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.

  • Original Article
  • Published:

Gene therapy of melanoma pulmonary metastasis by intramuscular injection of plasmid DNA encoding tissue inhibitor of metalloproteinases-1

Cancer Gene Therapy volume 9, pages 126–132 (2002)Cite this article

An Erratum to this article was published on 14 June 2002

Abstract

Tumor cell invasion and metastasis are a complex multistep process that involves the degradation of extracellular matrix proteins by matrix metalloproteinases. Tissue inhibitor of metalloproteinase-1 (TIMP-1) acts as a negative regulator of matrix metalloproteinases and thus prevents tumor cell invasion and metastasis by preserving extracellular matrix integrity. In the present study, we investigated whether increasing serum TIMP-1 levels by gene transfer would decrease experimental pulmonary metastasis of melanoma in C57BL/6 mice. Female animals bearing B16F10 melanoma pulmonary metastasis were injected intramuscularly twice per week with 100 μg of plasmid DNA encoding the human TIMP-1 cDNA (TIMP-1pDNA). Substantive levels of serum human TIMP-1 were observed 3 days after single injection and were found for 6 days thereafter. Pulmonary metastasis was significantly reduced in the mice following 4 weeks of TIMP-1 treatment as compared to the controls that were treated with the plasmid DNA vector alone. Further reduction of pulmonary metastasis and increase in survival were realized by intraperitoneal injection of 1000 U of IL-2 twice per week in combination with TIMP-1 treatment. In a parallel in vitro study, a 3-fold increase in TIMP-1 expression was observed in NIH3T3 cells after IL-2 treatment. Therefore, up-regulation of TIMP-1 expression by IL-2 likely contributed to the additive effect of IL-2 and TIMP-1 in reducing metastatic disease in the animal model. In conclusion, our findings support the potential of TIMP-1 gene therapy for the prevention of metastatic melanoma.

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
Figure 4
Figure 5
Figure 6

Similar content being viewed by others

References

  1. Hanahan D, Weinberg RA . The hallmarks of cancer Cell 2000 100: 57–70

    Article  CAS  PubMed  Google Scholar 

  2. Kohn EC, Liotta LA . Molecular insights into cancer invasion: strategies for prevention and intervention Cancer Res 1995 55: 1856–1862

    CAS  PubMed  Google Scholar 

  3. DeClerck YA . Interactions between tumor cells and stromal cells and proteolytic modification of the extracellular matrix by metalloproteinases in cancer Eur J Cancer 2000 36: 1258–1268

    Article  CAS  PubMed  Google Scholar 

  4. Stetler-Stevenson WG, Aznavoorian S, Liotta LA . Tumor cell interactions with the extracellular matrix during invasion and metastasis Annu Rev Cell Biol 1993 4: 541–573

    Article  Google Scholar 

  5. Nagase H, Woessner JF . Matrix metalloproteinases J Biol Chem 1999 274: 21491–21494

    Article  CAS  PubMed  Google Scholar 

  6. Bode W, Fernandez-Catalan C, Grams F et al. Insights into MMP–TIMP interactions Ann NY Acad Sci 1999 878: 73–91

    Article  CAS  PubMed  Google Scholar 

  7. Liotta LA, Tryggvason K, Garbisa S, Hart I, Foltz CM, Shafie S . Metastastic potential correlates with enzymatic degradation of basement membrane collagen Nature (London) 1980 284: 67–68

    Article  CAS  Google Scholar 

  8. Nakajima M, Welch DR, Belloni PN, Nicolson GL . Degradation of basement membrane type IV collagen and lung subendothelial matrix by rat mammary adenocarcinoma cell clones of differing metastatic potentials Cancer Res 1987 47: 4869–4876

    CAS  PubMed  Google Scholar 

  9. Murphy G, Reynolds J, Hembry RM . Metalloproteinases and cancer invasion and metastasis Int J Cancer 1989 44: 757–760

    Article  CAS  PubMed  Google Scholar 

  10. Sreenath T, Matrisian L, Stetler-Stevenson W, Gattoni-Celli S, Pozzatti R . Expression of matrix metalloproteinase genes in transformed rat cell lines of high and low metastatic potential Cancer Res 1992 52: 4942–4947

    CAS  PubMed  Google Scholar 

  11. Bernhard E, Gruber S, Muschel R . Direct evidence linking MMP-9 (92 kDa gelatinase/collagenase) expression to the metastatic phenotype in transformed rat embryo cells Proc Natl Acad Sci USA 1994 91: 4293–4297

