Enhanced colorectal cancer metastases in the alcohol-injured liver

Ashley M. Mohr, John J. Gould, Jacy L. Kubik, Geoffrey A Talmon, Carol A Casey, Peter Thomas, Dean J. Tuma, Benita L McVicker

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)171-184
Number of pages14
JournalClinical and Experimental Metastasis
Volume34
Issue number2
DOIs
StatePublished - Feb 1 2017

Fingerprint

Colorectal Neoplasms
Alcohols
Neoplasm Metastasis
Liver
Alcoholic Liver Diseases
Carcinoembryonic Antigen
Matrix Metalloproteinases
Liver Diseases
Ethanol
Diet
Injections
Wounds and Injuries
Intercellular Adhesion Molecule-1
Cytochromes
Liver Neoplasms
Endocytosis
Transaminases
Interleukin-1beta
Alcohol Drinking
Interleukin-10

Keywords

  • Alcoholic liver disease (ALD)
  • Asialoglycoprotein receptor (ASGPR)
  • Carcinoembryonic antigen (CEA)
  • Colorectal liver metastasis (CRLM)
  • Kupffer cells

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Enhanced colorectal cancer metastases in the alcohol-injured liver. / Mohr, Ashley M.; Gould, John J.; Kubik, Jacy L.; Talmon, Geoffrey A; Casey, Carol A; Thomas, Peter; Tuma, Dean J.; McVicker, Benita L.

In: Clinical and Experimental Metastasis, Vol. 34, No. 2, 01.02.2017, p. 171-184.

Research output: Contribution to journalArticle

Mohr, Ashley M. ; Gould, John J. ; Kubik, Jacy L. ; Talmon, Geoffrey A ; Casey, Carol A ; Thomas, Peter ; Tuma, Dean J. ; McVicker, Benita L. / Enhanced colorectal cancer metastases in the alcohol-injured liver. In: Clinical and Experimental Metastasis. 2017 ; Vol. 34, No. 2. pp. 171-184.
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abstract = "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.",
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AU - Mohr, Ashley M.

AU - Gould, John J.

AU - Kubik, Jacy L.

AU - Talmon, Geoffrey A

AU - Casey, Carol A

AU - Thomas, Peter

AU - Tuma, Dean J.

AU - McVicker, Benita L

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AB - 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.

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KW - Colorectal liver metastasis (CRLM)

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