Abstract
Metastasis of colorectal carcinomas rarely occurs in cirrhotic livers. Our study investigated the influence of activated Kupffer cells from cirrhotic rat livers on hepatic colonization and FasR-mediated apoptosis of colon cancer cells. A rat colon cancer cell line, RCN-9, was used to inoculate rat livers. Treatment with conditioned media of Kupffer cells isolated from CCl4-induced cirrhotic rat livers (cirrhotic KCM) significantly reduced the incidence of hepatic colonization of RCN-9 cells. In vitro cytotoxicity of Kupffer cells and tumour infiltrating lymphocytes (TILs) on RCN-9 cells was evaluated using [3H]-release assay. RCN-9 cells were resistant to cytotoxicity mediated by cirrhotic Kupffer cells, but were sensitized to TIL-mediated killing after treatment with cirrhotic KCM. The specific killing induced by TILs was FasR-mediated, as it was inhibited by ZB4, an antagonistic anti-FasR antibody. In agreement, cirrhotic KCM increased recombinant Fas ligand-induced apoptosis of RCN-9 cells, and up-regulated FasR expression on RCN-9 cells as evaluated by RT-PCR and flow cytometry. These findings suggest that Kupffer cells in cirrhotic livers sensitize metastatic colon cancer cells to FasR-mediated apoptosis by up-regulating the receptors, which thus prepare them to be eliminated by infiltrating lymphocytes. © 2001 Cancer Research Campaign http://www.bjcancer.com
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References
Armendáriz-Borunda J, Greenwel P and Rojkind M (1989) Kupffer cells from CCl4-treated rat livers induce skin fibroblast and liver fat-storing cell proliferation in culture. Matrix 9: 150–158
Boekelheide K, Lee J, Shipp EB, Richburg JH and Li G (1998) Expression of Fas system-related genes in the testis during development and after toxicant exposure. Toxicol Lett 102–103: 503–508
Bonnotte B, Favre N, Reveneau S, Micheau O, Droin N, Garrido C, Fontana A, Chauffert B, Solary E and Martin F (1998) Cancer cell sensitization to Fas-mediated apoptosis by sodium butyrate. Cell Death Differ 5: 480–487
Fukazawa T, Fujiwara T, Morimoto Y, Shao J, Nishizaki M, Kadowak S, Hizuta A, Owen-Schaub LB, Roth JA and Tanaka N (1999) Differential involvement of the CD95 (Fas/APO-1) receptor/ligand system on apoptosis induced by the wild-type p53 gene transferred human cancer cells. Oncogene 18: 2189–2199
Gressner AM (1996) Mediators of hepatic fibrogenesis. Hepatogastroenterol 43: 92–103
Griffini P, Smorenburg SM, Vogels IMC, Tigchelaar W and van Noorden CJF (1996) Kupffer cells and pit cells are not effective in the defense against experimentally induced colon carcinoma metastasis in rat liver. Clin Exp Metast 14: 367–380
Hauptmann S, Zwadlo KG, Jansen M, Klosterhalfen B and Kirkpatrick CJ (1993) Macrophages and multicellular tumor spheroids in co-culture: a three-dimensional model to study tumor-host interactions. Evidence for macrophage-mediated tumor cell proliferation and migration. Am J Pathol 143: 1406–1415
Hayashi S, Masuda H and Shigematsu M (1997) Liver metastasis rate in colorectal cancer patients with fatty liver. Hepatogastroenterol 44: 1069–1075
Houghton JA, Harwood FG, Gibson AA and Tillman DM (1997a) The Fas signaling pathway is functional in colon carcinoma cells and induces apoptosis. Clin Cancer Res 3: 2205–2209
Houghton JA, Harwood FG and Tillman DM (1997b) Thymineless death in colon carcinoma cells is mediated via Fas signaling. Proc Natl Acad Sci USA 94: 8144–8149
Inoue Y, Kashima Y, Aizawa K and Hatakeyama K (1991) A new rat colon cancer cell line metastasizes spontaneously: Biologic characteristics and chemotherapeutic response. Jpn J Cancer Res 82: 90–98
Krammer PH, Galle PR, Möller P and Debatin KM (1998) CD95 (APO-1/Fas)-mediated apoptosis in normal and malignant liver, colon, and hematopoietic cells. Adv Cancer Res 75: 251–273
Litton MJ, Dohlsten M, Lando PA, Kalland T, Ohlsson L, Andersson J and Andersson U (1996) Antibody-targeted superantigen therapy induces tumor-infiltrating lymphocytes, excessive cytokine production, and apoptosis in human colon carcinoma. Eur J Immunol 26: 1–9