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Greene J, Wang M, Liu YE, Raymond LA, Rosen C, Shi YE . Molecular cloning and characterization of human tissue inhibitor of metalloproteinase 4 J Biol Chem 1996 271: 30375–30380

    Article  CAS  PubMed  Google Scholar 

  13. Gomis-Ruth FX, Maskos K, Betz M et al. Mechanism of inhibition of the human matrix metalloproteinase stromelysin-1 by TIMP-1 Nature 1997 389: 77–81

    Article  CAS  PubMed  Google Scholar 

  14. Nagase H, Meng Q, Malinovskii V et al. Engineering of selective TIMPs Ann NY Acad Sci 1999 878: 1–11

    Article  CAS  PubMed  Google Scholar 

  15. Meng Q, Malinovskii V, Huang W et al. Residue 2 of TIMP-1 is a major determinant of affinity and specificity for matrix metalloproteinases but effects of substitutions do not correlate with those of the corresponding P1′ residue of substrate J Biol Chem 1999 274: 10184–10189

    Article  CAS  PubMed  Google Scholar 

  16. Kossakowska AE, Urbanski SJ, Edwards DR . Tissue inhibitor of metalloproteinases-1 (TIMP-1) RNA is expressed at elevated levels in malignant non-Hodgkin's lymphomas Blood 1991 77: 2475–2481

    CAS  PubMed  Google Scholar 

  17. Nakano A, Tani E, Miyazaki K, Yamamoto Y, Furuyama J . Matrix metalloproteinases and tissue inhibitors of metalloproteinases in human gliomas J Neurosurg 1995 83: 298–307

    Article  CAS  PubMed  Google Scholar 

  18. Lu X, Levy M, Weinstein BI, Santella RM . Immunological quantitation of levels of tissue inhibitor of metalloproteinase-1 in human colon cancer Cancer Res 1991 51: 6231–6235

    CAS  PubMed  Google Scholar 

  19. Shi Y, Parhar RS, Zou M et al. Tissue inhibitor of metalloproteinases-1 (TIMP-1) mRNA is elevated in advanced stages of thyroid carcinoma Br J Cancer 1999 79: 1234–1239

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Burt RK, Link C, Traynor A . Adoptive immunotherapy after hematopoietic stem cell transplantation Curr Opin Oncol 1998 10: 525–532

    Article  CAS  PubMed  Google Scholar 

  21. Lala PK, Parhar RS . Cure of B16F10 melanoma lung metastasis in mice by chronic indomethacin therapy combined with repeated rounds of IL-2: characteristics of killer cells generated in situ Cancer Res 1988 48: 1072–1079

    CAS  PubMed  Google Scholar 

  22. Fidler IJ . Biological behavior of malignant melanoma cells correlated to their survival in vivo Cancer Res 1975 35: 218–234

    CAS  PubMed  Google Scholar 

  23. Parhar RS, Shi Y, Zou MJ, Farid NR, Ernst P, Al-Sedairy ST . Effects of cytokine-mediated modulation of nm23 expression on the invasion and metastatic behavior of B16F10 melanoma cells Int J Cancer 1995 60: 204–210

    Article  CAS  PubMed  Google Scholar 

  24. Horton HM, Anderson D, Hernandez P, Barnhart KM, Norman JA, Parker SE . A gene therapy for cancer using intramuscular injection of plasmid DNA encoding interferon α Proc Natl Acad Sci USA 1999 96: 1553–1558

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Baker AH, Ahonen M, Kahari V-M . Potential applications of tissue inhibitor of metalloproteinase (TIMP) overexpression for cancer gene therapy Adv Exp Med Biol 2000 465: 469–483

    Article  CAS  PubMed  Google Scholar 

  26. Kruger A, Sanchez-Sweatman OH, Martin DC et al. Host TIMP-1 overexpression confers resistance to experimental brain metastasis of a fibrosarcoma cell line Oncogene 1998 16: 2419–2423

    Article  CAS  PubMed  Google Scholar 

  27. Martin DC, Sanchez-Sweatman OH, Ho AT, Inderdeo DS, Tsao MS, Khokha R . Transgenic TIMP-1 inhibits simian virus 40T antigen-induced hepatocarcinogenesis by impairment of hepatocellular proliferation and tumor angiogenesis Lab Invest 1999 79: 225–234

