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Enhanced colorectal cancer metastases in the alcohol-injured liver

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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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Abbreviations

ALD:

Alcoholic liver disease

ALT:

Alanine aminotransferase

AST:

Aspartate aminotransferase

ASGPR:

Asialoglycoprotein receptor

ASOR:

Asialoorosomucoid

ATCC:

American type culture collection

C:

Control

CCL 2, 7:

C–C motif chemokine ligand 2, 7

CEA:

Carcinoembryonic antigen

CRC:

Colorectal cancer

CRLM:

Colorectal liver metastasis

E:

Ethanol

ELISA:

Enzyme-linked immunosorbent assay

GAPDH:

Glyceraldehyde-3-phosphate dehydrogenase

H&E:

Hematoxylin and eosin

ICAM-1:

Intracellular adhesion molecule-1

IHC:

Immunohistochemical

IL-1β, IL-6, IL-10:

Interleukins (1-β, 6, 10)

KC:

Kupffer cell

LD:

Lieber-DeCarli

M1:

Macrophage marker 1

MMP-2 and 9:

Metalloprotease-2 and 9

mRNA:

Messenger RNA

PBS:

Phosphate-buffered saline

RT-PCR:

Real-time polymerase chain reaction

ROS:

Reactive oxygen species

SDS–PAGE:

Sodium dodecyl sulfate polyacrylamide gel electrophoresis

TNF-α:

Tumor necrosis factor alpha

References

  1. Siegel RL, Miller KD, Jemal A (2015) Cancer statistics, 2015. CA Cancer J Clin 65(1):5–29. doi:10.3322/caac.21254

    Article  PubMed  Google Scholar 

  2. Silberhumer GR, Paty PB, Denton B, Guillem J, Gonen M, Araujo RL, Nash GM, Temple LK, Allen PJ, DeMatteo RP, Weiser MR, Wong WD, Jarnagin WR, D’Angelica MI, Fong Y (2016) Long-term oncologic outcomes for simultaneous resection of synchronous metastatic liver and primary colorectal cancer. Surgery 160(1):67–73. doi:10.1016/j.surg.2016.02.029

    Article  PubMed  Google Scholar 

  3. Sheth KR, Clary BM (2005) Management of hepatic metastases from colorectal cancer. Clin Colon Rectal Surg 18(3):215–223. doi:10.1055/s-2005-916282

    Article  PubMed  PubMed Central  Google Scholar 

  4. Manfredi S, Lepage C, Hatem C, Coatmeur O, Faivre J, Bouvier AM (2006) Epidemiology and management of liver metastases from colorectal cancer. Ann Surg 244(2):254–259. doi:10.1097/01.sla.0000217629.94941.cf

    Article  PubMed  PubMed Central  Google Scholar 

  5. Haddad AJ, Bani Hani M, Pawlik TM, Cunningham SC (2011) Colorectal liver metastases. Int J Surg Oncol 2011:285840. doi:10.1155/2011/285840

    PubMed  PubMed Central  Google Scholar 

  6. Nelson DE, Jarman DW, Rehm J, Greenfield TK, Rey G, Kerr WC, Miller P, Shield KD, Ye Y, Naimi TS (2013) Alcohol-attributable cancer deaths and years of potential life lost in the United States. Am J Public Health 103(4):641–648. doi:10.2105/AJPH.2012.301199

    Article  PubMed  PubMed Central  Google Scholar 

  7. Stangl R, Altendorf-Hofmann A, Charnley RM, Scheele J (1994) Factors influencing the natural history of colorectal liver metastases. Lancet 343(8910):1405–1410

    Article  CAS  PubMed  Google Scholar 

  8. Rasool S, Kadla SA, Rasool V, Ganai BA (2013) A comparative overview of general risk factors associated with the incidence of colorectal cancer. Tumour Biol 34(5):2469–2476. doi:10.1007/s13277-013-0876-y

    Article  CAS  PubMed  Google Scholar 

  9. Maeda M, Nagawa H, Maeda T, Koike H, Kasai H (1998) Alcohol consumption enhances liver metastasis in colorectal carcinoma patients. Cancer 83(8):1483–1488

