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Circulating levels of soluble Fas ligand reflect disease progression in multiple myeloma

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Abstract

Multiple myeloma (MM) plasma cells are apoptosis resistant. The system of Fas with its ligand (Fas-L) participates actively in the extrinsic apoptotic system. In oncology, its role is controversial, since it has been reported both to suppress and promote tumor growth. The aim of this study was to measure serum levels of soluble Fas-L (sFas-L) in patients with active MM and to correlate them with markers of disease activity. We studied 57 patients with active MM, along with 22 healthy controls. We measured serum levels of sFas-L and interleukin-6 (IL-6) by enzyme-linked immunosorbent assays, as well of beta-2 microglobulin (B2M), C-reactive protein (CRP) and lactate dehydrogenase (LDH). We also measured the degree of bone marrow infiltration. All parameters were increased in patients, compared with controls (p < 0.001 for all cases) and also in parallel with disease stage (p < 0.001 for all cases). Positive correlations were noted between serum levels of sFas-L with IL-6, infiltration (p < 0.001 for both cases) and LDH (p < 0.04), but not with CRP and B2M. We suggest that the system of Fas/Fas-L participates actively in MM progression in a complex manner and that serum levels of sFas-L may reflect disease progression. Further studies are needed to determine its usefulness as a marker of disease activity.

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References

  1. Lichtenstein A, Tu Y, Fady C, Vescio R, Berenson J. Interleukin-6 inhibits apoptosis of malignant plasma cells. Cell Immunol. 1995;162:248–55.

    Article  CAS  PubMed  Google Scholar 

  2. Zhou Y, Uddin S, Zimmerman T, Kang JA, Ulaszek J, Wickrema A. Growth control of multiple myeloma cells through inhibition of glycogen synthase kinase-3. Leuk Lymphoma. 2008;49:1945–53.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  3. Klein B, Seckinger A, Moehler T, Hose D. Molecular pathogenesis of multiple myeloma: chromosomal aberrations, changes in gene expression, cytokine networks, and the bone marrow microenvironment. Recent Results Cancer Res. 2011;183:39–86.

    Article  PubMed  Google Scholar 

  4. Mitsiades CS, Mitsiades N, Poulaki V, Schlossman R, Akiyama M, Chauhan D, Hideshima T, Treon SP, Munshi NC, Richardson PG, Anderson KC. Activation of NF-kappaB and upregulation of intracellular anti-apoptotic proteins via the IGF-1/Akt signaling in human multiple myeloma cells: therapeutic implications. Oncogene. 2002;21:5673–83.

    Article  CAS  PubMed  Google Scholar 

  5. Elmore S. Apoptosis: a review of programmed cell death. Toxicol Pathol. 2007;35:495–516.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  6. Nagata S, Golstein P. The Fas death factor. Science. 1995;267:1449–56.

    Article  CAS  PubMed  Google Scholar 

  7. Lettau M, Paulsen M, Kabelitz D, Janssen O. Storage, expression and function of Fas ligand, the key death factor of immune cells. Curr Med Chem. 2008;15:1684–96.

    Article  CAS  PubMed  Google Scholar 

  8. Caldwell SA, Ryan MH, McDuffie E, Abrams SI. The Fas/Fas ligand pathway is important for optimal tumor regression in a mouse model of CTL adoptive immunotherapy of experimental CMS4 lung metastases. J Immunol. 2003;171:2402–12.

    Article  CAS  PubMed  Google Scholar 

  9. Sträter J, Hinz U, Hasel C, Bhanot U, Mechtersheimer G, Lehnert T, Möller P. Impaired CD95 expression predisposes for recurrence in curatively resected colon carcinoma: clinical evidence for immunoselection and CD95L mediated control of minimal residual disease. Gut. 2005;54:661–5.

    Article  PubMed Central  PubMed  Google Scholar 

  10. Guillen-Ahlers H, Suckow MA, Castellino FJ, Ploplis VA. Fas/CD95 deficiency in ApcMin/+ mice increases intestinal tumor burden. PLoS ONE. 2010;5:e9070.

    Article  PubMed Central  PubMed  Google Scholar 

  11. Chen L, Park SM, Tumanov AV, Hau A, Sawada K, Feig C, Turner JR, Fu YX, Romero IL, Lengyel E, Peter ME. CD95 promotes tumour growth. Nature. 2010;465:492–6.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  12. Matsuno H, Yudoh K, Watanabe Y, Nakazawa F, Aono H, Kimura T. Stromelysin-1 (MMP-3) in synovial fluid of patients with rheumatoid arthritis has potential to cleave membrane bound Fas ligand. J Rheumatol. 2001;28:22–8.

    CAS  PubMed  Google Scholar 

  13. Vargo-Gogola T, Crawford HC, Fingleton B, Matrisian LM. Identification of novel matrix metalloproteinase-7 (matrilysin) cleavage sites in murine and human Fas ligand. Arch Biochem Biophys. 2002;408:155–61.

    Article  CAS  PubMed  Google Scholar 

  14. Kanda Y, Ara C, Chizuka A, Yamamoto R, Hamaki T, Suguro M, Matsuyama T, Takezako N, Miwa A, Tohma J, Shirakawa K, Yatomi T, Nakamura N, Hirai H, Togawa A. Lack of correlation between clinical characteristics and serum soluble Fas ligand levels in patients with multiple myeloma. Leuk Lymphoma. 2001;40:351–6.

    Article  CAS  PubMed  Google Scholar 

  15. Kayagaki N, Kawasaki A, Ebata T, Ohmoto H, Ikeda S, Inoue S, Yoshino K, Okumura K, Yagita H. Metalloproteinase-mediated release of human Fas ligand. J Exp Med. 1995;182:1777–83.

