Skip to main content

Advertisement

SpringerLink
Log in

TIMP-1-GPI in combination with hyperthermic treatment of melanoma increases sensitivity to FAS-mediated apoptosis

  • Original Article
  • Published:
Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

Abstract

Resistance to apoptosis is a prominent feature of malignant melanoma. Hyperthermic therapy can be an effective adjuvant treatment for some tumors including melanoma. We developed a fusion protein based on the tissue inhibitor of matrix metalloproteinase-1 linked to a glycosylphosphatidylinositol anchor (TIMP-1-GPI). The TIMP-1-GPI-fusion protein shows unique properties. Exogenous administration of TIMP-1-GPI can result in transient morphological changes to treated cells including modulation of proliferation and decreased resistance to apoptosis. The effect of TIMP-1-GPI on the biology of melanoma in the context of a defined hyperthermic dose was evaluated in vitro. Clonogenic assays were used to measure cell survival. Gelatinase zymography determined secretion of MMP-2 and MMP-9. Monoclonal antibody against FAS/CD95 was applied to induce apoptosis. The expression of pro- and anti-apoptotic proteins and the secretion of immunoregulatory cytokines were then evaluated using Western blot and ELISA. TIMP-1-GPI combined with a sub-lethal hyperthermic treatment (41.8°C for 2 h) suppressed tumor cell growth capacity as measured by clonogenic assay. The co-treatment also significantly suppressed tumor cell proliferation, enhanced FAS receptor surface expression increased tumor cell susceptibility to FAS-mediated killing. The increased sensitivity to FAS-induced apoptosis was linked to alterations in the apoptotic mediators Bcl-2, Bax, Bcl-XL and Apaf-1. The agent works in concert with sub-lethal hyperthermic treatment to render melanoma cells sensitive to FAS killing. The targeted delivery of TIMP-1-GPI to tumor environments in the context of regional hyperthermic therapy could be optimized through the use of thermosensitive liposomes.

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. Egeblad M, Werb Z (2002) New functions for the matrix metalloproteinases in cancer progression. Nat Rev Cancer 2(3):161–174

    Article  PubMed  CAS  Google Scholar 

  2. Itoh Y, Nagase H (2002) Matrix metalloproteinases in cancer. Essays Biochem 38:21–36

    PubMed  CAS  Google Scholar 

  3. Bode W, Maskos K (2003) Structural basis of the matrix metalloproteinases and their physiological inhibitors, the tissue inhibitors of metalloproteinases. Biol Chem 384(6):863–872

    Article  PubMed  CAS  Google Scholar 

  4. Nagase H, Woessner JF Jr (1999) Matrix metalloproteinases. J Biol Chem 274(31):21491–21494

    Article  PubMed  CAS  Google Scholar 

  5. Brew K, Dinakarpandian D, Nagase H (2000) Tissue inhibitors of metalloproteinases: evolution, structure and function. Biochim Biophys Acta 1477(1–2):267–283

    PubMed  CAS  Google Scholar 

  6. Klier CM, Nelson EL, Cohen CD, Horuk R, Schlondorff D, Nelson PJ (2001) Chemokine-induced secretion of gelatinase B in primary human monocytes. Biol Chem 382(9):1405–1410

    Article  PubMed  CAS  Google Scholar 

  7. Sorensen NM, Bystrom P, Christensen IJ, Berglund A, Nielsen HJ, Brunner N, Glimelius B (2007) TIMP-1 is significantly associated with objective response and survival in metastatic colorectal cancer patients receiving combination of irinotecan, 5-fluorouracil, and folinic acid. Clin Cancer Res 13(14):4117–4122

    Article  PubMed  CAS  Google Scholar 

  8. Brand K (2002) Cancer gene therapy with tissue inhibitors of metalloproteinases (TIMPs). Curr Gene Ther 2(2):255–271

    Article  PubMed  CAS  Google Scholar 

  9. Chirco R, Liu XW, Jung KK, Kim HR (2006) Novel functions of TIMPs in cell signaling. Cancer Metastasis Rev 25(1):99–113

    Article  PubMed  CAS  Google Scholar 

  10. Medof ME, Nagarajan S, Tykocinski ML (1996) Cell-surface engineering with GPI-anchored proteins. FASEB J 10(5):574–586

    PubMed  CAS  Google Scholar 

  11. Djafarzadeh R, Mojaat A, Vicente AB, von Luttichau I, Nelson PJ (2004) Exogenously added GPI-anchored tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) displays enhanced and novel biological activities. Biol Chem 385(7):655–663