Micheau O, Solary E, Hammann A, Martin F and Dimanche-Boitrel MT (1997) Sensitization of cancer cells treated with cytotoxic drugs to Fas-mediated cytotoxicity. J Natl Cancer Inst 89: 783–789
Micheau O, Hammann A, Solary E and Dimanche-Boitrel MT (1999) STAT-1-independent upregulation of FADD and procaspase-3 and -8 in cancer cells treated with cytotoxic drugs. Biochem Biophys Res Commun 256: 603–607
Möller P, Koretz K, Leithauser F, Bruderlein S, Henne C, Quentmeier A and Krammer PH (1994) Expression of APO-1 (CD95), a member of the NGF/TGF receptor superfamily, in normal and neoplastic colon epithelium. Int J Cancer 57: 371–377
Moulian N, Renvoizé C, Desodt C, Serraf A and Berrih-Aknin S (1999) Fuctional Fas expression inhuman thymic epithelial cells. Blood 93: 2660–2670
Müschen M, Warskulat U, Douillard P, Gilbert E and Häussinger D (1998) Regulation of CD95 (APO-1/Fas) receptor and ligand expression by lipopolysaccharide and dexamethasone in parenchymal and nonparenchymal rat liver cells. Hepatology 27: 200–208
Nadeau KC, Azuma H and Tilney NL (1995) Sequential cytokine dynamics in chronic rejection of rat renal allografts: Roles for cytokines RANTES and MCP-1. Proc Natl Acad Sci USA 92: 8729–8733
Nagata S (1997) Apoptosis by death factor. Cell 88: 355–365
O'Connell J, O'Sullivan GC, Collins JK and Shanahan F (1996) The Fas counterattack: Fas-mediated T cell killing by colon cancer cells expressing Fas ligand. J Exp Med 184: 1075–1082
O'Connell J, Bennett MW, O'Sullivan GC, Roche D, Kelly J, Collins JK and Shanahan F (1998) Fas ligand expression in primary colon adenocarcinomas: evidence that the Fas counterattack is a prevalent mechanism of immune evasion in human colon cancer. J Pathol 186: 240–246
Okuno K, Hirai N, Lee YS, Kawai I, Shigeoka H and Yasutomi M (1998) Involvement of liver-associated immunity in hepatic metastasis formation. J Surg Res 75: 148–152
Seymour K and Charnley RM (1999) Evidence that metastasis is less common in cirrhotic than normal liver: a systematic review of post-mortem case-control studies. Br J Surg 86: 1237–1242
Tamura T, Aoyama N, Saya H, Haga H, Futami S, Miyamoto M, Koh T, Ariyasu T, Tachi M, Kasuga M and Takahashi R (1995) Induction of Fas-mediated apoptosis in p53-transfected human colon carrcinoma cells. Oncogene 11: 1939–1946
Thomas C, Nijenhuis AM, Timens W, Kuppen PJK, Daemen T and Scherphof GL (1993) Liver metastasis model of colon cancer in the rat: immunohistochemical characterization. Invas Metast 13: 102–112
Tillman DM, Harwood FG, Gibson AA and Houghton JA (1998) Expression of genes that regulate Fas signalling and Fas-mediated apoptosis in colon carcinoma cells. Cell Death Differ 5: 450–457
Utsunomiya T, Saitsu H, Saku M, Yoshida K, Matsumata T, Shimada M and Sugimachi K (1999) Rare occurrence of colorectal cancer metastasis in livers infected with Hepatitis B or C virus. Am J Surg 177: 279–281
Von Reyher U, Strater J, Kittstein W, Gschwendt M, Krammer PH and Möller P (1998) Colon carcinoma cells use different mechanisms to escape CD95-mediated apoptosis. Cancer Res 58: 526–534
Yoong KF and Adams DH (1998) Interleukin-2 restores CD3 zeta chain expression but fails to generate specific cytolytic activity in tumor infiltrating lymphocytes isolated from patients with hepatic colorectal metastases. Br J Cancer 77: 1072–1081
Yoong KF, Afford SC, Randhawa S, Hubscher SG and Adams DH (1999) Fas/Fas ligand interaction in human colorectal hepatic metastases. Am J Pathol 154: 693–703
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Song, E., Chen, J., Ouyang, N. et al. Kupffer cells of cirrhotic rat livers sensitize colon cancer cells to Fas-mediated apoptosis. Br J Cancer 84, 1265–1271 (2001). https://doi.org/10.1054/bjoc.2000.1737
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DOI: https://doi.org/10.1054/bjoc.2000.1737
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