Skip to main content

Advertisement

SpringerLink
Log in

A biochemical mechanism for resistance of intervertebral discs to metastatic cancer: Fas ligand produced by disc cells induces apoptotic cell death of cancer cells

  • SSE Basic Science Award
  • Published:
European Spine Journal Aims and scope Submit manuscript

Abstract

Metastatic spinal cancer is characterized by the maintenance of normal disc structure until the vertebral body is severely destroyed by cancer cells. Anatomic features of the discs have been thought to be the main factor which confer the discs their resistance to metastatic cancer. However, little is known about the biochemical mechanism to prevent or attenuate the local infiltration of cancer cells into the discs. The purpose of this study was to investigate whether Fas ligand (FasL) produced by disc cells can kill Fas-bearing breast cancer cells by Fas and FasL interaction. Two human breast cancer cells (MCF-7 and MDA-MB-231) were obtained and cultured (1 × 106 cells/well), and the expression of Fas was investigated by western blot analysis. Annulus fibrosus cells were isolated and cultured, and the presence of FasL was quantified in the supernatants of three different numbers of annulus fibrosus cells (1×, 2×, and 4 × 106 cells/well) by ELISA assay. The MCF-7 and MDA-MB-231 cancer cells were cultured with supernatants of annulus fibrosus cells for 48 h. As controls, MCF-7 and MDA-MB-231 cancer cells were also cultured by themselves for 48 h. Finally, we determined and quantified the apoptosis rates of MCF-7 and MDA-MB-231 cancer cells by Annexin V–FITC and PI and TUNEL at 48 h, respectively. The expression of Fas was identified in MCF-7 and MDA-MB-231 cancer cells. The mean concentrations of FasL in supernatants of annulus fibrosus cells (1×, 2×, and 4 × 106 cells/well) were 10.8, 29.6, and 56.4 pg/mL, respectively. After treatment with the supernatant of three different numbers of annulus fibrosus cells, the mean apoptosis rate of MCF-7 cancer cells was increased (2.8%, P < 0.01; 6.7%, P < 0.001; 31.0%, P < 0.001) in a dose-dependent manner of FasL compared to that of control (1.1%). The mean apoptosis rate of MDA-MB-231 cancer cells was also increased (5.7%, P < 0.01; 11.1%, P < 0.001; 25.3%, P < 0.001) in a dose-dependent manner of FasL compared to that of control (2.1%). TUNEL also demonstrated direct evidence of apoptoses of MCF-7 and MDA-MB-231 cancer cells. Our results demonstrate that Fas-bearing cancer cells undergo apoptosis by FasL produced by disc cells, which may be considered as a potential biochemical explanation for the disc’s resistance to metastatic cancer.

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

Similar content being viewed by others

References

  1. Asdourian PL, Weidenbaum M, DeWald RL, et al (1990) The pattern of vertebral involvement in metastatic vertebral breast cancer. Clin Orthop 250:164–170

    PubMed  Google Scholar 

  2. Batson OV (1940) The function of the vertebral veins and their role ion the spread of metastases. Ann Surg 112:138–149

    Article  Google Scholar 

  3. Berrettoni BA, Carter JR (1986) Current concepts review: mechanisms of cancer metastasis to bone. J Bone Joint Surg Am 68:308–312

    PubMed  CAS  Google Scholar 

  4. Boland PJ, Lane JM, Sundaresan N (1982) Metastatic disease of the spine. Clin Orthop 169:95–102

    PubMed  Google Scholar 

  5. Dunne AA, Grobe A, Sesterhenn AM, et al (2005) Influence of matrix metalloproteinase 9 (MMP-9) on the metastatic behavior of oropharyngeal cancer. Anticancer Res 25:4129–4134

    PubMed  CAS  Google Scholar 

  6. Fujita T, Ueda Y, Kawahara N, et al (1997) Local spread of metastatic vertebral tumors: a histologic study. Spine 22:1905–1912

    Article  PubMed  CAS  Google Scholar 

  7. Griffith TS, Brunner T, Fletcher SM, et al (1995) Fas ligand-induced apoptosis as a mechanism of immune privilege. Science 270:1189–1192

    Article  PubMed  CAS  Google Scholar 

  8. Griffith TS, Ferguson TA (1997) The role of FasL-induced apoptosis in immune privilege. Immunol Today 18:240–244

    Article  PubMed  CAS  Google Scholar 

  9. Gruber HE, Ashraf N, Kilburn J, et al (2005) Vertebral endplate architecture and vascularization: application of micro-computerized tomography, a vascular tracer, and immunocytochemistry in analyses of disc degeneration in the aging sand rat. Spine 30:2593–2600

    Article  PubMed  Google Scholar 

  10. Harrington KD (1986) Metastatic disease of the spine. J Bone Joint Surg Am 68:1110–1115

    PubMed  CAS  Google Scholar 

  11. Kamat AA, Fletcher M, Gruman LM, et al (2006) The clinical relevance of stromal matrix metalloproteinase expression in ovarian cancer. Clin Cancer Res 12:1707–1714

    Article  PubMed  CAS  Google Scholar 

  12. Kauppila LI (1995) Ingrowth of blood vessels in disc degeneration. Angiographic and histological studies of Cadaveric spines. J Bone Joint Surg Am 77:26–31

    PubMed  CAS  Google Scholar 

  13. Krishnamurthy GT, Tubis M, Hiss J, et al (1977) Distribution pattern of metastatic bone disease: a need for total body skeletal image. JAMA 237:2504–2506