    Article  PubMed  CAS  Google Scholar 

  12. Djafarzadeh R, Noessner E, Engelmann H, Schendel DJ, Notohamiprodjo M, von Luettichau I, Nelson PJ (2006) GPI-anchored TIMP-1 treatment renders renal cell carcinoma sensitive to FAS-meditated killing. Oncogene 25(10):1496–1508

    Article  PubMed  CAS  Google Scholar 

  13. Brown O, Cowen RL, Preston CM, Castro MG, Lowenstein PR (2000) Subcellular post-transcriptional targeting: delivery of an intracellular protein to the extracellular leaflet of the plasma membrane using a glycosyl-phosphatidylinositol (GPI) membrane anchor in neurons and polarised epithelial cells. Gene Ther 7(22):1947–1953

    Article  PubMed  CAS  Google Scholar 

  14. Garbe C, Eigentler TK (2007) Diagnosis, treatment of cutaneous melanoma: state of the art 2006. Melanoma Res 17(2):117–127

    Article  PubMed  Google Scholar 

  15. La Porta CA (2007) Drug resistance in melanoma: new perspectives. Curr Med Chem 14(4):387–391

    Article  PubMed  CAS  Google Scholar 

  16. Facchetti F, Previdi S, Ballarini M, Minucci S, Perego P, La Porta CA (2004) Modulation of pro- and anti-apoptotic factors in human melanoma cells exposed to histone deacetylase inhibitors. Apoptosis 9(5):573–582

    Article  PubMed  CAS  Google Scholar 

  17. Soengas MS, Lowe SW (2003) Apoptosis and melanoma chemoresistance. Oncogene 22(20):3138–3151

    Article  PubMed  CAS  Google Scholar 

  18. Overgaard J, Gonzalez Gonzalez D, Hulshof MC, Arcangeli G, Dahl O, Mella O, Bentzen SM (1995) Randomised trial of hyperthermia as adjuvant to radiotherapy for recurrent or metastatic malignant melanoma. European Society for Hyperthermic Oncology. Lancet 345(8949):540–543

    Article  PubMed  CAS  Google Scholar 

  19. van der Zee J, Gonzalez Gonzalez D, van Rhoon GC, van Dijk JD, van Putten WL, Hart AA (2000) Comparison of radiotherapy alone with radiotherapy plus hyperthermia in locally advanced pelvic tumours: a prospective, randomised, multicentre trial. Dutch Deep Hyperthermia Group. Lancet 355(9210):1119–1125

    Article  PubMed  Google Scholar 

  20. Jones EL, Oleson JR, Prosnitz LR, Samulski TV, Vujaskovic Z, Yu D, Sanders LL, Dewhirst MW (2005) Randomized trial of hyperthermia and radiation for superficial tumors. J Clin Oncol 23(13):3079–3085

    Article  PubMed  Google Scholar 

  21. Fraker DL (2004) Management of in-transit melanoma of the extremity with isolated limb perfusion. Curr Treat Options Oncol 5(3):173–184

    Article  PubMed  Google Scholar 

  22. Sanki A, Kam PC, Thompson JF (2007) Long-term results of hyperthermic, isolated limb perfusion for melanoma: a reflection of tumor biology. Ann Surg 245(4):591–596

    Article  PubMed  Google Scholar 

  23. Kampinga HH (2006) Cell biological effects of hyperthermia alone or combined with radiation or drugs: a short introduction to newcomers in the field. Int J Hyperthermia 22(3):191–196

    Article  PubMed  CAS  Google Scholar 

  24. Milani V, Frankenberger B, Heinz O, Brandl A, Ruhland S, Issels RD, Noessner E (2005) Melanoma-associated antigen tyrosinase but not Melan-A/MART-1 expression and presentation dissociate during the heat shock response. Int Immunol 17(3):257–268

    Article  PubMed  CAS  Google Scholar 

  25. Rivoltini L, Barracchini KC, Viggiano V, Kawakami Y, Smith A, Mixon A, Restifo NP, Topalian SL, Simonis TB, Rosenberg SA et al (1995) Quantitative correlation between HLA class I allele expression and recognition of melanoma cells by antigen-specific cytotoxic T lymphocytes. Cancer Res 55(14):3149–3157

    PubMed  CAS  Google Scholar 

  26. Kirby AC, Hill V, Olsen I, Porter SR (1995) LFA-3 delta D2: a novel in vivo isoform of lymphocyte function-associated antigen 3. Biochem Biophys Res Commun 214(1):200–205

    Article  PubMed  CAS  Google Scholar 

  27. Mack M, Riethmuller G, Kufer P (1995) A small bispecific antibody construct expressed as a functional single-chain molecule with high tumor cell cytotoxicity. Proc Natl Acad Sci USA 92(15):7021–7025

    Article  PubMed  CAS  Google Scholar 

  28. Overgaard J, Suit HD (1979) Time-temperature relationship the hyperthermic treatment of malignant and normal tissue in vivo. Cancer Res 39(8):3248–3253

