Abstract
Fas-L (CD95L, APO-1L) expresses in a variety of tumours and has been proposed to play a role in tumour formation and metastasis. The contribution of Fas-L to tumour growth, however, is not conclusive especially in systems using cells with over-expressed Fas-L. In this study we down-regulated the expression o Fas-L in human glioma cells by a hammerhead ribozyme (Fas-Lribozyme) targeting against Fas-L mRNA. Fas-Lribozyme-carrying cells exhibited slightly enhanced growth rate and less degree of spontaneous apoptosis in vitro as compared with vector controls. In nude mice, Fas-Lribozyme-carrying cells grew faster with lesser apoptosis, formed bigger tumour with significantly fewer infiltrating cells in the tumour area, and triggered relatively milder tumour-associated liver damage than vector controls did. Thus, down-regulation of Fas-L not only improved viability of glioma cells but also reduces local immune responses that may consequently affect tumour formation. Taken together, our findings imply that endogenous expression of Fas-L in malignant cells is not always growth promoting. © 2001 Cancer Research Campaign http://www.bjcancer.com
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References
Alderson MR, Armitage RJ, Maraskovsky EW, Tough T, Roux E, Schooley K, Ramsdell F and Lynch DH (1993) Fas transduces activation signals in normal human T lymphocytes. J Exp Med 178: 2231–2235
Alderson MR, Tough TW, Davis-Smith T, Braddy S, Falk B, Schooley KA, Goodwin RG, Smith CA, Ramsdell F and Lynch DH (1995) Fas ligand mediates activation-induced cell death in human T lymphocytes. J Exp Med 181: 71–77
Arai H, Gordon D, Nabel EG and Nabel GJ (1997) Gene transfer of Fas ligand induces tumor regression in vivo. Proc Natl Acad Sci USA 94: 13862–13867
Birikh KR, Paul A and Eckstein HF (1997) The structure, function and application of the hammerhead ribozyme. Eur J Biochem 245: 1–16
Chang MY, Won SJ and Liu HS (1997) A ribozyme specifically suppresses transformation and tumorigenicity of Ha-ras oncogene transformed NIH-3T3 cell lines. J Cancer Res Clin Onc 123: 91–99
Chattergoon MA, Kim JJ, Yang JS, Robinson TM, Lee DJ, Dentchev T, Wilson DM, Ayyavoo V and Weiner DB (2000) Targeted antigen delivery to antigen-presenting cells including dendritic cells by engineered Fas-mediated apoptosis. Nature Biotech 18: 974–979
Chen JJ, Sun Y and Nabel GJ (1998) Regulation of the proinflammatory effects of Fas ligand (CD95L). Science 282: 1714–1717
Chervonsky AV, Wang Y, Wong FS, Visintin I, Flavell RA, Janeway CA and Matis LA (1997) The role of Fas in autoimmune diabetes. Cell 89: 17–24
Cleary ML, Smith SD and Sklar J (1986) Cloning and structural analysis of cDNAs for bcl-2 and a hybrid bcl-2/immunoglobulin transcript resulting from the t(14;18) translocation. Cell 47: 19–28
Du Z, Ricordi C, Podack E and Pastori RL (1996) A hammerhead ribozyme that cleaves perforin and fas-ligand RNAs in vitro. Biochem Biophy Res Comm 226: 595–600
Gratas C, Tohma Y, Van Meir EG, Klein M, Tenan M, Ishii N, Tachibana O, Kleihues P and Ohgaki H (1997) Fas ligand expression in glioblastoma cell lines and primary astrocytic brain tumors. Brain Pathol 7: 863–869
Hahne M, Rimoldi D, Schroter M, Romero P, Schreier M, French LE, Schneider P, Bornand T, Fontana A, Lienard D, Cerottini J and Tschopp J (1996) Melanoma cell expression of Fas (Apo-I/CD95) ligand: implications for tumor immune escape. Science 274: 1363–1366
Horino K, Nishiura H, Ohsako T, Shibuya Y, Hiraoka T, Kitamura N and Yamamoto T (1998) A monocyte chemotactic factor, S19 ribosomal protein dimer, in phagocytic clearance of apoptotic cells. Lab Invest 78: 603–617
Itoh N, Yonehara S, Ishii A, Yonehara M, Mizushima S, Sameshima M, Hase A, Seto Y and Nagata S (1991) The polypeptide encoded by the cDNA for human cell surface antigen Fas can mediate apoptosis. Cell 66: 233–243
Nagata S (1997) Apoptosis by death factor. Cell 88: 355–365
Ogasawara J, Watanabe-Fukunaga R, Adachi M, Matsuzawa A, Kasugai T, Kitamura Y, Itoh N, Suda T and Nagata S (1993) Lethal effect of the anti-Fas antibody in mice. Nature 364: 806–809
Owen-Schaub LB, Radinsky R, Kruzel E, Berry K and Yonehara S (1994) Anti-Fas on nonhematopoietic tumors: levels of Fas/APO-1 and bcl-2 are not protective of biological responsiveness. Cancer Res 54: 1580–1586
