Abstract
We hypothesize that a major factor regulating hepatic metastasis is the ability of CEA (carcinoembryonic antigen) producing colorectal carcinomas to activate Kupffer cells. CEA and NCA (nonspecific cross-reacting antigen) bind to an 80 kDa Kupffer cell receptor by the peptide sequence PELPK and stimulate cytokine production. Cytokines induce sinusoidal endothelial cells to express intercellular adhesion molecules and increase adhesion of the tumor cells and retention in the liver. In this study human Kupffer cells were acti-vated in vitro with CEA, NCA, and the peptide PELPK. This resulted in release of IL-1b, TNF-a and IL-6. CEA non-producing MIP-101 colon carcinoma cells labeled with 51 Cr were incubated on monolayers of ECV-304 human umbilical vein endothelial cells treated with these Kupffer cell derived cytokines or with comparable recombinant human (rH) cytokines. Specific antibodies to the adhesion molecules ICAM-1, VCAM-1, E-selectin and b 2 integrin were used to block their functions. A significant enhancement in the adhesion of colorectal carcinoma cells occurred when endothelial cells were stimulated with a very low concentration of Kupffer-cell derived cytokines. Activated endothelium demonstrated significant up-regu-lation primarily of ICAM-1. The adhesion was blocked by an antibody to ICAM-1. A combination of Kupffer-cell derived cytokines was more effective than IL-1b or TNF-a alone. IL-6 alone did not influence adhesion under our conditions. Our results suggest a mechanism for CEA in the modulation of colorectal carcinoma adhesion to the hepatic endothelium and its enhancement of metastatic potential.© Kluwer Academic Publishers 1998
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Wagner HE, Toth CA, Steele GD and Thomas P, 1992, Invasive and metastatic potential of human colorectal cancer cell lines: relationship to cellular differentiation and carcinoembryonic antigen production. Clin Exp Metastasis, 10,25-31.
Benchimol S, Fuks A, et al.1989, Carcinoembryonic antigen, a human tumor marker, functions as an intercellular adhesion molecule. Cell, 57, 327-34.
Jessup JM, Petrick AT, Toth CA, et al.1993, Carcinoembryonic antigen: Enhancement of liver colonization through retention of human colorectal carcinoma cells. Br J Cancer, 67,464-70.
Thomas P, Gangopadhyay A, Steele G, et al.1995, The effect of transfection of the CEA gene on the metastatic behavior of the human colorectal cancer cell line MIP-101. Cancer Lett, 92,59-66.
Hashino J, Fukada Y, Oikawa S, et al.1994, Metastatic potential of human colorectal carcinoma SW1222 cells transfected with cDNA encoding carcinoembryonic antigen. Clin Exp Metastasis, 12,324-8.
Wagner HE, Thomas P, Wolf BC, et al.1990, Characterization of the tumorigenic and metastatic potential of a poorly differentiated human colon cancer cell line. Invasion and Metastasis, 10,253-66.
Gangopadhyay A, Lazure DA, Kelly TM and Thomas P, 1996a, Purification and analysis of an 80-kDa carcinoembryonic antigen-binding protein from Kupffer cells. Arch Biochem Biophys, 328,151-7.
Gangopadhyay A and Thomas P, 1996b, Processing of carcinoembryonic antigen by Kupffer cells: Recognition of a penta-peptide sequence. Arch Biochem Biophys, 334,151-7.
Luster MI, Germolec DR, Yoshida T, et al.1994, Endotoxin-induced cytokine gene expression and excretion in the liver. Hepatology, 19,480-8.
Oppenheimer-Marks N, Davis LS, Bogue DT, et al.1991, Differential utilization of ICAM-1 and VCAM-1 during the adhesion and transendothelial migration of human T lymphocytes. J Immunol, 147,2913-21.
Carols T, Kovach N, Schwartz B, et al.1991, Human monocytes bind to two cytokine-induced adhesive ligands on cultured human endothelial cells: endothelial-leukocyte adhesion molecule-1 and vascular cell adhesion molecule-1. Blood, 77,2266-71.
Lafrenie RM, Buchanan MR and Orr FW, 1993, Adhesion molecules and their role in cancer metastasis. Cell Biophysics, 23,3-89.
Toth CA, Thomas P, Broitman SA and Zamcheck N, 1985, Receptor mediated endocytosis of carcinoembryonic antigen by rat liver Kupffer cells. Cancer Res, 45,392-7.