    Article  CAS  PubMed  Google Scholar 

  16. Schneider P, Holler N, Bodmer JL, Hahne M, Frei K, Fontana A, Tschopp J. Conversion of membrane-bound Fas (CD95) ligand to its soluble form is associated with downregulation of its proapoptotic activity and loss of liver toxicity. J Exp Med. 1998;187:1205–13.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  17. Mogi M, Fukuo K, Yang J, Suhara T, Ogihara T. Hypoxia stimulates release of the soluble form of fas ligand that inhibits endothelial cell apoptosis. Lab Invest. 2001;81:177–84.

    Article  CAS  PubMed  Google Scholar 

  18. Holler N, Tardivel A, Kovacsovics-Bankowski M, Hertig S, Gaide O, Martinon F, Tinel A, Deperthes D, Calderara S, Schulthess T, Engel J, Schneider P, Tschopp J. Two adjacent trimeric Fas ligands are required for Fas signaling and formation of a death-inducing signaling complex. Mol Cell Biol. 2003;23:1428–40.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  19. Tanaka M, Suda T, Haze K, Nakamura N, Sato K, Kimura F, Motoyoshi K, Mizuki M, Tagawa S, Ohga S, Hatake K, Drummond AH, Nagata S. Fas ligand in human serum. Nat Med. 1996;2:317–22.

    Article  CAS  PubMed  Google Scholar 

  20. Sato K, Kimura F, Nakamura Y, Murakami H, Yoshida M, Tanaka M, Nagata S, Kanatani Y, Wakimoto N, Nagata N, Motoyoshi K. An aggressive nasal lymphoma accompanied by high levels of soluble Fas ligand. Br J Haematol. 1996;94:379–82.

    Article  CAS  PubMed  Google Scholar 

  21. Munakata S, Watanabe O, Ohashi K, Morino H. Expression of Fas ligand and bcl-2 in cervical carcinoma and their prognostic significance. Am J Clin Pathol. 2005;123:879–85.

    Article  CAS  PubMed  Google Scholar 

  22. Wingender G, Krebs P, Beutler B, Kronenberg M. Antigen-specific cytotoxicity by invariant NKT cells in vivo is CD95/CD178-dependent and is correlated with antigenic potency. J Immunol. 2010;185:2721–9.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  23. Houghton JA, Harwood FG, Gibson AA, Tillman DM. The fas signaling pathway is functional in colon carcinoma cells and induces apoptosis. Clin Cancer Res. 1997;3:2205–9.

    CAS  PubMed  Google Scholar 

  24. Kägi D, Vignaux F, Ledermann B, Bürki K, Depraetere V, Nagata S, Hengartner H, Golstein P. Fas and perforin pathways as major mechanisms of T cell-mediated cytotoxicity. Science. 1994;265:528–30.

    Article  PubMed  Google Scholar 

  25. Müschen M, Warskulat U, Beckmann MW. Defining CD95 as a tumor suppressor gene. J Mol Med (Berl). 2000;78:312–25.

    Article  PubMed  Google Scholar 

  26. O’ Reilly LA, Tai L, Lee L, Kruse EA, Grabow S, Fairlie WD, Haynes NM, Tarlinton DM, Zhang JG, Belz GT, Smyth MJ, Bouillet P, Robb L, Strasser A. Membrane-bound Fas ligand only is essential for Fas-induced apoptosis. Nature. 2009;461:659–63.

    Article  PubMed Central  PubMed  Google Scholar 

  27. Liu F, Bardhan K, Yang D, Thangaraju M, Ganapathy V, Waller JL, Liles GB, Lee JR, Liu K. NF-κB directly regulates Fas transcription to modulate Fas-mediated apoptosis and tumor suppression. J Biol Chem. 2012;287:25530–40.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  28. Mottolese M, Buglioni S, Bracalenti C, Cardarelli MA, Ciabocco L, Giannarelli D, Botti C, Natali PG, Concetti A, Venanzi FM. Prognostic relevance of altered Fas (CD95)-system in human breast cancer. Int J Cancer. 2000;89:127–32.

    Article  CAS  PubMed  Google Scholar 

  29. Nagashima H, Mori M, Sadanaga N, Mashino K, Yoshikawa Y, Sugimachi K. Expression of Fas ligand in gastric carcinoma relates to lymph node metastasis. Int J Oncol. 2001;18:1157–62.

    CAS  PubMed  Google Scholar 

  30. Kase H, Aoki Y, Tanaka K. Fas ligand expression in cervical adenocarcinoma: relevance to lymph node metastasis and tumor progression. Gynecol Oncol. 2003;90:70–4.

    Article  CAS  PubMed  Google Scholar 

  31. Younes M, Schwartz MR, Ertan A, Finnie D, Younes A. Fas ligand expression in esophageal carcinomas and their lymph node metastases. Cancer. 2000;88:524–8.

    Article  CAS  PubMed  Google Scholar 

  32. Hekimgil M, Cağirgan S, Pehlivan M, Doğanavşargil B, Tombuloğlu M, Soydan S. Immunohistochemical detection of CD 95 (Fas) & Fas ligand (Fas-L) in plasma cells of multiple myeloma and its correlation with survival. Leuk Lymphoma. 2006;47:271–80.

    Article  CAS  PubMed  Google Scholar 

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Correspondence to Michael G. Alexandrakis.

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Alexandrakis, M.G., Pappa, C.A., Kolovou, A. et al. Circulating levels of soluble Fas ligand reflect disease progression in multiple myeloma. Med Oncol 31, 953 (2014). https://doi.org/10.1007/s12032-014-0953-0

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