The significance of Fas, tumor necrosis factor-related apoptosis-inducing ligand and fibrinolytic factors in the assessment of malignant pleural effusion


  • Jong Weon Choi Department of Laboratory Medicine, College of Medicine, Inha University, Incheon, Republic of Korea
  • Moon Hee Lee Department of Internal Medicine, College of Medicine, Inha University, Incheon, Republic of Korea
  • Tatsuyoshi Fujii Department of Internal Medicine, Tsukuba University Hospital Mito Clinical Education and Training Center, Mito Kyodo General Hospital, Ibaraki, Japan



pleural effusion, apoptosis, malignancy, fibrinolytic factor, Fas, TRAIL


Paper description:

  • Pleural effusion occurs as a complication of different diseases, resulting from a disruption in pleural homeostasis and increased pleural permeability.
  • Patients with pleural effusion were evaluated by measuring Fas, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), tissue-type plasminogen activator (tPA), plasminogen activator inhibitor-1 (PAI-1), D-dimers, and lactate dehydrogenase (LD).
  • Fas and TRAIL levels were significantly higher in malignant pleural effusion, and Fas had a significantly higher ability to identify malignant effusion than tPA and LD. Fas was positively correlated with tPA and D-dimers, but not with biochemical parameters.
  • These results contribute to evaluations of patients with suspected malignant pleural effusion.

Abstract: Few studies have examined the usefulness of soluble apoptotic markers for the screening of pleural effusion. This study aimed to investigate the significance of Fas, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and fibrinolytic factors for the assessment of patients with malignant pleural effusion. A total of 137 patients with pleural effusion were evaluated. Soluble Fas, TRAIL, tissue-type plasminogen activator (tPA), plasminogen activator inhibitor-1 (PAI-1), D-dimers and lactate dehydrogenase (LD) levels were measured. Pleural fluid/blood ratios (P/B) of fibrinolytic factors were calculated. Fas and TRAIL levels were significantly higher in patients with malignant effusion than in those with non-malignant effusion. Malignant effusion was 1.6-fold more prevalent in patients with elevated Fas than in those without (48.5% vs 30.4%, P=0.031). The P/B ratio of tPA was 2.5-fold higher in malignant effusion than in non-malignant effusion (4.65 vs 1.83, P<0.001). Fas was positively correlated with tPA and D-dimers, but not with biochemical parameters. The ability of Fas to identify malignant effusions was significantly greater than those of tPA and LD. In conclusion, measurements of Fas and TRAIL in conjunction with fibrinolytic factors may provide information useful for monitoring patients with suspected malignant pleural effusion.


Download data is not yet available.


Jantz MA, Antony VB. Pathophysiology of the pleura. Respiration. 2008;75(2):121-33.

Sahn SA. Diagnosis and management of parapneumonic effusions and empyema. Clin Infect Dis. 2007;45(11):1480-6.

Mutsaers SE, Prele CM, Brody AR, Idell S. Pathogenesis of pleural fibrosis. Respirology. 2004;9(4):428-40.

Chung CL, Chen CH, Sheu JR, Chen YC, Chang SC. Proinflammatory cytokines, transforming growth factor-beta1, and fibrinolytic enzymes in loculated and free-flowing pleural exudates. Chest. 2005;128(2):690-7.

Light RW. The Light criteria: the beginning and why they are useful 40 years later. Clin Chest Med. 2013;34(1):21-6.

Marel M, Stastny B, Melínová L, Svandová E, Light RW. Diagnosis of pleural effusions. Experience with clinical studies, 1986 to 1990. Chest. 1995;107(6):1598-603.

Knipping E, Debatin KM, Stricker K, Heilig B, Eder A, Krammer PH. Identification of soluble APO-1 in supernatants of human B- and T-cell lines and increased serum levels in B- and T-cell leukemias. Blood. 1995;85(6):1562-9.

Baetu TM, Hiscott J. On the TRAIL to apoptosis. Cytokine Growth Factor Rev. 2002;13(3):199-207.

Martin TR, Hagimoto N, Nakamura M, Matute-Bello G. Apoptosis and epithelial injury in the lungs. Proc Am Thorac Soc. 2005;2(3):214-20.

Mitani K, Nishioka Y, Yamabe K, Ogawa H, Miki T, Yanagawa H, Sone S. Soluble Fas in malignant pleural effusion and its expression in lung cancer cells. Cancer Sci. 2003;94(3):302-7.

Lee KS, Chung JY, Jung YJ, Chung WY, Park JH, Sheen SS, Lee KB, Park KJ. The significance of caspase-cleaved cytokeratin 18 in pleural effusion. Tuberc Respir Dis (Seoul). 2014;76(1):15-22.

Light RW, Macgregor MI, Luchsinger PC, Ball WC Jr. Pleural effusions: the diagnostic separation of transudates and exudates. Ann Intern Med. 1972;77(4):507-13.