Thomas P, 1993, Metastatic Potential of Human Colorectal Cancer Cell Lines. Austin, TX: R.G. Landes Company.
Hostetter RB, Augustus LB, Mankarious R, et al.1990, Carcinoembryonic antigen as a selective enhancer of colorectal cancer metastases. J Natl Cancer lnst, 82,380-5.
Gangopadhyay A, Bajenova O, Kelly TM and Thomas P, 1996c, Carcinoembryonic antigen induces cytokine expression in Kupffer cells: implications for hepatic metastasis from colorectal cancer. Cancer Res, 56,4805-10.
Regimbald LH, Pilarski LM, Logenecker BM, et al.1996; The breast mucin MUC1 as a novel adhesion ligand for endothelial intercellular adhesion molecule 1 in breast cancer. Cancer Res, 56,4244-9.
Cotran RS, 1987, American Association of Pathologists President’s Address: New roles for the endothelium in inflammation and immunity. Am J Pathol, 129,407-13.
Dejana E, Bertocchi F, Bortolami MC, et al.1988, Interleukin 1 promotes tumor cell adhesion to cultured human endothelial cells. J Clin Invest, 82,1466-70.
Edmiston KH, Gangopadhyay A, Shoji Y, et al.1997, In Vivoinduction of murine cytokine production by carcinoembryonic antigen. Cancer Res, 57,4432-36.
Murphy P, Alexander P, Senior PV, et al.1988, Mechanisms of organ selective tumor growth by blood borne cancer cells. Brit J Cancer, 57,19-31.
Orr FW, Adamson IYR and Young L, 1985, Pulmonary inflammation generates chemotactic activity for tumor cells and promotes lung metastasis. Amer Rev Resp Dis, 131,607-11.
Dinarello CA, 1989, Interleukin-1 and its biologically related cytokines. Advanc Immunol, 44,153-205.
Mannel DN, Orosz P, Hafner M and Falk W, 1994, Mechanisms involved in metastasis enhanced by inflammatory mediators. Circulatory Shock, 44,9-13.
Steinbach F, Tanabe K, Alexander J, et al.1996, The influence of cytokines on the adhesion of renal cancer cells to endothelium. J Urol, 155,743-48.
Tamaki M, Aoyagi M, Morita I, et al.1995, Cell adhesion molecules acting between C6 glioma and endothelial cells. J Neuro-Oncol, 24,181-8. 11111
Tanikawa K, 1995, Cytokines and adhesion molecules in the liver. In: Gerok W, Decker K, Andus T and Gross V, eds. Cytokines and the Liver, Proceedings of 78th FALK Symposium. Kluwer Academic Publishers: Dordrecht, The Netherlands, pp. 37-45.
Okahara H, Yagita H, Miyake K and Okumura K, 1994, Involvement of very late activation antigen 4 (VLA-4) and vascular cell adhesion molecule 1 (VCAM-1) in tumor necrosis factor a enhancement of experimental metastasis. Cancer Res, 54,3233-36.
Feder LS, McCloskey TW and Laskin DL, 1991, Characterization of interleukin-1 (IL-1) and interleukin-6 (IL-6) production by resident and lipopolysaccharide (LPS) activated hepatic macrophages and endothelial cells. In: Wisse E. Knook DL and McCuskey RS, eds. Cells of the Hepatic Sinusoid. vol. 3, Leiden, The Netherlands: Kupffer Cell Foundation, pp. 37-39.
Vidal-Vanaclocha F, Amezaga C, Asumendi A, et al.1994, Interleukin-1 receptor blockage reduces the number and size of murine B16 melanoma hepatic metastases. Cancer Res, 54,2667-72.
Osborn L, 1990, Leukocyte adhesion to endothelium in inflammation. Cell, 62,3-6.
Lauri D, Needham L, Matrin-Padura I and Dejana E, 1991, Tumor cell adhesion to endothelial cells: endothelial leukocyte adhesion molecule-1 as an inducible adhesive receptor specific for colon carcinoma cells. J Natl Cancer Inst, 83,1321-24.
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Gangopadhyay, A., Lazure, D.A. & Thomas, P. Adhesion of colorectal carcinoma cells to the endothelium is mediated by cytokines from CEA stimulated Kupffer cells. Clin Exp Metastasis 16, 703–712 (1998). https://doi.org/10.1023/A:1006576627429
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DOI: https://doi.org/10.1023/A:1006576627429