    PubMed  CAS  Google Scholar 

  29. Issels RD, Nagele A (1990) Influence of thiols on thermosensitivity of mammalian cells in vitro. Methods Enzymol 186:696–708

    Article  PubMed  CAS  Google Scholar 

  30. Schwabe RF, Hess S, Johnson JP, Engelmann H (1997) Modulation of soluble CD40 ligand bioactivity with anti-CD40 antibodies. Hybridoma 16(3):217–226

    Article  PubMed  CAS  Google Scholar 

  31. Noessner E, Gastpar R, Milani V, Brandl A, Hutzler PJ, Kuppner MC, Roos M, Kremmer E, Asea A, Calderwood SK, Issels RD (2002) Tumor-derived heat shock protein 70 peptide complexes are cross-presented by human dendritic cells. J Immunol 169(10):5424–5432

    PubMed  CAS  Google Scholar 

  32. Dewhirst MW, Viglianti BL, Lora-Michiels M, Hanson M, Hoopes PJ (2003) Basic principles of thermal dosimetry and thermal thresholds for tissue damage from hyperthermia. Int J Hyperthermia 19(3):267–294

    Article  PubMed  CAS  Google Scholar 

  33. Ko HM, Kang JH, Jung B, Kim HA, Park SJ, Kim KJ, Kang YR, Lee HK, Im SY (2007) Critical role for matrix metalloproteinase-9 in platelet-activating factor-induced experimental tumor metastasis. Int J Cancer 120(6):1277–1283

    Article  PubMed  CAS  Google Scholar 

  34. Qu XJ, Yuan YX, Tian ZG, Xu WF, Chen MH, Cui SX, Guo Q, Gai R, Makuuchi M, Nakata M, Tang W (2006) Using caffeoyl pyrrolidine derivative LY52, a potential inhibitor of matrix metalloproteinase-2, to suppress tumor invasion and metastasis. Int J Mol Med 18(4):609–614

    PubMed  CAS  Google Scholar 

  35. Igney FH, Krammer PH (2002) Death and anti-death: tumour resistance to apoptosis. Nat Rev Cancer 2(4):277–288

    Article  PubMed  CAS  Google Scholar 

  36. Bao Q, Shi Y (2007) Apoptosome: a platform for the activation of initiator caspases. Cell Death Differ 14(1):56–65

    Article  PubMed  CAS  Google Scholar 

  37. Rothhammer T, Poser I, Soncin F, Bataille F, Moser M, Bosserhoff AK (2005) Bone morphogenic proteins are overexpressed in malignant melanoma and promote cell invasion and migration. Cancer Res 65(2):448–456

    PubMed  CAS  Google Scholar 

  38. Karsdal MA, Larsen L, Engsig MT, Lou H, Ferreras M, Lochter A, Delaisse JM, Foged NT (2002) Matrix metalloproteinase-dependent activation of latent transforming growth factor-beta controls the conversion of osteoblasts into osteocytes by blocking osteoblast apoptosis. J Biol Chem 277(46):44061–44067

    Article  PubMed  CAS  Google Scholar 

  39. Illman SA, Lehti K, Keski-Oja J, Lohi J (2006) Epilysin (MMP-28) induces TGF-beta mediated epithelial to mesenchymal transition in lung carcinoma cells. J Cell Sci 119(Pt 18):3856–3865

    Article  PubMed  CAS  Google Scholar 

  40. Polak ME, Borthwick NJ, Gabriel FG, Johnson P, Higgins B, Hurren J, McCormick D, Jager MJ, Cree IA (2007) Mechanisms of local immunosuppression in cutaneous melanoma. Br J Cancer 96(12):1879–1887

    Article  PubMed  CAS  Google Scholar 

  41. Barnhart BC, Lee JC, Alappat EC, Peter ME (2003) The death effector domain protein family. Oncogene 22(53):8634–8644

    Article  PubMed  CAS  Google Scholar 

  42. Jaattela M (2004) Multiple cell death pathways as regulators of tumour initiation and progression. Oncogene 23(16):2746–2756

    Article  PubMed  CAS  Google Scholar 

  43. Shi Y (2006) Mechanical aspects of apoptosome assembly. Curr Opin Cell Biol 18(6):677–684

    Article  PubMed  CAS  Google Scholar 

  44. Gorelik L, Flavell RA (2002) Transforming growth factor-beta in T-cell biology. Nat Rev Immunol 2(1):46–53

    Article  PubMed  CAS  Google Scholar 

  45. Gold LI (1999) The role for transforming growth factor-beta (TGF-beta) in human cancer. Crit Rev Oncog 10(4):303–360

    PubMed  CAS  Google Scholar 

  46. Peng Y, Gorelik L, Laouar Y, Li MO, Flavell RA (2006) TGFbeta-mediated immunoregulation. Ernst Schering Res Found Workshop, (56):155–60

