Abstract
The status of Fas and Fas ligand (Fas L) expression was investigated in this study for 103 hepatocellular carcinomas (HCC). We studied the expression of the following three factors, Fas and Fas L expression in carcinoma cells and Fas L expression in stromal mononuclear cells (defined as stromal Fas L index). Fas expression in HCC cells was significantly decreased in cases with poor differentiation (P< 0.0001) and of larger size (P = 0.0058). Fas L expression in carcinoma cells was observed exclusively in moderately or poorly differentiated cases. Furthermore, each factor had prognostic significance for disease-free survival (DFS) (P< 0.0001, P = 0.0222 and 0.0027 respectively). We then scored the results of each factor and defined the total score as ‘Fas-Fas L risk score’. The P -value of the score for DFS was even lower than that of the clinical stage by multivariate analysis. These results suggest that the evaluation of Fas and Fas ligand expression potentially has a significant prognostic value for DFS of HCC patients, in addition to the clinical stage, and can be regarded as a new prognostic marker. © 2000 Cancer Research Campaign
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References
Barry MA, Behnke CA and Eastman A (1990) Activation of programmed cell death (apoptosis) by cisplatin, other anticancer drugs, toxins and hyperthermia. Biochem Pharmacol 40: 2353–2362
Cheng J, Zhou T, Liu C, Shapiro JP, Braner MJ, Kiefer MC and Bar PJ (1994) Protection from Fas-mediated apoptosis by a soluble form of the Fas molecule. Science 263: 1759–1762
Dowling P, Shang G, Raval S, Menonna J, Cook S and Husar W (1996) Involvement of the CD95 (APO-1/Fas) receptor/ligand system in multiple sclerosis brain. J Exp Med 184: 1513–1518
Falk MH, Traugh BC, Debatin K-M, Klas C, Gregory CD, Rickinson AB, Calendar A, Lenoir GM, Ellwart JW and Krammer PH (1992) Expression of the APO-1 antigen in Burkitt lymphoma cell lines correlates with a shift towards a lymphoblastoid phenotype. Blood 79: 3300–3306
Giordano C, Stassi G, Maria RD, Todaro M, Richiusa P, Papoff G, Ruberti G, Bagnasoco M, Testi R and Galluzzo A (1997) A potential involvement of Fas and its ligand in the pathogenesis of Hashimoto's thyroiditis. Science 275: 960–963
Gratas C, Thoma Y, Barnas C, Taniere P, Hainaut P and Ohgaki H (1998) Up-regulation of Fas (APO-1/CD95) ligand and down-regulation of Fas expression in human esophageal cancer. Cancer Res 58: 2057–2062
Heatley MK (1995) Association between the apoptotic index and established prognostic parameters in endometrial adenocarcinoma. Histopathology 27: 469–472
Higaki K, Yano H and Kojiro M (1996) Fas antigen expression and its relationship with apoptosis in human hepatocellular carcinoma and noncancerous tissues. Am J Pathol 149: 429–437
Hiramatsu N, Hayashi N, Katayama K, Mochizuki K, Kawanishi Y, Kasahara A, Fusamoto H and Kamada T (1994) Immunohistochemical detection of Fas antigen in liver tissue of patients with chronic hepatitis C. Hepatology 19: 1354–1359
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
Ito Y, Takeda T, Umeshita K, Sakon M, Wakasa K, Matsuura N and Monden M (1998) Fas antigen expression in hepatocellular carcinoma tissues. Oncol Rep 5: 41–44
Ito Y, Matsuura N, Sakon M, Takeda T, Umeshita K, Nagano H, Nakamori S, Dono K, Tsujimoto M, Nakahara M, Nakao K and Monden M (1999) Both cell proliferation and apoptosis significantly predict shortened disease-free survival in hepatocellular carcinoma. Br J Cancer,
Kagi D, Ledermann B, Burki K, Seiler P, Odermatt B, Olsen KJ, Podack ER, Zinkernagel RM and Henegartner H (1994) Cytotoxicity mediated by T cells and natural killer cells is greatly impaired in perforin-deficient mice. Nature 369: 31–37
Kerr JFR, Wyllie AH and Currie AR (1971) Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer 26: 239–257
Kiener PA, Dovis PM, Rankin BM, Klebanoff SJ, Ledbetter JA, Starling GC and Liles WC (1997) Human monocytic cells contain high levels of intracellular Fas ligand. Rapid release following cellular activation. J Immunol 159: 1594–1598
Komaki R, Miles L, Ro JY, Fujii T, Perkins P, Allen P, Sikes CR, Mountain CF and Ordonez NG (1998) Prognostic biomarker study in pathologically stage N1 non-small-cell lung cancer. Int J Radiat Oncol Biol Phys 40: 787–796
Koomagi R and Volm M (1999) Expression of Fas (CD95/APO-1) and FAs ligand in lung cancer, its prognostic and predictive relevance. Int J Cancer 84: 239–243
Kubo K, Matsuzaki Y, Okazaki M, Kato A, Kobayashi N and Okita K (1998) The Fas system is not significantly involved in apoptosis in human hepatocellular carcinoma. Liver 18: 117–123
Leithauser F, Dhein J, Mechtersheimer G, Koretz K, Bruderlein S, Henne C, Schmidt A, Debatin KM, Krammer PH and Moller P (1993) Constitutive and induced expression of APO-1, a new member of the nerve growth factor/tumor necrosis factor receptor superfamily, in normal and neoplastic cells. Lab Invest 69: 415–429
Ling YH, Priebe W and Perez SZ (1993) Apoptosis induced by anthracycline antibiotics in P 388 parent and multidrug-resistant cells. Cancer Res 53: 1845–1852
