (ASGPR); Carcinoembryonic antigen (CEA); Colorectal liver metastasis (CRLM); Kupffer cells