    Article  CAS  PubMed  Google Scholar 

  10. Lieber CS (2004) Alcoholic fatty liver: its pathogenesis and mechanism of progression to inflammation and fibrosis. Alcohol 34(1):9–19. doi:10.1016/j.alcohol.2004.07.008

    Article  CAS  PubMed  Google Scholar 

  11. Schaffert CS, Duryee MJ, Hunter CD, Hamilton BC 3rd, DeVeney AL, Huerter MM, Klassen LW, Thiele GM (2009) Alcohol metabolites and lipopolysaccharide: roles in the development and/or progression of alcoholic liver disease. World J Gastroenterol 15(10):1209–1218

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Ceni E, Mello T, Galli A (2014) Pathogenesis of alcoholic liver disease: role of oxidative metabolism. World J Gastroenterol 20(47):17756–17772. doi:10.3748/wjg.v20.i47.17756

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Cederbaum AI (2001) Introduction-serial review: alcohol, oxidative stress and cell injury. Free Radic Biol Med 31(12):1524–1526

    Article  CAS  PubMed  Google Scholar 

  14. Dalton SR, Wiegert RL, Baldwin CR, Kassel KM, Casey CA (2003) Impaired receptor-mediated endocytosis by the asialoglycoprotein receptor in ethanol-fed mice: implications for studying the role of this receptor in alcoholic apoptosis. Biochem Pharmacol 65(4):535–543

    Article  CAS  PubMed  Google Scholar 

  15. Tworek BL, Tuma DJ, Casey CA (1996) Decreased binding of asialoglycoproteins to hepatocytes from ethanol-fed rats. Consequence of both impaired synthesis and inactivation of the asialoglycoprotein receptor. J Biol Chem 271(5):2531–2538

    Article  CAS  PubMed  Google Scholar 

  16. McVicker BL, Thiele GM, Casey CA, Osna NA, Tuma DJ (2013) Susceptibility to T cell-mediated liver injury is enhanced in asialoglycoprotein receptor-deficient mice. Int Immunopharmacol 16(1):17–26

    Article  CAS  PubMed  Google Scholar 

  17. McVicker BL, Tuma DJ, Kharbanda KK, Kubik JL, Casey CA (2007) Effect of chronic ethanol administration on the in vitro production of proinflammatory cytokines by rat Kupffer cells in the presence of apoptotic cells. Alcohol Clin Exp Res 31(1):122–129. doi:10.1111/j.1530-0277.2006.00270.x

    Article  CAS  PubMed  Google Scholar 

  18. McVicker BL, Tuma DJ, Kubik JA, Hindemith AM, Baldwin CR, Casey CA (2002) The effect of ethanol on asialoglycoprotein receptor-mediated phagocytosis of apoptotic cells by rat hepatocytes. Hepatology 36(6):1478–1487. doi:10.1053/jhep.2002.37137

    CAS  PubMed  Google Scholar 

  19. Thakur V, Pritchard MT, McMullen MR, Wang Q, Nagy LE (2006) Chronic ethanol feeding increases activation of NADPH oxidase by lipopolysaccharide in rat Kupffer cells: role of increased reactive oxygen in LPS-stimulated ERK1/2 activation and TNF-alpha production. J Leukoc Biol 79(6):1348–1356. doi:10.1189/jlb.1005613

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Thurman RG (1998) II. Alcoholic liver injury involves activation of Kupffer cells by endotoxin. Am J Physiol 275(4 Pt 1):G605–G611

    CAS  PubMed  Google Scholar 

  21. Park PH, Thakur V, Pritchard MT, McMullen MR, Nagy LE (2006) Regulation of Kupffer cell activity during chronic ethanol exposure: role of adiponectin. J Gastroenterol Hepatol 21(Suppl 3):S30–S33. doi:10.1111/j.1440-1746.2006.04580.x

    Article  CAS  PubMed  Google Scholar 

  22. Bird NC, Mangnall D, Majeed AW (2006) Biology of colorectal liver metastases: a review. J Surg Oncol 94(1):68–80. doi:10.1002/jso.20558

