Abstract
The Fas/FasL system has been suggested to play an important role in the establishment of immune privilege status for tumors by inducing Fas-mediated apoptosis in tumor-specific lymphocytes. However, the role of cell-surface expressed FasL in tumor cell protection has recently become controversial.
Our laboratory has focused on the study of the role of the Fas/FasL system in the normal tissue remodeling of the female reproductive tract and in immune-privileged organs. Our studies have demonstrated a connection between sex hormones and the regulation of the Fas/FasL pathway in immune and reproductive cells. More recently, we have investigated the resistance of tumor cells to Fas-mediated apoptosis. We have also characterized a new form of FasL, different from the classical membranal form, which is secreted by ovarian cancer cells. In this review we describe the main techniques used in these studies.
Similar content being viewed by others
References
Igney, F. H. and Krammer, P. H. (2002) Immune escape of tumors: apoptosis resistance and tumor counterattack. J. Leukoc. Biol. 71, 907–920.
O’Connell, J., O’Sullivan, G., Collins, J., and Shanahan, F. (1996) The Fas counter attack: Fas mediated T cell killing by colon cancer cells expressing Fas ligand. J. Exp. Med. 184, 1075–1082.
Griffith, T., Brunner, T., Fletcher, S., Gree, D., and Ferguson, T. (1995) Fas ligand induces apoptosis as a mechanism of immune privilege. Science 270, 1187–1192.
Gutierrez, L. S., Eliza, M., Niven-Fairchild, T., Naftolin, F., and Mor, G. (1999) The Fas/Fas-ligand system: a mechanism for immune evasion in human breast carcinomas. Breast Cancer Res. Treat. 54, 245–253.
Reimer, T., Herrnring, C., Koczan, D., et al. (2000) FasL:Fas ratio—a prognostic factor in breast carcinomas. Cancer Res. 60, 822–828.
Niehans, G., Brunner, T., Frizelle, S., et al. (1997) Human lung carcinomas express Fas ligand. Cancer Res. 57, 1007–1012.
Shiraki, K., Tsuji, N., Shioda, T., Isselbacher, K., and Takahashi, H. (1997) Expression of Fas ligand in liver metastases of human colonic adenocarcinomas. Proc. Natl. Acad. Sci. USA 94, 6420–6425.
Mor, G., Kohen, F., Garcia-Velasco, J., et al. (2000) Regulation of Fas ligand expression in breast cancer cells by estrogen: functional differences between estradiol and tamoxifen. J. Steroid Biochem. Mol. Biol. 73, 185–194.
Chappell, D. B. and Restifo, N. P. (1998) T cell-tumor cell: a fatal interaction? Cancer Immunol. Immunother. 47, 65–71.
Chappell, D. B., Zaks, T. Z., Rosenberg, S. A., and Restifo, N. P. (1999) Human melanoma cells do not express Fas (Apo-1/CD95) ligand. Cancer Res. 59, 59–62.
Nagata, S. (1994) Fas and Fas ligand: a death factor and its receptor. Adv. Immunol. 57, 129–135.
Mogil, R., Radvanyi, L., Gonzalez-Quintial, R., et al. (1995) Fas (CD95) participates in peripheral T cell deletion and associated apoptosis in vivo. Int. Immunol. 7, 1451–1458.
Brunner, T., Mogil, R., LaFace, D., et al. (1995) Cell-autonomous Fas (CD95)/Fas-ligand interaction mediates activation-induced apoptosis in T-cell hybridomas. Nature 373, 441–444.
Rouvier, E., Luciani, M., and Golstein, P. (1993) Fas involvement in Ca(2+)-independent T cell-mediated cytotoxicity. J. Exp. Med. 177, 195–200.
Song, J., Sapi, E., Brown, W., et al. (2000) Roles of Fas and Fas ligand during mammary gland remodeling. J. Clin. Invest. 106, 1209–1220.
Song, J., Rutherford, T., Brown, S., and Mor, G. (2002) Hormonal regulation of Fas and FasL expression and apoptosis in the normal human endometrium. Mol. Hum. Reprod. 8, 447–455.
Mor, G., Gutierrez, L., Eliza, M., Kahyaoglu, F., and Arici, A. (1998) Fas-Fas ligand system induced apoptosis in human placenta and gestational trophoblastic disease. Am. J. Reprod. Immunol. 40, 89–94.
Bechmann, I., Mor, G., Nilsen, J., Eliza, M., Nitsch, R., and Naftolin, F. (1999) FasL (CD95L, Ap01L) is expressed in the normal rat and human brain: evidence for the existence of an immunological brain barrier. Glia 27, 62–74.
Bellgrau, D., Gold, D., Selawry, H., Moore, J., Franzusoff, A., and Duke, R. (1995) A role for CD95 ligand in preventing graft rejection. Science 377, 630–632.
Nagata, S. (1997) Apoptosis by death factor. Cell 88, 355–365.
Wallach, D., Varfolomeev, E. E., Malinin, N. L., Goltsev, Y. V., Kovalenko, A. V., and Boldin, M. P. (1999) Tumor necrosis factor receptor and Fas signaling mechanisms. Annu. Rev. Immunol. 17, 331–367.
