Enhanced colorectal cancer metastases in the alcohol-injured liver

Autor: Ashley M. Mohr, Geoffrey A. Talmon, Carol A. Casey, Benita L. McVicker, Dean J. Tuma, John J. Gould, Peter Thomas, Jacy L. Kubik
Rok vydání: 2017
Předmět:
0301 basic medicine
Cancer Research
Alcoholic liver disease
medicine.medical_specialty
Pathology
Colorectal cancer
Gastroenterology
Immunocompromised Host
Mice
03 medical and health sciences
Liver Neoplasms
Experimental
0302 clinical medicine
Carcinoembryonic antigen
Surgical oncology
Cell Line
Tumor
Internal medicine
medicine
Animals
Humans
Liver Diseases
Alcoholic
Homeodomain Proteins
Mice
Knockout
Liver injury
Hematology
Ethanol
biology
business.industry
Cytochrome P-450 CYP2E1
Metastatic liver disease
General Medicine
medicine.disease
Endocytosis
digestive system diseases
Neoplasm Proteins
Mice
Inbred C57BL
030104 developmental biology
Oncology
Enzyme Induction
030220 oncology & carcinogenesis
Hepatocytes
biology.protein
Cytokines
Heterografts
Steatosis
medicine.symptom
Colorectal Neoplasms
business
Neoplasm Transplantation
Zdroj: Clinical & Experimental Metastasis. 34:171-184
ISSN: 1573-7276
0262-0898
DOI: 10.1007/s10585-017-9838-x
Popis: 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.
Databáze: OpenAIRE
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