Skip to main content
PMC home page
British Journal of Cancer logoLink to British Journal of Cancer
. 2000 Feb 21;82(6):1211–1217. doi: 10.1054/bjoc.1999.1065

The status of Fas and Fas ligand expression can predict recurrence of hepatocellular carcinoma

Y Ito 1,2, M Monden 1, T Takeda 1, H Eguchi 1, K Umeshita 1, H Nagano 1, S Nakamori 1, K Dono 1, M Sakon 1, M Nakamura 3, M Tsujimoto 4, M Nakahara 5, K Nakao 5, Y Yokosaki 2, N Matsuura 1,2
PMCID: PMC2363358  PMID: 10735508

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

Keywords: Fas, Fas ligand, immunohistochemistry, hepatocellular carcinoma, prognostic factor

Full Text

The Full Text of this article is available as a PDF (305.2 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Barry M. A., Behnke C. A., Eastman A. Activation of programmed cell death (apoptosis) by cisplatin, other anticancer drugs, toxins and hyperthermia. Biochem Pharmacol. 1990 Nov 15;40(10):2353–2362. doi: 10.1016/0006-2952(90)90733-2. [DOI] [PubMed] [Google Scholar]
  2. Cheng J., Zhou T., Liu C., Shapiro J. P., Brauer M. J., Kiefer M. C., Barr P. J., Mountz J. D. Protection from Fas-mediated apoptosis by a soluble form of the Fas molecule. Science. 1994 Mar 25;263(5154):1759–1762. doi: 10.1126/science.7510905. [DOI] [PubMed] [Google Scholar]
  3. Dowling P., Shang G., Raval S., Menonna J., Cook S., Husar W. Involvement of the CD95 (APO-1/Fas) receptor/ligand system in multiple sclerosis brain. J Exp Med. 1996 Oct 1;184(4):1513–1518. doi: 10.1084/jem.184.4.1513. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Falk M. H., Trauth B. C., Debatin K. M., Klas C., Gregory C. D., Rickinson A. B., Calender A., Lenoir G. M., Ellwart J. W., Krammer P. H. Expression of the APO-1 antigen in Burkitt lymphoma cell lines correlates with a shift towards a lymphoblastoid phenotype. Blood. 1992 Jun 15;79(12):3300–3306. [PubMed] [Google Scholar]
  5. Giordano C., Stassi G., De Maria R., Todaro M., Richiusa P., Papoff G., Ruberti G., Bagnasco M., Testi R., Galluzzo A. Potential involvement of Fas and its ligand in the pathogenesis of Hashimoto's thyroiditis. Science. 1997 Feb 14;275(5302):960–963. doi: 10.1126/science.275.5302.960. [DOI] [PubMed] [Google Scholar]
  6. Gratas C., Tohma Y., Barnas C., Taniere P., Hainaut P., Ohgaki H. Up-regulation of Fas (APO-1/CD95) ligand and down-regulation of Fas expression in human esophageal cancer. Cancer Res. 1998 May 15;58(10):2057–2062. [PubMed] [Google Scholar]
  7. Heatley M. K. Association between the apoptotic index and established prognostic parameters in endometrial adenocarcinoma. Histopathology. 1995 Nov;27(5):469–472. doi: 10.1111/j.1365-2559.1995.tb00312.x. [DOI] [PubMed] [Google Scholar]
  8. Higaki K., Yano H., Kojiro M. Fas antigen expression and its relationship with apoptosis in human hepatocellular carcinoma and noncancerous tissues. Am J Pathol. 1996 Aug;149(2):429–437. [PMC free article] [PubMed] [Google Scholar]
  9. Hiramatsu N., Hayashi N., Katayama K., Mochizuki K., Kawanishi Y., Kasahara A., Fusamoto H., Kamada T. Immunohistochemical detection of Fas antigen in liver tissue of patients with chronic hepatitis C. Hepatology. 1994 Jun;19(6):1354–1359. [PubMed] [Google Scholar]