Lipponen PK and Aaltomaa S (1994) Apoptosis in bladder cancer as related to standard prognostic factors and prognosis. J Pathol 173: 333–339
Loro LL, Vintermyr OK, Johannessen AC, Liavaag PG and Jonsson R (1999) Suppression of Fas receptor and negative correlation of Fas ligand with differentiation and apoptosis in oral squamous cell carcinoma. J Oral Pathol Med 28: 82–87
Matsuno T, Nakagawa K, Sasaki H, Ishine N, Inagaki M, Yagi T, Haisa M, Tanaka N, Sakagami K and Orita K (1994) Apoptosis in acute tubular necrosis and acute renal allograft rejection. Transplant Proc 26: 2170–2173
Mochizuki K, Hayashi K, Hiamatsu N, Katayama K, Kawanishi Y, Kasahara A, Fusamoto H and Kamada T (1996) Fas antigen expression in liver tissues of patients with chronic hepatitis B. J Hepatol 24: 1–7
Niehans GA, Brunner T, Frizelle SP, Liston JC, Salerno CT, Knapp DJ, Green DR and Kratzke RA (1997). Human lung carcinomas express Fas ligand 57: 1007–1012
O'Connell J, O'Sullivan GC, Collins JK 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
Oehm A, Behrmann I, Falk W, Pawlita M, Maier G, Klas C, Li-Weber M, Richards S, Dhein J and Trauth BC (1992) Purification and molecular cloning of the APO-1 cell surface antigen, a member of the tumor necrosis factor/nerve growth factor receptor superfamily: sequence identify with the Fas antigen. J Biol Chem 267: 10709–10715
Olive C, Chaung C, Nicol D and Falk MC (1999) Expression of apoptotic regulatory molecules in renal cell carcinoma: elevated expression of Fas ligand. Immunol Cell Biol 77: 11–18
Peduto Eberl L, Guillou L, Saraga E, Schroter M, French LE, Tschopp J and Juillerat-Jeanneret L (1999) Fas and Fas ligand expression in tumor cells and in vascular smooth-muscle cells of colonic and renal carcinomas. Int J Cancer 31: 772–778
Rouvier E, Luciani M-F and Golstein P (1993) Fas involvement in Ca++-independent T cell-mediated cytotoxicity. J Exp Med 177: 195–200
Shiraki K, Tsuji N, Shioda 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?. Nat Med 2: 1361–1366
Strater J, Wellisch I, Riedl S, Walczak H, Koretz K, Tandara A, Krammer PH and Moller P (1997) CD95(APO-1/Fas)-mediated apoptosis in colon epithelial cells: a possible role in ulcerative colitis. Gastroenterology 113: 160–167
Suda T and Nagata S (1994) Purification and characterization of the Fas ligand that induces apoptosis. J Exp Med 179: 873–877
Suda T, Takahashi T, Golstein P and Nagata S (1993) Molecular cloning and expression of the Fas ligand, a novel member of the tumor necrosis factor family. Cell 75: 1169–1178
Tauchi H and Sawada S (1994) Analysis of mitotic cell death caused by radiation in mouse leukemia L5178Y cells: apoptosis is the ultimate form of cell death following mitotic failure. Int J Radiat Biol 4: 449–455
Terada T and Nakanuma Y (1996) Expression of apoptosis, proliferating cell nuclear antigen and apoptosis-related antigens (bcl-2, c-myc, Fas, Lewis Y, and p53) in human cholangiocarcinomas and hepatocellular carcinomas. Pathol Int 46: 764–770
Todd D, Yang G, Brown RW, Cao J, D'Agati V, Thompson TS and Truong LD (1996) Apoptosis in renal cell carcinoma: detection by in situ end-labeling of fragmented DNA and correlation with other prognostic factors. Hum Pathol 27: 1012–1017
Tormanen U, Eerola AK, Rainio PO, Vahakangas K, Soini Y, Sormunen R, Bloigu R, Lehto VP and Paakko P (1995) Enhanced apoptosis predicts shortened survival in non-small cell lung carcinoma. Cancer Res 55: 5595–5602
Vasaslainen S, Lipponen P, Talija M and Syrjanen K (1994) Histological grade, perineural infiltration, tumour-infiltrating lymphocytes and apoptosis as determinants of long-term prognosis in prostatic adenocarcinoma. Eur J Cancer 30: 1797–1803
von Bernstorff W, Spanjaard RA, Chan AK, Lockhart DC, Sadanaga N, Wood I, Peiper M, Goedegebuure PS and Eberelein TJ (1999) Pancreatic cancer cells can evade immune surveillance via nonfunctional FAs (APO-1/CD95) receptors and aberrant expression of vfunctional Fas ligand. Surgery 125: 73–84
Xerri L, Devilard E, Hassoun J, Mawas C and Birg F (1997) Fas ligand is not only expressed in immune privileged human organs but is also coexpressed with Fas in various epithelial tissues. Mol Pathol 50: 87–91
Yamasaki F, Tokunaga O and Sugimori H (1997) Apoptotic index in ovarian carcinoma: correlation with clinicopathologic factors and prognosis. Gynecol Oncol 66: 394–400
Yoshino T, Kondo E, Cao L, Takahashi K, Hayashi K, Nomura S and Akagi T (1994) Inverse expression of bcl-2 protein and Fas antigen in lymphoblasts in peripheral lymph nodes and activated peripheral blood T and B lymphocytes. Blood 83: 1856–1861
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Ito, Y., Monden, M., Takeda, T. et al. The status of Fas and Fas ligand expression can predict recurrence of hepatocellular carcinoma. Br J Cancer 82, 1211–1217 (2000). https://doi.org/10.1054/bjoc.1999.1065
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DOI: https://doi.org/10.1054/bjoc.1999.1065
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