Skip to main content

Advertisement

SpringerLink
Log in

Proapoptotic CD95L levels in normal human serum and sera of breast cancer patients

  • Research Article
  • Published:
Tumor Biology

Abstract

The CD95 pathway is a critical apoptotic pathway used by immune cells to avoid cancer development. CD95 ligand (CD95L) is found in several forms, as a cell membrane-associated form, a soluble metalloprotease-cleaved form, and a soluble but membrane-bound CD95L released on cell-derived exosomes. In this study, we used a cell-based assay to evaluate the activity of proapoptotic CD95L in sera from healthy individuals and breast cancer patients. We confirmed that our cell-based assay using Jurkat cells was sensitive to the presence of proapoptotic CD95L in serum, and apoptosis induction by mechanisms other than CD95 was discriminated using apoptosis-resistant Jurkat subclones. Our results indicated a proapoptotic potential of normal serum that involved CD95L. Sera from breast cancer patients exhibited significantly decreased apoptosis induction, due to increased CD95 receptor levels compared with healthy women. Apoptotic potential tended to decrease as the Breast Imaging Reporting and Data System grade increased, and we observed restoration of proapoptotic potential after tumor removal. The CD95L in serum responsible for apoptotic induction was associated with high-molecular-weight particles, perhaps with exosomes. The sera of healthy individuals generally contain a proapoptotic environment, and this property is mainly maintained by the presence of CD95L. Furthermore, measurement of CD95L-mediated apoptosis induction by sera could be a useful parameter to be evaluated during cancer development and therapeutic response.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Hengartner MO. The biochemistry of apoptosis. Nature. 2000;407(6805):770–6. doi:10.1038/35037710.

    Article  CAS  PubMed  Google Scholar 

  2. Birkeland SA, Storm HH, Lamm LU, Barlow L, Blohme I, Forsberg B, et al. Cancer risk after renal transplantation in the Nordic countries, 1964-1986. Int J Cancer. 1995;60(2):183–9.

    Article  CAS  PubMed  Google Scholar 

  3. Vajdic CM, McDonald SP, McCredie MR, van Leeuwen MT, Stewart JH, Law M, et al. Cancer incidence before and after kidney transplantation. JAMA. 2006;296(23):2823–31.

    Article  CAS  PubMed  Google Scholar 

  4. Bonnet F, Chene G. Evolving epidemiology of malignancies in HIV. Curr Opin Oncol. 2008;20(5):534–40. doi:10.1097/CCO.0b013e32830a5080.

    Article  PubMed  Google Scholar 

  5. Lavrik I, Golks A, Krammer PH. Death receptor signaling. J Cell Sci. 2005;118(Pt 2):265–7. doi:10.1242/jcs.01610.

    Article  CAS  PubMed  Google Scholar 

  6. Leithauser F, Dhein J, Mechtersheimer G, Koretz K, Bruderlein S, Henne C, et al. 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 Investig. 1993;69(4):415–29.

    CAS  PubMed  Google Scholar 

  7. Keane MM, Ettenberg SA, Lowrey GA, Russell EK, Lipkowitz S. Fas expression and function in normal and malignant breast cell lines. Cancer Res. 1996;56(20):4791–8.

    CAS  PubMed  Google Scholar 

  8. Gupta S, Su H, Bi R, Agrawal S, Gollapudi S. Life and death of lymphocytes: a role in immunesenescence. Immun Ageing. 2005;2:12. doi:10.1186/1742-4933-2-12.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Martinez-Lorenzo MJ, Anel A, Gamen S, Monle NI, Lasierra P, Larrad L. Activated human T cells release bioactive Fas ligand and APO2 ligand in microvesicles. J Immunol. 1999;163(3):1274–81.

    CAS  PubMed  Google Scholar 

  10. Monleon I, Martinez-Lorenzo MJ, Monteagudo L, Lasierra P, Taules M, Iturralde M, et al. Differential secretion of Fas ligand- or APO2 ligand/TNF-related apoptosis-inducing ligand-carrying microvesicles during activation-induced death of human T cells. J Immunol. 2001;167(12):6736–44.

    Article  CAS  PubMed  Google Scholar 

  11. Kim JW, Wieckowski E, Taylor DD, Reichert TE, Watkins S, Whiteside TL. Fas ligand-positive membranous vesicles isolated from sera of patients with oral cancer induce apoptosis of activated T lymphocytes. Clin Cancer Res: Off J Am Assoc Cancer Res. 2005;11(3):1010–20.