Papoff G, Cascino I, Eramo A, Starace G, Lynch DH, Ruberti G. An N-terminal domain shared by Fas/Apo-1 (CD95) soluble variants prevents cell death in vitro. J Immunol. 1996;156(12):4622-30.

Krams SM, Fox CK, Beatty PR, Cao S, Villanueva JC, Esquivel CO, Martinez OM. Human hepatocytes produce an isoform of FAS that inhibits apoptosis. Transplantation. 1998;65(5):713-21.

Sikora J, Dworacki G, Zeromski J. Expression of Fas and Fas ligand and apoptosis in tumor-associated lymphocytes and in tumor cells from malignant pleural effusions. Nat Immun. 1998;16(5-6):244-55.

Aguiar LM, Antonangelo L, Vargas FS, Zerbini MC, Sales MM, Uip DE, Saldiva PH. Malignant and tuberculous pleural effusions: immunophenotypic cellular characterization. Clinics (Sao Paulo). 2008;63(5):637-44.

Walczak H, Miller RE, Ariail K, Gliniak B, Griffith TS, Kubin M, Chin W, Jones J, Woodward A, Le T, Smith C, Smolak P, Goodwin RG, Rauch CT, Schuh JC, Lynch DH. Tumoricidal activity of tumor necrosis factor-related apoptosis-inducing ligand in vivo. Nat Med. 1999;5(2):157-63.

Dai X, Zhang J, Arfuso F, Chinnathambi A, Zayed ME, Alharbi SA, Kumar AP, Ahn KS, Sethi G. Targeting TNF-related apoptosis-inducing ligand (TRAIL) receptor by natural products as a potential therapeutic approach for cancer therapy. Exp Biol Med (Maywood). 2015;240(6):760-73.

Prado-Garcia H, Romero-Garcia S, Morales-Fuentes J, Aguilar-Cazares D, Lopez-Gonzalez JS. Activation-induced cell death of memory CD8+ T cells from pleural effusion of lung cancer patients is mediated by the type II Fas-induced apoptotic pathway. Cancer Immunol Immunother. 2012;61(7):1065-80.

Karatolios K, Pankuweit S, Goettsch C, Hofbauer LC, Timmesfeld N, Al-Fakhri N, Maisch B, Schoppet M. Osteoprotegerin (OPG) and TNF-related apoptosis-inducing ligand (TRAIL) levels in malignant and benign pericardial effusions. Clin Biochem. 2012;45(3):237-42.

Danø K, Andreasen PA, Grøndahl-Hansen J, Kristensen P, Nielsen LS, Skriver L. Plasminogen activators, tissue degradation, and cancer. Adv Cancer Res. 1985;44:139-266.

Saksela O, Rifkin DB. Cell-associated plasminogen activation: regulation and physiological functions. Annu Rev Cell Biol. 1988;4:93-126.

Stefansson S, McMahon GA, Petitclerc E, Lawrence DA. Plasminogen activator inhibitor-1 in tumor growth, angiogenesis and vascular remodeling. Curr Pharm Des. 2003;9(19):1545-64.

Andreasen PA, Kjøller L, Christensen L, Duffy MJ. The urokinase-type plasminogen activator system in cancer metastasis: a review. Int J Cancer. 1997;72(1):1-22.<1::aid-ijc1>;2-z

Kwaan HC, Wang J, Svoboda K, Declerck PJ. Plasminogen activator inhibitor 1 may promote tumour growth through inhibition of apoptosis. Br J Cancer. 2000;82(10):1702-8.

Philip-Joët F, Alessi MC, Philip-Joët C, Aillaud M, Barriere JR, Arnaud A, Juhan-Vague I. Fibrinolytic and inflammatory processes in pleural effusions. Eur Respir J. 1995;8(8):1352-6.

Wang PS, Chen YM, Hsieh YL, Yu CF, Tsai CM, Perng RP. Pleural effusion and serum soluble fas-ligand levels are elevated in different clinical conditions. Lung. 2002;180(1):25-32.

Janek T, Krasowska A, Radwańska A, Łukaszewicz M. Lipopeptide biosurfactant pseudofactin II induced apoptosis of melanoma A 375 cells by specific interaction with the plasma membrane. PLoS One. 2013;8(3):e57991.

Chan FK, Moriwaki K, De Rosa MJ. Detection of necrosis by release of lactate dehydrogenase activity. Methods Mol Biol. 2013;979:65-70.

Parhamifar L, Andersen H, Moghimi SM. Lactate dehydrogenase assay for assessment of polycation cytotoxicity. Methods Mol Biol. 2013;948:13-22.

Backman LJ, Danielson P. Akt-mediated anti-apoptotic effects of substance P in Anti-Fas-induced apoptosis of human tenocytes. J Cell Mol Med. 2013;17(6):723-33.




How to Cite

Choi JW, Lee MH, Fujii T. The significance of Fas, tumor necrosis factor-related apoptosis-inducing ligand and fibrinolytic factors in the assessment of malignant pleural effusion. Arch Biol Sci [Internet]. 2022Jun.27 [cited 2022Aug.15];74(2):119-26. Available from: