Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Short Report
  • Published:

Cleavage of CD95 by matrix metalloproteinase-7 induces apoptosis resistance in tumour cells

Oncogene volume 23, pages 3732–3736 (2004)Cite this article

Abstract

The ability of tumour cells to resist apoptosis-inducing signals by cytotoxic T cells may decide the success or failure of tumour elimination. An important effector of apoptosis is the CD95/CD95 ligand system (APO-1/Fas) that mediates perforin-independent cytotoxic T-cell killing of tumour cells. We propose a new strategy by which tumour cells can resist CD95-induced apoptosis. We identified matrix metalloproteinase-7, MMP-7 (Martilysin), as the first physiologically relevant protease that can specifically cleave CD95. MMP-7 is of unique importance because it is produced by the tumour cells themselves at early stages of tumour development. Microsequencing of the positions in CD95 cleaved by MMP-7 revealed two sites in the N-terminal extracellular domain of CD95, important for preligand assembly of CD95. MMP-7 cleavage of CD95 results in reduced CD95 surface expression and decreased CD95-mediated apoptosis sensitivity of tumour cells. Treatment of MMP-7-positive HT-29 tumour cells with MMP-7-antisense oligonucleotides led to an increase in CD95-mediated apoptosis sensitivity. Finally, specific cytotoxic T-cell killing was reduced in the presence of MMP-7. Thus, MMP-7 expression in tumour cells may contribute to an apoptosis-resistant phenotype, which ultimately promotes immune escape. This activity may account for the well-established role of MMP-7 in early tumour development.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3

Similar content being viewed by others

References

  • Dunn GP, Bruce AT, Ikeda H, Old LJ and Schreiber RD . (2002). Nat. Immunol., 3, 991–998.

  • Egeblad M and Werb Z . (2002). Nat. Rev. Cancer, 161–174.

  • Fingleton B, Vargo-Gogola T, Crawford HC and Matrisian LM . (2001). Neoplasia, 6, 459–468.

  • Galle PR, Hofmann WJ, Walczak H, Schaller H, Otto G, Stremmel W, Krammer PH and Runkel L . (1995). J. Exp. Med., 182, 1223–1230.

  • Galle PR and Krammer PH . (1998). Sem. Liv. Dis., 18, 141–151.

  • Khong HT and Restifo NP . (2002). Nat. Immunol., 3, 999–1005.

  • Kondo T, Suda T, Fukuyama H, Adachi M and Nagata S . (1997). Nat. Med., 3, 409–413.

  • Krammer PH . (2000). Nature, 407, 789–795.

  • Lustgarten J, Theobald M, Labadie C, Laface D, Peterson P, Disis ML, Cheever MA and Sherman LA . (1997). Hum. Immunol., 52, 109–118.

  • Medema JP, de Jong J, Hall, TV, Melief CJ and Offringa R . (1999). J.Exp. Med., 190, 1033–1037.

  • Mitsiades N, Yu W, Poulaki V, Tsokos M and Stamenkovic I . (2001). Cancer Res., 61, 577–581.

  • Mizutani Y, Hongo F, Sato N, Ogawa O, Yoshida O and Miki T . (2001). Cancer, 15, 287–293.

  • Nicoletti I, Miglioratic G, Paggliacci MC, Grignani F and Riccardi CA . (1991). J. Immunol. Methods, 139, 271–279.

  • Nonomura N, Nishimura K, Ono Y, Fukui T, Harada Y, Takaha N, Takahara S and Okuyama A . (2000). Urology, 55, 151–155.

  • Osorio LM, Aguilar-Santelises M, De Santiago A, Hachiya T, Mellstedt H and Jondal M . (2001). Eur. J. Haematol., 66, 342–346.

  • Pikul S, McDow Dunham KL, Almstead NG, De B, Natchus MG, Anastasio MV, McPhail SJ, Snider CE, Taiwo YO, Rydel T, Dunaway CM, Gu F and Mieling GE . (1998). J. Med. Chem., 41, 3568–3571.

  • Powell WC, Fingleton B, Wilson CL, Boothby M and Matrisian LM . (1999). Curr. Biol., 24, 1441–1447.

  • Rosenberg SA . (1999). Immunity, 10, 281–287.

  • Rudolph-Owen LA, Chan R, Muller WJ and Matrisian LM . (1998). Cancer Res., 58, 5500–5506.

  • Seki N, Brooks A, Carter C, Back T, Parsoneault E, Smyth M, Wiltrout R and Sayers T . (2002). J. Immunol., 168, 3484–3492.

  • Shresta S, Pham CT, Thomas DA, Grauber TA and Ley TJ . (1998). Curr. Opin. Immunol., 10, 581–587.

  • Siegel RM, Frederiksen JK, Zacharias DA, Chan FK, Johnson M, Lynch D, Tsien RY and Lenardo MJ . (2000). Science, 288, 2354–2357.

  • Strand S, Hofmann WJ, Grambihler A, Hug H, Volkmann M, Otto G, Wesch H, Mariani SM, Hack V, Stremmel W, Krammer PH and Galle PR . (1998). Nat. Med., 4, 588–593.

  • Strand S, Hofmann WJ, Hug H, Müller M, Otto G, Strand D, Stremmel W, Krammer PH and Galle PR . (1996). Nat. Med., 2, 1361–1367.

  • Tanaka M, Itai T, Adachi M and Nagata S . (1998). Nat. Med., 1, 31–36.

  • Theobald M, Biggs J, Dittmer D, Levine AJ and Sherman LA . (1995). Proc. Natl. Acad. Sci. USA, 92, 11993–11997.

  • Ugurel S, Rappl G, Tilgen W and Reinhold U . (2001). Clin. Cancer Res., 7, 1282–1286.

  • Vargo-Gogola T, Fingleton B, Crawford HC and Matrisian LM . (2002). Cancer Res., 62, 5559–5563.

  • Wilson CL, Heppner KJ, Labosky PA, Hogan BL and Matrisian LM . (1997). Proc. Natl. Acad. Sci. USA, 94, 1402–1407.

  • Woessner JF and Nagase H (eds) (2000). Matrix Metalloproteinases and TIMPs. Oxford University Press, Inc.: New York.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. I. Department of Internal Medicine, Johannes Gutenberg University, Obere Zahlbacherstr. 63, Mainz, 55101, Germany

    Susanne Strand, Petra Vollmer, Lothar van den Abeelen, Daniela Gottfried, Vijay Alla, Peter R Galle & Dennis Strand

  2. Department of Cell Biology, German Cancer Research Center, Heidelberg, 69120, Germany

    Hans Heid

  3. Department of Hematology and Oncology, Johannes Gutenberg University, Mainz, 55101, Germany

    Jürgen Kuball & Matthias Theobald

Authors
  1. Susanne Strand
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Petra Vollmer
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Lothar van den Abeelen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Daniela Gottfried
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Vijay Alla
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hans Heid
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jürgen Kuball
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Matthias Theobald
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Peter R Galle
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Dennis Strand
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Susanne Strand.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Strand, S., Vollmer, P., van den Abeelen, L. et al. Cleavage of CD95 by matrix metalloproteinase-7 induces apoptosis resistance in tumour cells. Oncogene 23, 3732–3736 (2004). https://doi.org/10.1038/sj.onc.1207387

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1207387

Keywords

This article is cited by

Search

Advanced search

Quick links