    Article  CAS  PubMed  Google Scholar 

  23. Thomas P, Forse RA, Bajenova O (2011) Carcinoembryonic antigen (CEA) and its receptor hnRNP M are mediators of metastasis and the inflammatory response in the liver. Clin Exp Metastasis 28(8):923–932. doi:10.1007/s10585-011-9419-3

    Article  CAS  PubMed  Google Scholar 

  24. Paschos KA, Majeed AW, Bird NC (2014) Natural history of hepatic metastases from colorectal cancer–pathobiological pathways with clinical significance. World J Gastroenterol 20(14):3719–3737. doi:10.3748/wjg.v20.i14.3719

    Article  PubMed  PubMed Central  Google Scholar 

  25. Steele L, Cooper EH, Mackay AM, Losowsky MS, Goligher JC (1974) Combination of carcinoembryonic antigen and gamma glutamyl transpeptidase in the study of the evolution of colorectal cancer. Br J Cancer 30(4):319–324

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Thomas P, Zamcheck N (1983) Role of the liver in clearance and excretion of circulating carcinoembryonic antigen (CEA). Dig Dis Sci 28(3):216–224

    Article  CAS  PubMed  Google Scholar 

  27. McVicker B, Tuma DJ, Lazure KE, Thomas P, Casey CA (2015) Alcohol, carcinoembryonic antigen processing and colorectal liver metastases. Adv Exp Med Biol 815:295–311. doi:10.1007/978-3-319-09614-8_17

    Article  PubMed  Google Scholar 

  28. Aldulaymi B, Bystrom P, Berglund A, Christensen IJ, Brunner N, Nielsen HJ, Glimelius B (2010) High plasma TIMP-1 and serum CEA levels during combination chemotherapy for metastatic colorectal cancer are significantly associated with poor outcome. Int Soc Cell 79(1–2):144–149. doi:10.1159/000320686

    CAS  Google Scholar 

  29. Bell H, Orjasaeter H, Lange HF (1979) Carcinoembryonic antigen (CEA) in patients with alcoholic liver diseases. Scand J Gastroenterol 14(3):273–279

    Article  CAS  PubMed  Google Scholar 

  30. Scoccianti C, Straif K, Romieu I (2013) Recent evidence on alcohol and cancer epidemiology. Future Oncol 9(9):1315–1322. doi:10.2217/fon.13.94

    Article  CAS  PubMed  Google Scholar 

  31. Wan J, Benkdane M, Teixeira-Clerc F, Bonnafous S, Louvet A, Lafdil F, Pecker F, Tran A, Gual P, Mallat A, Lotersztajn S, Pavoine C (2014) M2 Kupffer cells promote M1 Kupffer cell apoptosis: a protective mechanism against alcoholic and nonalcoholic fatty liver disease. Hepatology 59(1):130–142. doi:10.1002/hep.26607

    Article  CAS  PubMed  Google Scholar 

  32. Dalton SR, Lee SM, King RN, Nanji AA, Kharbanda KK, Casey CA, McVicker BL (2009) Carbon tetrachloride-induced liver damage in asialoglycoprotein receptor-deficient mice. Biochem Pharmacol 77(7):1283–1290. doi:10.1016/j.bcp.2008.12.023

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Tibbetts LM, Doremus CM, Tzanakakis GN, Vezeridis MP (1993) Liver metastases with 10 human colon carcinoma cell lines in nude mice and association with carcinoembryonic antigen production. Cancer 71(2):315–321

    Article  CAS  PubMed  Google Scholar 

  34. Wagner HE, Toth CA, Steele GD Jr, Thomas P (1992) Metastatic potential of human colon cancer cell lines: relationship to cellular differentiation and carcinoembryonic antigen production. Clin Exp Metastasis 10(1):25–31

    Article  CAS  PubMed  Google Scholar 

  35. Thomas P, Gangopadhyay A, Steele G Jr, Andrews C, Nakazato H, Oikawa S, Jessup JM (1995) The effect of transfection of the CEA gene on the metastatic behavior of the human colorectal cancer cell line MIP-101. Cancer Lett 92(1):59–66