  10. Ito Y., Takeda T., Umeshita K., Sakon M., Wakasa K., Matsuura N., Monden M. Fas antigen expression in hepatocellular carcinoma tissues. Oncol Rep. 1998 Jan-Feb;5(1):41–44. [PubMed] [Google Scholar]
  11. Itoh N., Yonehara S., Ishii A., Yonehara M., Mizushima S., Sameshima M., Hase A., Seto Y., Nagata S. The polypeptide encoded by the cDNA for human cell surface antigen Fas can mediate apoptosis. Cell. 1991 Jul 26;66(2):233–243. doi: 10.1016/0092-8674(91)90614-5. [DOI] [PubMed] [Google Scholar]
  12. Kerr J. F., Wyllie A. H., Currie A. R. Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer. 1972 Aug;26(4):239–257. doi: 10.1038/bjc.1972.33. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Kiener P. A., Davis P. M., Rankin B. M., Klebanoff S. J., Ledbetter J. A., Starling G. C., Liles W. C. Human monocytic cells contain high levels of intracellular Fas ligand: rapid release following cellular activation. J Immunol. 1997 Aug 15;159(4):1594–1598. [PubMed] [Google Scholar]
  14. Komaki R., Milas L., Ro J. Y., Fujii T., Perkins P., Allen P., Sikes C. R., Mountain C. F., Ordonez N. G. Prognostic biomarker study in pathologically staged N1 non-small cell lung cancer. Int J Radiat Oncol Biol Phys. 1998 Mar 1;40(4):787–796. doi: 10.1016/s0360-3016(97)00898-5. [DOI] [PubMed] [Google Scholar]
  15. Koomägi R., Volm M. Expression of Fas (CD95/APO-1) and Fas ligand in lung cancer, its prognostic and predictive relevance. Int J Cancer. 1999 Jun 21;84(3):239–243. doi: 10.1002/(sici)1097-0215(19990621)84:3<239::aid-ijc7>3.0.co;2-s. [DOI] [PubMed] [Google Scholar]
  16. Kubo K., Matsuzaki Y., Okazaki M., Kato A., Kobayashi N., Okita K. The Fas system is not significantly involved in apoptosis in human hepatocellular carcinoma. Liver. 1998 Apr;18(2):117–123. doi: 10.1111/j.1600-0676.1998.tb00136.x. [DOI] [PubMed] [Google Scholar]
  17. Kägi D., Ledermann B., Bürki K., Seiler P., Odermatt B., Olsen K. J., Podack E. R., Zinkernagel R. M., Hengartner H. Cytotoxicity mediated by T cells and natural killer cells is greatly impaired in perforin-deficient mice. Nature. 1994 May 5;369(6475):31–37. doi: 10.1038/369031a0. [DOI] [PubMed] [Google Scholar]
  18. Leithäuser F., Dhein J., Mechtersheimer G., Koretz K., Brüderlein S., Henne C., Schmidt A., Debatin K. M., Krammer P. H., Möller P. 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. 1993 Oct;69(4):415–429. [PubMed] [Google Scholar]
  19. Ling Y. H., Priebe W., Perez-Soler R. Apoptosis induced by anthracycline antibiotics in P388 parent and multidrug-resistant cells. Cancer Res. 1993 Apr 15;53(8):1845–1852. [PubMed] [Google Scholar]
  20. Lipponen P. K., Aaltomaa S. Apoptosis in bladder cancer as related to standard prognostic factors and prognosis. J Pathol. 1994 Aug;173(4):333–339. doi: 10.1002/path.1711730408. [DOI] [PubMed] [Google Scholar]
  21. Loro L. L., Vintermyr O. K., Johannessen A. C., Liavaag P. G., Jonsson R. Suppression of Fas receptor and negative correlation of Fas ligand with differentiation and apoptosis in oral squamous cell carcinoma. J Oral Pathol Med. 1999 Feb;28(2):82–87. doi: 10.1111/j.1600-0714.1999.tb02001.x. [DOI] [PubMed] [Google Scholar]