    Article  PubMed  CAS  Google Scholar 

  14. Langer R, Brem H, Falterman K, et al (1976) Isolation of a cartilage factor that inhibits tumor neovascularization. Science 193:70–72

    Article  PubMed  CAS  Google Scholar 

  15. Müllauer L, Mosberger I, Grusch M, et al (2000) Fas ligand is expressed in normal breast epithelial cells and is frequently up-regulated in breast cancer. J Pathol 190:20–30

    Article  PubMed  Google Scholar 

  16. Muneta Y, Shimoji Y, Inumaru S, et al (2001) Molecular cloning, characterization, and expression of porcine Fas ligand (CD95 Ligand). J Interferon Cytokine Res 21:305–312

    Article  PubMed  CAS  Google Scholar 

  17. Nikkola J, Vihinen P, Vuoristo MS, et al (2005) High serum levels of matrix metalloproteinase-9 and matrix metalloproteinase-1 are associated with rapid progression in patients with metastatic melanoma. Clin Cancer Res 11:5158–5166

    Article  PubMed  CAS  Google Scholar 

  18. Nishida K, Kang JD, Gilbertson LG, et al (1999) Modulation of the biologic activity of the rabbit intervertebral disc by gene therapy: an in vivo study of adenovirus-mediated transfer of the human transforming growth factor beta 1 encoding gene. Spine 24:2419–2425

    Article  PubMed  CAS  Google Scholar 

  19. Park JB, Chang H, Kim KW (2001) Expression of Fas ligand and apoptosis of disc cells in herniated lumbar disc tissue. Spine 26:618–621

    Article  PubMed  CAS  Google Scholar 

  20. Reichmann E (2002) The biological role of the Fas/FasL system during tumor formation and progression. Cancer Biol 12:309–315

    Article  CAS  Google Scholar 

  21. Roberts S, Evans H, Trivedi J, et al (2006) Histology and pathology of the human intervertebral disc. J Bone Joint Surg Am 88:S10–S14

    Article  Google Scholar 

  22. Schneider P, Holler N, Bodmer JL, et al (1998) 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 187:1205–1213

    Article  PubMed  CAS  Google Scholar 

  23. Sprague JE, LI QP, Liang K, et al (2006) In vitro and in vivo investigation of matrix metalloproteinase expression in metastatic tumor models. Nucl Med Biol 33:227–237

    Article  PubMed  CAS  Google Scholar 

  24. Suda T, Nagata S (1994) Purification and characterization of the Fas-ligand that induces apoptosis. J Exp Med 179:873–879

    Article  PubMed  CAS  Google Scholar 

  25. Takada T, Nishida K, Doita M, et al (2002) Fas ligand expression on intervertebral disc cells: a potential molecular mechanism for immune privileged of the disc. Spine 27:1526–1530

    Article  PubMed  Google Scholar 

  26. Takahashi T, Tanaka M, Inazawa J, et al (1994) Human Fas ligand: gene structure, chromosomal location and species specificity. Int Immunol 6:1567–1574

    Article  PubMed  CAS  Google Scholar 

  27. Tanaka M, Itai T, Adachi M, et al (1998) Downregulation of Fas ligand by shedding. Nat Med 4:31–36

    Article  PubMed  CAS  Google Scholar 

  28. Tsuyuki S, Kono M, Bloom ET (2002) Cloning and potential utility of porcine Fas ligand: overexpression in porcine endothelial cells protects them from attack by human cytolytic cells. Xenotransplantation 9:410–421

    Article  PubMed  Google Scholar 

  29. Urban JP, Smith S, Fairbank JC (2004) Nutrition of the intervertebral disc. Spine 29:2700–2709

    Article  PubMed  Google Scholar 

  30. Yasuma T, Yamauchi Y, Arai K, et al (1989) Histopathologic study on tumor infiltration into the intervertebral disc. Spine 14:1245–1248

    Article  PubMed  CAS  Google Scholar 

  31. Younes M, Schwartz MR, Ertan A, et al (2000) Fas ligand expression in esophageal carcinomas and their lymph node metastases. Cancer 88:524–528

    Article  PubMed  CAS  Google Scholar 

  32. Yuh WTC, Quets JP, Lee HJ, et al (1996) Anatomic distribution of metastases in the vertebral body and modes of hematogenous spread. Spine 21:2243–2250

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Orthopaedic Surgery, The Catholic University of Korea School of Medicine, Uijongbu-si, Kyunggi-do, 480-717, South Korea

    Jong-Beom Park, Sung-Tae Cho & Eun-Young Park

  2. Department of Laboratory Medicine, Korea Cancer Center Hospital, Seoul, South Korea

    Jin-Kyung Lee

  3. Department of Orthopaedic Surgery, Washington University School of Medicine, St Louis, MO, USA

    K. Daniel Riew

Authors
  1. Jong-Beom Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jin-Kyung Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sung-Tae Cho
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Eun-Young Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. K. Daniel Riew
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jong-Beom Park.

Additional information

This is the EuroSpine Winning Paper 2007 on Basic Science.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Park, JB., Lee, JK., Cho, ST. et al. A biochemical mechanism for resistance of intervertebral discs to metastatic cancer: Fas ligand produced by disc cells induces apoptotic cell death of cancer cells. Eur Spine J 16, 1319–1324 (2007). https://doi.org/10.1007/s00586-007-0463-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00586-007-0463-2

Keywords

Search

Navigation