    CAS  Google Scholar 

  12. Penna A, Khadra N, Tauzin S, Vacher P, Legembre P. The CD95 signaling pathway: to not die and fly. Commun Integr Biol. 2012;5(2):190–2. doi:10.4161/cib.18888.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Lu L, Qian S, Hershberger PA, Rudert WA, Lynch DH, Thomson AW. Fas ligand (CD95L) and B7 expression on dendritic cells provide counter-regulatory signals for T cell survival and proliferation. J Immunol. 1997;158(12):5676–84.

    CAS  PubMed  Google Scholar 

  14. Hamann KJ, Dorscheid DR, Ko FD, Conforti AE, Sperling AI, Rabe KF, et al. Expression of Fas (CD95) and FasL (CD95L) in human airway epithelium. Am J Respir Cell Mol Biol. 1998;19(4):537–42. doi:10.1165/ajrcmb.19.4.3100.

    Article  CAS  PubMed  Google Scholar 

  15. Walczak H. Death receptor-ligand systems in cancer, cell death, and inflammation. Cold Spring Harbor Perspect Biol. 2013;5(5):a008698. doi:10.1101/cshperspect.a008698.

    Article  Google Scholar 

  16. Tanaka M, Suda T, Haze K, Nakamura N, Sato K, Kimura F, et al. Fas ligand in human serum. Nat Med. 1996;2(3):317–22.

    Article  CAS  PubMed  Google Scholar 

  17. Gillis S, Watson J. Biochemical and biological characterization of lymphocyte regulatory molecules. V. Identification of an interleukin 2-producing human leukemia T cell line. J Exp Med. 1980;152(6):1709–19.

    Article  CAS  PubMed  Google Scholar 

  18. Weis M, Schlegel J, Kass GE, Holmstrom TH, Peters I, Eriksson J, et al. Cellular events in Fas/APO-1-mediated apoptosis in JURKAT T lymphocytes. Exp Cell Res. 1995;219(2):699–708. doi:10.1006/excr.1995.1281.

    Article  CAS  PubMed  Google Scholar 

  19. Martinez-Lorenzo MJ, Alava MA, Anel A, Pineiro A, Naval J. Release of preformed Fas ligand in soluble form is the major factor for activation-induced death of Jurkat T cells. Immunology. 1996;89(4):511–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Peter ME, Dhein J, Ehret A, Hellbardt S, Walczak H, Moldenhauer G, et al. APO-1 (CD95)-dependent and -independent antigen receptor-induced apoptosis in human T and B cell lines. Int Immunol. 1995;7(11):1873–7.

    Article  CAS  PubMed  Google Scholar 

  21. Juo P, Woo MS, Kuo CJ, Signorelli P, Biemann HP, Hannun YA, et al. FADD is required for multiple signaling events downstream of the receptor Fas. Cell Growth Diff: Molec Biol J Am Assoc Cancer Res. 1999;10(12):797–804.

    CAS  Google Scholar 

  22. Juo P, Kuo CJ, Yuan J, Blenis J. Essential requirement for caspase-8/FLICE in the initiation of the Fas-induced apoptotic cascade. Curr Biol: CB. 1998;8(18):1001–8.

    Article  CAS  PubMed  Google Scholar 

  23. Sedgwick E. The breast ultrasound lexicon: breast imaging reporting and data system (BI-RADS). Semin Roentgenol. 2011;46(4):245–51. doi:10.1053/j.ro.2011.04.001.

    Article  PubMed  Google Scholar 

  24. Sheen-Chen SM, Chen HS, Eng HL, Chen WJ. Circulating soluble Fas in patients with breast cancer. World J Surg. 2003;27(1):10–3. doi:10.1007/s00268-002-6378-5.

    Article  PubMed  Google Scholar 

  25. Hewala TI, Abd El-Monaim NA, Anwar M, Ebied SA. The clinical significance of serum soluble Fas and p53 protein in breast cancer patients: comparison with serum CA 15-3. Pathol Oncol Res. 2012;18(4):841–8. doi:10.1007/s12253-012-9512-1.

    Article  CAS  PubMed  Google Scholar 

  26. Kato K, Ohshima K, Ishihara S, Anzai K, Suzumiya J, Kikuchi M. Elevated serum soluble Fas ligand in natural killer cell proliferative disorders. Br J Haematol. 1998;103(4):1164–6.