    Article  CAS  PubMed  Google Scholar 

  36. Lieber CS, DeCarli LM (1982) The feeding of alcohol in liquid diets: two decades of applications and 1982 update. Alcohol Clin Exp Res 6(4):523–531

    Article  CAS  PubMed  Google Scholar 

  37. Van den Eynden GG, Majeed AW, Illemann M, Vermeulen PB, Bird NC, Hoyer-Hansen G, Eefsen RL, Reynolds AR, Brodt P (2013) The multifaceted role of the microenvironment in liver metastasis: biology and clinical implications. Cancer Res 73(7):2031–2043. doi:10.1158/0008-5472.CAN-12-3931

    Article  PubMed  Google Scholar 

  38. Bhattacharjya S, Aggarwal R, Davidson BR (2006) Intensive follow-up after liver resection for colorectal liver metastases: results of combined serial tumour marker estimations and computed tomography of the chest and abdomen: a prospective study. Br J Cancer 95(1):21–26. doi:10.1038/sj.bjc.6603219

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Xu J, Chi F, Tsukamoto H (2015) Notch signaling and M1 macrophage activation in obesity-alcohol synergism. Clin Res Hepatol Gastroenterol 39(Suppl 1):S24–28. doi:10.1016/j.clinre.2015.05.016

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Im HJ, Kim HG, Lee JS, Kim HS, Cho JH, Jo IJ, Park SJ, Son CG (2016) A preclinical model of chronic alcohol consumption reveals increased metastatic seeding of colon cancer cells in the liver. Cancer Res 76(7):1698–1704. doi:10.1158/0008-5472.CAN-15-2114

    Article  CAS  PubMed  Google Scholar 

  41. Bertola A, Park O, Gao B (2013) Chronic plus binge ethanol feeding synergistically induces neutrophil infiltration and liver injury in mice: a critical role for E-selectin. Hepatology 58(5):1814–1823. doi:10.1002/hep.26419

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Neuman MG, French SW, Casey CA, Kharbanda KK, Nanau RM, Rasineni K, McVicker BL, Kong V, Donohue TM Jr (2013) Changes in the pathogenesis of alcohol-induced liver disease: preclinical studies. Exp Mol Pathol 95(3):376–384. doi:10.1016/j.yexmp.2013.10.006

    Article  CAS  PubMed  Google Scholar 

  43. Karass M, Grossniklaus E, Seoud T, Kamel R, Teniola O, Oprea G, Goldstein DA, Jain S (2015) Metastatic colorectal cancer in a cirrhotic liver with synchronous hepatocellular carcinoma. Ann Transl Med 3(20):321

    PubMed  PubMed Central  Google Scholar 

  44. Pereira-Lima JE, Lichtenfels E, Barbosa FS, Zettler CG, Kulczynski JM (2003) Prevalence study of metastases in cirrhotic livers. Hepatogastroenterology 50(53):1490–1495

    PubMed  Google Scholar 

  45. Jequier E (1999) Alcohol intake and body weight: a paradox. Am J Clin Nutr 69(2):173–174

    CAS  PubMed  Google Scholar 

  46. Pirola RC, Lieber CS (1972) The energy cost of the metabolism of drugs, including ethanol. Pharmacology 7(3):185–196

    Article  CAS  PubMed  Google Scholar 

  47. Zhang Y, Davis C, Ryan J, Janney C, Pena MM (2013) Development and characterization of a reliable mouse model of colorectal cancer metastasis to the liver. Clin Exp Metastasis 30(7):903–918. doi:10.1007/s10585-013-9591-8

    Article  PubMed  Google Scholar 

  48. Mittal VK, Bhullar JS, Jayant K (2015) Animal models of human colorectal cancer: current status, uses and limitations. World J Gastroenterol 21(41):11854–11861. doi:10.3748/wjg.v21.i41.11854

    Article  PubMed  PubMed Central  Google Scholar 

  49. Duffy MJ (2001) Carcinoembryonic antigen as a marker for colorectal cancer: is it clinically useful? Clin Chem 47(4):624–630

    CAS  PubMed  Google Scholar 

  50. Beauchemin N, Arabzadeh A (2013) Carcinoembryonic antigen-related cell adhesion molecules (CEACAMs) in cancer progression and metastasis. Cancer Metastasis Rev 32(3–4):643–671. doi:10.1007/s10555-013-9444-6