Schmitz, I., Kirchhoff, S., and Krammer, P. H. (2000) Regulation of death receptor-mediated apoptosis pathways. Int. J. Biochem. Cell. Biol. 32, 1123–1136.
Miyashita, T., Mami, U., Inoue, T., Reed, J. C., and Yamada, M. (1997) Bcl-2 relieves the trans-repressive function of the glucocorticoid receptor and inhibits the activation of CPP32-like cysteine proteases. Biochem. Biophys. Res. Commun. 233, 781–787.
Muzio, M., Chinnaiyan, A. M., Kischkel, F. C., et al. (1996) FLICE, a novel FADD-homologous ICE/CED-3-like protease, is recruited to the CD95 (Fas/APO-1) death-inducing signaling complex. Cell 85, 817–827.
Kim, Y., Suh, N., Sporn, M., and Reed, J. C. (2002) An inducible pathway for degradation of FLIP protein sensitizes tumor cells to TRAIL-induced apoptosis. J. Biol. Chem. 277, 22,320–22,329.
Krueger, A., Schmitz, I., Baumann, S., Krammer, P. H., and Kirchhoff, S. (2001) Cellular FLICE-inhibitory protein splice variants inhibit different steps of caspase-8 activation at the CD95 death-inducing signaling complex. J. Biol. Chem. 276, 20,633–20,640.
Deveraux, Q. L., Roy, N., Stennicke, H. R., et al. (1998) IAPs block apoptotic events induced by caspase-8 and cytochrome c by direct inhibition of distinct caspases. EMBO J. 17, 2215–2223.
Kamsteeg, M., Rutherford, T., Sapi, E., et al. (2003) Phenoxodiol—an isoflavon analogue—induces apoptosis in chemo-resistant ovarian cancer cells. Oncogene, 22, 2611–2620.
Rabinowich, H., Reichert, T., Kashii, Y., Gastman, B., Bell, M., and Whiteside, T. (1998) Lymphocyte apoptosis induced by Fas ligand-expressing ovarian carcinoma cells: implications for altered expression of T cell receptor in tumor-associated lymphocytes. J. Clin. Invest. 101, 2579–2588.
Allison, J., Georgiou, H. M., Strasser, A., and Vaux, D. L. (1997) Transgenic expression of CD95 ligand on islet beta cells induces a granulocytic infiltration but does not confer immune privilege on islet allografts. Proc. Natl. Acad. Sci. USA 94, 3943–3947.
Chen, J., Sun, Y., and Nabel, G. (1998) Regulation of the proinflammatory effects of Fas ligand (CD95L). Science 282, 1714–1717.
Kang, S. M., Hoffmann, A., Le, D., Springer, M. L., Stock, P. G., and Blau, H. M. (1997) Immune response and myoblasts that express Fas ligand. Science 278, 1322–1324.
Restifo, N. P. (2000) Not so Fas: Re-evaluating the mechanisms of immune privilege and tumor escape. Nat. Med. 6, 493–495.
Andreola, G., Rivoltini, L., Castelli, C., et al. (2002) Induction of lymphocyte apoptosis by tumor cell secretion of FasL-bearing microvesicles. J. Exp. Med. 195, 1303–1316.
Abrahams, V., Straszewski, S., Kamsteeg, M., et al. (2003) Epithelial ovarian cancer secrete functional Fas ligand. Cancer Res., in press.
Kang, S. M., Braat, D., Schneider, D. B., et al. (2000) A noncleavable mutant of Fas ligand does not prevent neutrophilic destruction of islet transplants. Transplantation 69, 1813–1817.
Hohlbaum, A. M., Moe, S., and Marshak-Rothstein, A. (2000) Opposing effects of transmembrane and soluble Fas ligand expression on inflammation and tumor cell survival. J. Exp. Med. 191, 1209–1220.
Mor, G., Wei, Y., Santen, R., et al. (1998) Macrophages, estrogen and the microenvironment of breast cancer. J. Steroid Biochem. Mol. Biol. 67, 403–411.
Ben-Hur, H., Gurevich, P., Huszar, M., et al. (2000) Apoptosis and apoptosis-related proteins (Fas, Fas ligand, Blc-2, p53) in lymphoid elements of human ovarian tumors. Eur. J. Gynaecol. Oncol. 21, 53–57.
Song, J., Sapi, E., Brown, W., et al. (2000) Expression of Fas and Fas ligand during pregnancy, lactation and involution and its potential role during mammary gland remodeling. J. Clin. Invest. 106, 1209–1224.
Mor, G., Straszewski, S., and Kamsteeg, M. (2002) Role of the Fas/Fas ligand system in female reproductive organs: survival and apoptosis. Biochem. Pharmacol. 64, 1305.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Abrahams, V.M., Kamsteeg, M. & Mor, G. The Fas/Fas ligand system and cancer. Mol Biotechnol 25, 19–30 (2003). https://doi.org/10.1385/MB:25:1:19
Issue Date:
DOI: https://doi.org/10.1385/MB:25:1:19