    Article  CAS  PubMed  Google Scholar 

  27. Mizutani Y, Hongo F, Sato N, Ogawa O, Yoshida O, Miki T. Significance of serum soluble Fas ligand in patients with bladder carcinoma. Cancer. 2001;92(2):28–93.

    Article  Google Scholar 

  28. Mizutani Y, Hongo F, Sato N, Ogawa O, Yoshida O, Miki T. Significance of serum soluble Fas ligand in patients with bladder carcinoma. Cancer. 2001;45(3):199–204.

    Google Scholar 

  29. Malleter M, Tauzin S, Bessede A, Castellano R, Goubard A, Godey F, et al. CD95L cell surface cleavage triggers a prometastatic signaling pathway in triple-negative breast cancer. Cancer Res. 2013;73(22):6711–21. doi:10.1158/0008-5472.CAN-13-1794.

    Article  CAS  PubMed  Google Scholar 

  30. Koncz G, Hancz A, Chakrabandhu K, Gogolak P, Kerekes K, Rajnavolgyi E, et al. Vesicles released by activated T cells induce both Fas-mediated RIP-dependent apoptotic and Fas-independent nonapoptotic cell deaths. J Immunol. 2012;189(6):2815–23. doi:10.4049/jimmunol.1102827.

    Article  CAS  PubMed  Google Scholar 

  31. Barnhart BC, Legembre P, Pietras E, Bubici C, Franzoso G, Peter ME. CD95 ligand induces motility and invasiveness of apoptosis-resistant tumor cells. EMBO J. 2004;23(15):3175–85. doi:10.1038/sj.emboj.7600325.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Chen L, Park SM, Tumanov AV, Hau A, Sawada K, Feig C, et al. CD95 promotes tumour growth. Nature. 2010;465(7297):492–6. doi:10.1038/nature09075.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. LA OR, Tai L, Lee L, Kruse EA, Grabow S, Fairlie WD, et al. Membrane-bound Fas ligand only is essential for Fas-induced apoptosis. Nature. 2009;461(7264):659–63. doi:10.1038/nature08402.

    Article  Google Scholar 

  34. Kern P, Dietrich M, Hemmer C, Wellinghausen N. Increased levels of soluble Fas ligand in serum in Plasmodium falciparum malaria. Infect Immun. 2000;68(5):3061–3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Sugita S, Taguchi C, Takase H, Sagawa K, Sueda J, Fukushi K, et al. Soluble Fas ligand and soluble Fas in ocular fluid of patients with uveitis. Br J Ophthalmol. 2000;84(10):1130–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Abe R, Shimizu T, Shibaki A, Nakamura H, Watanabe H, Shimizu H. Toxic epidermal necrolysis and Stevens-Johnson syndrome are induced by soluble Fas ligand. Am J Pathol. 2003;162(5):1515–20. doi:10.1016/S0002-9440(10)64284-8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Holm AM, Tjonnfjord G, Yndestad A, Beiske K, Muller F, Aukrust P, et al. Polyclonal expansion of large granular lymphocytes in common variable immunodeficiency - association with neutropenia. Clin Exp Immunol. 2006;144(3):418–24. doi:10.1111/j.1365-2249.2006.03086.x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Nabipour I, Kalantarhormozi M, Assadi M, Jafari SM, Gharibi M, Ahmadi E, et al. Influence of levothyroxine treatment on serum levels of soluble Fas (CD95) and Fas Ligand (CD95L) in chronic autoimmune hypothyroidism. Endocrine. 2010;38(3):406–11. doi:10.1007/s12020-010-9401-x.

    Article  CAS  PubMed  Google Scholar 

  39. Paunel-Gorgulu A, Flohe S, Scholz M, Windolf J, Logters T. Increased serum soluble Fas after major trauma is associated with delayed neutrophil apoptosis and development of sepsis. Crit Care. 2011;15(1):R20. doi:10.1186/cc9965.

    Article  PubMed  PubMed Central  Google Scholar 

  40. D’Agostino S, Salamone M, Di Liegro I, Vittorelli ML. Membrane vesicles shed by oligodendroglioma cells induce neuronal apoptosis. Int J Oncol. 2006;29(5):1075–85.