    Article  CAS  PubMed  Google Scholar 

  51. Gangopadhyay A, Lazure DA, Thomas P (1997) Carcinoembryonic antigen induces signal transduction in Kupffer cells. Cancer Lett 118(1):1–6

    Article  CAS  PubMed  Google Scholar 

  52. Gangopadhyay A, Lazure DA, Thomas P (1998) Adhesion of colorectal carcinoma cells to the endothelium is mediated by cytokines from CEA stimulated Kupffer cells. Clin Exp Metastasis 16(8):703–712

    Article  CAS  PubMed  Google Scholar 

  53. Gangopadhyay A, Bajenova O, Kelly TM, Thomas P (1996) Carcinoembryonic antigen induces cytokine expression in Kuppfer cells: implications for hepatic metastasis from colorectal cancer. Cancer Res 56(20):4805–4810

    CAS  PubMed  Google Scholar 

  54. Thomas P, Toth CA (1990) Carcinoembryonic antigen binding to Kupffer cells is via a peptide located at the junction of the N-terminal and first loop domains. Biochem Biophys Res Commun 170(1):391–396

    Article  CAS  PubMed  Google Scholar 

  55. Ashwell G, Harford J (1982) Carbohydrate-specific receptors of the liver. Annu Rev Biochem 51:531–554. doi:10.1146/annurev.bi.51.070182.002531

    Article  CAS  PubMed  Google Scholar 

  56. Lee L, Alloosh M, Saxena R, Van Alstine W, Watkins BA, Klaunig JE, Sturek M, Chalasani N (2009) Nutritional model of steatohepatitis and metabolic syndrome in the Ossabaw miniature swine. Hepatology 50(1):56–67. doi:10.1002/hep.22904

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. French SW (1993) Nutrition in the pathogenesis of alcoholic liver disease. Alcohol Alcohol 28(1):97–109

    CAS  PubMed  Google Scholar 

  58. Edmiston KH, Gangopadhyay A, Shoji Y, Nachman AP, Thomas P, Jessup JM (1997) In vivo induction of murine cytokine production by carcinoembryonic antigen. Cancer Res 57(19):4432–4436

    CAS  PubMed  Google Scholar 

  59. de la MHP, Lieber CS, DeCarli LM, French SW, Lindros KO, Jarvelainen H, Bode C, Parlesak A, Bode JC (2001) Models of alcoholic liver disease in rodents: a critical evaluation. Alcohol Clin Exp Res 25(5 Suppl ISBRA):254S–261S

    Google Scholar 

  60. Friedman SL (1999) Stellate cell activation in alcoholic fibrosis: an overview. Alcohol Clin Exp Res 23(5):904–910

    CAS  PubMed  Google Scholar 

  61. Kang N, Gores GJ, Shah VH (2011) Hepatic stellate cells: partners in crime for liver metastases? Hepatology 54(2):707–713. doi:10.1002/hep.24384

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank the staff of the UNMC Tissue Science Facility for tissue processing services and excellent technical assistance. Support for this work was provided by the Department of Veterans Affairs and the National Institute of Health Grant AA022556 awarded to C.A.C. and P.T.

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Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA

    Ashley M. Mohr

  2. Research Service, VA Nebraska-Western Iowa Health Care System, Omaha, NE, USA

    John J. Gould, Jacy L. Kubik, Carol A. Casey & Benita L. McVicker

  3. Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, USA

    Jacy L. Kubik, Carol A. Casey, Dean J. Tuma & Benita L. McVicker

  4. Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA

    Geoffrey A. Talmon

  5. Department of Surgery and Biomedical Sciences, Creighton University, Omaha, NE, USA

    Peter Thomas

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  1. Ashley M. Mohr
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Correspondence to Benita L. McVicker.

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Mohr, A.M., Gould, J.J., Kubik, J.L. et al. Enhanced colorectal cancer metastases in the alcohol-injured liver. Clin Exp Metastasis 34, 171–184 (2017). https://doi.org/10.1007/s10585-017-9838-x

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