  22. Matsuno T., Nakagawa K., Sasaki H., Ishine N., Inagaki M., Yagi T., Haisa M., Tanaka N., Sakagami K., Orita K. Apoptosis in acute tubular necrosis and acute renal allograft rejection. Transplant Proc. 1994 Aug;26(4):2170–2173. [PubMed] [Google Scholar]
  23. Mochizuki K., Hayashi N., Hiramatsu N., Katayama K., Kawanishi Y., Kasahara A., Fusamoto H., Kamada T. Fas antigen expression in liver tissues of patients with chronic hepatitis B. J Hepatol. 1996 Jan;24(1):1–7. doi: 10.1016/s0168-8278(96)80178-4. [DOI] [PubMed] [Google Scholar]
  24. Niehans G. A., Brunner T., Frizelle S. P., Liston J. C., Salerno C. T., Knapp D. J., Green D. R., Kratzke R. A. Human lung carcinomas express Fas ligand. Cancer Res. 1997 Mar 15;57(6):1007–1012. [PubMed] [Google Scholar]
  25. O'Connell J., O'Sullivan G. C., Collins J. K., Shanahan F. The Fas counterattack: Fas-mediated T cell killing by colon cancer cells expressing Fas ligand. J Exp Med. 1996 Sep 1;184(3):1075–1082. doi: 10.1084/jem.184.3.1075. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Oehm A., Behrmann I., Falk W., Pawlita M., Maier G., Klas C., Li-Weber M., Richards S., Dhein J., Trauth B. C. Purification and molecular cloning of the APO-1 cell surface antigen, a member of the tumor necrosis factor/nerve growth factor receptor superfamily. Sequence identity with the Fas antigen. J Biol Chem. 1992 May 25;267(15):10709–10715. [PubMed] [Google Scholar]
  27. Olive C., Cheung C., Nicol D., Falk M. C. Expression of apoptotic regulatory molecules in renal cell carcinoma: elevated expression of Fas ligand. Immunol Cell Biol. 1999 Feb;77(1):11–18. doi: 10.1046/j.1440-1711.1999.00791.x. [DOI] [PubMed] [Google Scholar]
  28. Peduto Eberl L., Guillou L., Saraga E., Schröter M., French L. E., Tschopp J., Juillerat-Jeanneret L. Fas and Fas ligand expression in tumor cells and in vascular smooth-muscle cells of colonic and renal carcinomas. Int J Cancer. 1999 May 31;81(5):772–778. doi: 10.1002/(sici)1097-0215(19990531)81:5<772::aid-ijc18>3.0.co;2-s. [DOI] [PubMed] [Google Scholar]
  29. Rouvier E., Luciani M. F., Golstein P. Fas involvement in Ca(2+)-independent T cell-mediated cytotoxicity. J Exp Med. 1993 Jan 1;177(1):195–200. doi: 10.1084/jem.177.1.195. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Shiraki K., Tsuji N., Shioda T., Isselbacher K. J., Takahashi H. Expression of Fas ligand in liver metastases of human colonic adenocarcinomas. Proc Natl Acad Sci U S A. 1997 Jun 10;94(12):6420–6425. doi: 10.1073/pnas.94.12.6420. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Strand S., Hofmann W. J., Hug H., Müller M., Otto G., Strand D., Mariani S. M., Stremmel W., Krammer P. H., Galle P. R. Lymphocyte apoptosis induced by CD95 (APO-1/Fas) ligand-expressing tumor cells--a mechanism of immune evasion? Nat Med. 1996 Dec;2(12):1361–1366. doi: 10.1038/nm1296-1361. [DOI] [PubMed] [Google Scholar]