  47. Conti P, Kempuraj D, Kandere K, Di Gioacchino M, Barbacane RC, Castellani ML, Felaco M, Boucher W, Letourneau R, Theoharides TC (2003) IL-10, an inflammatory/inhibitory cytokine, but not always. Immunol Lett 86(2):123–129

    Article  PubMed  CAS  Google Scholar 

  48. Lauw FN, Pajkrt D, Hack CE, Kurimoto M, van Deventer SJ, van der Poll T (2000) Proinflammatory effects of IL-10 during human endotoxemia. J Immunol 165(5):2783–2789

    PubMed  CAS  Google Scholar 

  49. Santin AD, Hermonat PL, Ravaggi A, Bellone S, Pecorelli S, Roman JJ, Parham GP, Cannon MJ (2000) Interleukin-10 increases Th1 cytokine production and cytotoxic potential in human papillomavirus-specific CD8(+) cytotoxic T lymphocytes. J Virol 74(10):4729–4737

    Article  PubMed  CAS  Google Scholar 

  50. Sharma D, Chelvi TP, Kaur J, Ralhan R (1998) Thermosensitive liposomal taxol formulation: heat-mediated targeted drug delivery in murine melanoma. Melanoma Res 8(3):240–244

    Article  PubMed  CAS  Google Scholar 

  51. Han HD, Choi MS, Hwang T, Song CK, Seong H, Kim TW, Choi HS, Shin BC (2006) Hyperthermia-induced antitumor activity of thermosensitive polymer modified temperature-sensitive liposomes. J Pharm Sci 95(9):1909–1917

    Article  PubMed  CAS  Google Scholar 

  52. Minko T, Pakunlu RI, Wang Y, Khandare JJ, Saad M (2006) New generation of liposomal drugs for cancer. Anticancer Agents Med Chem 6(6):537–552

    Article  PubMed  CAS  Google Scholar 

  53. Noorda EM, Vrouenraets BC, Nieweg OE, Klaase JM, van der Zee J, Kroon BB (2003) Long-term results of a double perfusion schedule using high dose hyperthermia and melphalan sequentially in extensive melanoma of the lower limb. Melanoma Res 13(4):395–399

    Article  PubMed  CAS  Google Scholar 

  54. Robins HI, D’Oleire F, Grosen E, Spriggs D (1997) Rationale and clinical status of 41.8 degrees C systemic hyperthermia tumor necrosis factor, and melphalan for neoplastic disease. Anticancer Res 17(4B):2891–2894

    PubMed  CAS  Google Scholar 

  55. Pagani E, Falcinelli S, Pepponi R, Turriziani M, Caporaso P, Caporali S, Bonmassar E, D’Atri S (2007) Combined effect of temozolomide and hyperthermia on human melanoma cell growth and O6-methylguanine-DNA methyltransferase activity. Int J Oncol 30(2):443–451

    PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The work described here was supported by DFG grant NE 648/2-3 to PJN, SFB 455 to EN, SFB-TR36 to PJN and EN, and by a grant from the Sanitätsrat Emil Hübner Stiftung to IvL.

Author information

Authors and Affiliations

  1. Medizinische Poliklinik, Ludwig-Maximilians-Universität München, Schillerstrasse 42, 80336, Munich, Germany

    Roghieh Djafarzadeh, Nicole Rieth, Irene von Luettichau, Monika Hofstetter & Peter J. Nelson

  2. Medical Clinic III, Ludwig-Maximilians-University of Munich, Munich, Germany

    Valeria Milani

  3. Department of Paediatrics, Technical University, Munich, Germany

    Irene von Luettichau

  4. Helmholz Zentrum Munich-Institute of Molecular Immunology, Munich, Germany

    Petra S. Skrablin & Elfriede Noessner

Authors
  1. Roghieh Djafarzadeh
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Valeria Milani
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Nicole Rieth
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Irene von Luettichau
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Petra S. Skrablin
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Monika Hofstetter
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Elfriede Noessner
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Peter J. Nelson
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Peter J. Nelson.

Additional information

Elfriede Noessner, Peter J. Nelson are equal contributors.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Djafarzadeh, R., Milani, V., Rieth, N. et al. TIMP-1-GPI in combination with hyperthermic treatment of melanoma increases sensitivity to FAS-mediated apoptosis. Cancer Immunol Immunother 58, 361–371 (2009). https://doi.org/10.1007/s00262-008-0559-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00262-008-0559-5

Keywords

Search

Navigation