Poeschla E and Wong-Staal F (1997) Antiviral and anticancer ribozymes. Cur Opin Oncol 6: 601–606
Reid S, Cross R and Snow ED (1996) Combined hoechst 33342 and merocyanine 540 staining to examine murine B cell cycle sage, viability and apoptosis. J Immunol Meth 192: 43–54
Rensing-Ehl A, Frei K, Flury R, Matiba B, Mariani SM, Weller M, Aebischer P, Krammer PH and Fontana A (1995) Local Fas/APO-1 (CD95) ligand-mediated tumor cell killing in vivo. Eur J Immunol 25: 2253–2258
Saas P, Walker PR, Hahne M, Quiquerez AL, Schnuriger V, Perrin G, French L, Van Meir EG, de Tribolet N, Tschopp J and Dietrich PY (1997) Fas ligand expression by astrocytoma in vivo: maintaining immune privilege in the brain?. J Clin Invest 99: 1173–1178
Sato T, Irie S, Kitada S and Reed J (1995) FAP-1 a protein tyrosine phosphatase that associates with Fas. Science 268: 411–415
Scanlon KJ, Jiao L, Funato T, Wang W, Tone T, Rossi JJ and Kashani-sabet M (1991) Ribozyme-mediated cleavage of c-fos mRNA reduces gene expression of DNA synthesis enzymes and metallothionein. Proc Natl Acad Sci USA 88: 10591–10595
Seino KI, Kayagaki N, Tsukada N, Fukao K, Yagita H and Okumura K (1997) Transplantation of CD95 ligand-expressing grafts. Influence of transplantation site and difficulty in protecting allo- and xenografts. Transplantation 64: 1050–1054
Shinohara H, Yagita H, Ikawa Y and Oyaizu N (2000) Fas drives cell cycle progression in glioma cells via extracellular signal-regulated kinase activation. Cancer Res 60: 1766–1772
Shinoura N, Yoshida Y, Sadata A, Hanada KI, Yamamoto S, Kirino T, Asai A and Hamada H (1998) Apoptosis by retrovirus- and adenovirus-mediated gene transfer of Fas ligand to glioma cells: implications for gene therapy. Hum Gene Ther 9: 1983–1993
Shiraki K, Tsuji N, Shiod T, Isselbacher KJ and Takahashi H (1997) Expression of Fas ligand in liver metastases of human colonic adenocarcinomas. Proc Natl Acad Sci USA 94: 6420–6425
Strand S, Hofmann WJ, Hug H, Muller M, Otto G, Strand D, Mariani SM, Stremmel W, Krammer PH and Galle PR (1996) Lymphocyte apoptosis induced by CD95 (APO-1/Fas) ligand-expressing tumor cells – A mechanism of immune evasion?. Nature Med 2: 1361–1366
Suzuki I and Fink PJ (1998) Maximal proliferation of cytotoxic T lymphocytes requires reverse signaling through Fas ligand. J Exp Med 187: 123–128
Takahashi T, Tanaka M, Inazawa J, Abe T, Suda T and Nagata S (1994) Human Fas ligand: gene structure, chromosomal location and species specificity. Int Immunol 6: 1567–1574
Van Parijs L and Abbas AK (1996) Homeostasis and self-tolerance in the immune system: turning lymphocytes off. Science 280: 243–248
Walker PR, Saas P and Dietrich PY (1998) Tumor expression of Fas ligand (CD95L) and the consequences. Curr Opin Immunol 10: 564–572
Weller M, Frei K, Groscurth P, Krammer PH, Yonekawa Y and Fontana A (1994) Anti-Fas/APO-1 antibody-mediated apoptosis of cultured human glioma cells. Induction and modulation of sensitivity by cytokines. J Clin Invest 94: 954–964
Yang BC and Yang TL (1998) Differential expression of cytokine genes and apoptosis in glioma cell lines upon exposure to bacteria and lipopolysaccharides. J Microbiol Immunol Infect 31: 95–100
Yang BC, Wang YS, Wang CH, Lin HH, Tang MJ and Yang TL (1999) Insulin-elicited transient apoptosis in serum-starved glioma cells involved Fas/Fas-L and Bcl-2. Cell Biol Intern 23: 533–540
Yang BC, Wang YS, HS Liu, and Lin SJ (2000) Ras signaling is involved in the expression of Fas-L in glioma. Lab Invest 80: 529–537
Zeytun A, Nagarkatti M and Nagarkatti PS (2000) Growth of FasL-bearing tumor cells in syngeneic murine host induces apoptosis and toxicity in Fas+ organs. Blood 95: 2111–2117
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Chio, CC., Wang, YS., Chen, YL. et al. Down-regulation of Fas-L in glioma cells by ribozyme reduces cell apoptosis, tumour-infiltrating cells, and liver damage but accelerates tumour formation in nude mice. Br J Cancer 85, 1185–1192 (2001). https://doi.org/10.1054/bjoc.2001.2055
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DOI: https://doi.org/10.1054/bjoc.2001.2055
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