    PubMed  Google Scholar 

  41. Bergmann C, Strauss L, Wieckowski E, Czystowska M, Albers A, Wang Y, et al. Tumor-derived microvesicles in sera of patients with head and neck cancer and their role in tumor progression. Head Neck. 2009;31(3):371–80. doi:10.1002/hed.20968.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Arbuckle E, Langlois NE, Eremin O, Heys SD. Evidence for Fas counter attack in vivo from a study of colorectal cancer. Oncol Rep. 2000;7(1):45–7.

    CAS  PubMed  Google Scholar 

  43. Debatin KM. CD95 system counter attack and prognostic impact. Onkologie. 2006;29(8-9):358–9. doi:10.1159/000094698.

    PubMed  Google Scholar 

  44. Hefler L, Mayerhofer K, Nardi A, Reinthaller A, Kainz C, Tempfer C. Serum soluble Fas levels in ovarian cancer. Obstet Gynecol. 2000;96(1):65–9.

    CAS  PubMed  Google Scholar 

  45. Furuya Y, Nagakawa O, Fuse H. Prognostic significance of serum soluble Fas level and its change during regression and progression of advanced prostate cancer. Endocr J. 2003;50(5):629–33.

    Article  PubMed  Google Scholar 

  46. Abbasova SG, Vysotskii MM, Ovchinnikova LK, Obusheva MN, Digaeva MA, Britvin TA, et al. Cancer and soluble FAS. Bull Exp Biol Med. 2009;148(4):638–42.

    Article  CAS  PubMed  Google Scholar 

  47. Aguilar-Lemarroy A, Romero-Ramos JE, Olimon-Andalon V, Hernandez-Flores G, Lerma-Diaz JM, Ortiz-Lazareno PC, et al. Apoptosis induction in Jurkat cells and sCD95 levels in women’s sera are related with the risk of developing cervical cancer. BMC Cancer. 2008;8:99. doi:10.1186/1471-2407-8-99.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

VOA is grateful for the scholarship obtained from CONACyT Mexico. We are very grateful to Leticia Ramos-Zavala for her efficient technical support in the laboratory. This work was supported by the Fondo de Investigación en Salud, IMSS (grants FIS/IMSS/PROT/G10/874 to AAL and FIS/IMSS/PROT/G09/744 to LFJS).

Conflicts of interest

None

Author information

Authors and Affiliations

  1. Escuela de Biología, Universidad Autónoma de Sinaloa, Culiacán, Sinaloa, Mexico

    Vicente Olimón-Andalón

  2. Programa de Doctorado en Ciencias Biomédicas, Centro Universitario de Ciencias de la Salud (CUCS), Universidad de Guadalajara, Guadalajara, Jalisco, Mexico

    Vicente Olimón-Andalón

  3. División de Inmunología, Centro de Investigación Biomédica de Occidente (CIBO), Instituto Mexicano del Seguro Social (IMSS), Sierra Mojada No. 800, Col. Independencia, 44340, Guadalajara, Jalisco, México

    Adriana Aguilar-Lemarroy, Sarah Ratkovich-González, Aida Uribe-López, Pablo Ortiz-Lazareno, Georgina Hernández-Flores, Ruth de Celis, Alejandro Bravo-Cuellar & Luis F. Jave-Suárez

  4. UMAE Hospital de Especialidades del Centro Médico Nacional de Occidente, IMSS, Guadalajara, Jalisco, Mexico

    Ignacio Mariscal-Ramírez & Raúl Delgadillo-Cristerna

Authors
  1. Vicente Olimón-Andalón
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Adriana Aguilar-Lemarroy
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sarah Ratkovich-González
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Aida Uribe-López
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ignacio Mariscal-Ramírez
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Raúl Delgadillo-Cristerna
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Pablo Ortiz-Lazareno
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Georgina Hernández-Flores
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Ruth de Celis
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Alejandro Bravo-Cuellar
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Luis F. Jave-Suárez
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Luis F. Jave-Suárez.

Additional information

Vicente Olimón-Andalón and Adriana Aguilar-Lemarroy participated equally.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Olimón-Andalón, V., Aguilar-Lemarroy, A., Ratkovich-González, S. et al. Proapoptotic CD95L levels in normal human serum and sera of breast cancer patients. Tumor Biol. 36, 3669–3678 (2015). https://doi.org/10.1007/s13277-014-3005-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13277-014-3005-7

Keywords

Search

Navigation