  32. Sträter J., Wellisch I., Riedl S., Walczak H., Koretz K., Tandara A., Krammer P. H., Möller P. CD95 (APO-1/Fas)-mediated apoptosis in colon epithelial cells: a possible role in ulcerative colitis. Gastroenterology. 1997 Jul;113(1):160–167. doi: 10.1016/s0016-5085(97)70091-x. [DOI] [PubMed] [Google Scholar]
  33. Suda T., Nagata S. Purification and characterization of the Fas-ligand that induces apoptosis. J Exp Med. 1994 Mar 1;179(3):873–879. doi: 10.1084/jem.179.3.873. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Suda T., Takahashi T., Golstein P., Nagata S. Molecular cloning and expression of the Fas ligand, a novel member of the tumor necrosis factor family. Cell. 1993 Dec 17;75(6):1169–1178. doi: 10.1016/0092-8674(93)90326-l. [DOI] [PubMed] [Google Scholar]
  35. Tauchi H., Sawada S. Analysis of mitotic cell death caused by radiation in mouse leukaemia L5178Y cells: apoptosis is the ultimate form of cell death following mitotic failure. Int J Radiat Biol. 1994 Apr;65(4):449–455. doi: 10.1080/09553009414550521. [DOI] [PubMed] [Google Scholar]
  36. Terada T., Nakanuma Y. 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. 1996 Oct;46(10):764–770. doi: 10.1111/j.1440-1827.1996.tb03546.x. [DOI] [PubMed] [Google Scholar]
  37. Todd D., Yang G., Brown R. W., Cao J., D'Agati V., Thompson T. S., Truong L. D. Apoptosis in renal cell carcinoma: detection by in situ end-labeling of fragmented DNA and correlation with other prognostic factors. Hum Pathol. 1996 Oct;27(10):1012–1017. doi: 10.1016/s0046-8177(96)90276-2. [DOI] [PubMed] [Google Scholar]
  38. Törmänen U., Eerola A. K., Rainio P., Vähäkangas K., Soini Y., Sormunen R., Bloigu R., Lehto V. P., Päkkö P. Enhanced apoptosis predicts shortened survival in non-small cell lung carcinoma. Cancer Res. 1995 Dec 1;55(23):5595–5602. [PubMed] [Google Scholar]
  39. Vesalainen S., Lipponen P., Talja M., Syrjänen K. Histological grade, perineural infiltration, tumour-infiltrating lymphocytes and apoptosis as determinants of long-term prognosis in prostatic adenocarcinoma. Eur J Cancer. 1994;30A(12):1797–1803. doi: 10.1016/0959-8049(94)e0159-2. [DOI] [PubMed] [Google Scholar]
  40. Xerri L., Devilard E., Hassoun J., Mawas C., Birg F. Fas ligand is not only expressed in immune privileged human organs but is also coexpressed with Fas in various epithelial tissues. Mol Pathol. 1997 Apr;50(2):87–91. doi: 10.1136/mp.50.2.87. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Yoshino T., Kondo E., Cao L., Takahashi K., Hayashi K., Nomura S., Akagi T. Inverse expression of bcl-2 protein and Fas antigen in lymphoblasts in peripheral lymph nodes and activated peripheral blood T and B lymphocytes. Blood. 1994 Apr 1;83(7):1856–1861. [PubMed] [Google Scholar]
  42. von Bernstorff W., Spanjaard R. A., Chan A. K., Lockhart D. C., Sadanaga N., Wood I., Peiper M., Goedegebuure P. S., Eberlein T. J. Pancreatic cancer cells can evade immune surveillance via nonfunctional Fas (APO-1/CD95) receptors and aberrant expression of functional Fas ligand. Surgery. 1999 Jan;125(1):73–84. doi: 10.1067/msy.2099.93570. [DOI] [PubMed] [Google Scholar]

Articles from British Journal of Cancer are provided here courtesy of Cancer Research UK

RESOURCES