    CAS  PubMed  Google Scholar 

  28. Brand K, Baker AH, Perez-Canto A et al. Treatment of colorectal liver metastases by adenoviral transfer of tissue inhibitor of metalloproteinases-2 into the liver tissue Cancer Res 2000 60: 5723–5730

    CAS  PubMed  Google Scholar 

  29. Alvarez OA, Carmichael DF, DeClerck YA . Inhibition of collagenolytic activity and metastasis of tumor cells by a recombinant human tissue inhibitor of metalloproteinases J Natl Cancer Inst 1990 80: 589–595

    Article  Google Scholar 

  30. Schultz RM, Silberman S, Persky B, Bajkowski AS, Carmichael DF . Inhibition by human recombinant tissue inhibitor of metalloproteinases of human amnion invasion and lung colonization by murine B16F10 melanoma cells Cancer Res 1988 48: 5539–5545

    CAS  PubMed  Google Scholar 

  31. Wojtowicz-Praga SM, Dickson RB, Hawkins MJ . Matrix metalloproteinase inhibitors Invest New Drugs 1997 15: 61–75

    Article  CAS  PubMed  Google Scholar 

  32. Brown PD . Synthetic inhibitors of matrix metalloproteinases In: WC Parks, RP Mecham, eds. Matrix Metalloproteinases San Diego: Academic Press 1998 243–261

  33. Rowinsky EK, Humphrey R, Hammond LA et al. Phase 1 and pharmacologic study of the specific matrix metalloproteinase inhibitor BAY 12-9566 on a protracted oral daily dosing schedule in patients with solid malignancies J Clin Oncol 2000 18: 178–186

    Article  CAS  PubMed  Google Scholar 

  34. Kim MH, Kitson RP, Albertsson P et al. Secreted and membrane-associated matrix metalloproteinases of IL-2–activated NK cells and their inhibitors J Immunol 2000 164: 5883–5889

    Article  CAS  PubMed  Google Scholar 

  35. Ma C, Chegini N . Regulation of matrix metalloproteinases (MMPs) and their tissue inhibitors in human myometrial smooth muscle cells by TGF-beta1 Mol Hum Reprod 1999 5: 950–954

    Article  CAS  PubMed  Google Scholar 

  36. Burger D, Rezzonico R, Li JM et al. Imbalance between interstitial collagenase and tissue inhibitor of metalloproteinases 1 in synoviocytes and fibroblasts upon direct contact with stimulated T lymphocytes: involvement of membrane-associated cytokines Arthritis Rheum 1998 41: 1748–1759

    Article  CAS  PubMed  Google Scholar 

  37. Bugno M, Witek B, Bereta J, Bereta M, Edwards DR, Kordula T . Reprogramming of TIMP-1 and TIMP-3 expression profiles in brain microvascular endothelial cells and astrocytes in response to proinflammatory cytokines FEBS Lett 1999 448: 9–14

    Article  CAS  PubMed  Google Scholar 

  38. Eickelberg O, Kohler E, Reichenberger F et al. Extracellular matrix deposition by primary human lung fibroblasts in response to TGF-beta1 and TGF-beta3 Am J Physiol 1999 276: L814–L824

    CAS  PubMed  Google Scholar 

  39. Forni G, Lollini PL, Musiani P, Colombo MP . Immunoprevention of cancer: is the time ripe? Cancer Res 2000 60: 2571–2575

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Shaheen Nakeeb and Raafat M El-Sayed from the Animal Facility for their excellent support.

Author information

Authors and Affiliations

  1. Department of Biological and Medical Research, King Faisal Specialist Hospital and Research Center, Riyadh, 11211, Saudi Arabia

    Yufei Shi, Ranjit S Parhar, Minjing Zou, Futwan A Al-Mohanna & Malcolm C Paterson

Authors
  1. Yufei Shi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ranjit S Parhar
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Minjing Zou
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Futwan A Al-Mohanna
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Malcolm C Paterson
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yufei Shi.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Shi, Y., Parhar, R., Zou, M. et al. Gene therapy of melanoma pulmonary metastasis by intramuscular injection of plasmid DNA encoding tissue inhibitor of metalloproteinases-1. Cancer Gene Ther 9, 126–132 (2002). https://doi.org/10.1038/sj.cgt.7700426

Download citation

  • Received:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.cgt.7700426

Keywords

This article is cited by

Search

Advanced search

Quick links