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:

Patterns of protease production during prostate cancer progression: proteomic evidence for cascades in a transgenic model

Prostate Cancer and Prostatic Diseases volume 6, pages 272–280 (2003)Cite this article

Abstract

Extracellular proteases are recognized as critical factors in the progression of a number of carcinomas, including prostate cancer. Matrix metalloproteases (MMP) are important in processes of tumor growth, invasion and dissemination, but other classes of proteases, such as serine and cysteine proteases, also contribute. We utilized the TRAMP model for prostate cancer to elucidate proteases involved in prostate cancer progression. General proteomic analysis was performed on normal murine prostate, early TRAMP tumors and advanced TRAMP tumors, as well as normal and involved lymph nodes. Zymography and antigenic analyses revealed increased expression of mainly pro-MMP in early TRAMP tumors but substantial elaboration of activated MMP only in late TRAMP tumors. Progressive increase in cysteine, serine and certain membrane-bound proteases from normal to early to advanced prostate tumors, was also seen. Our results implicate pericellular proteases as initiators of major proteolytic cascades during tumor progression and suggest targets for maximal therapeutic effect.

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 3
Figure 4
Figure 5
Figure 2
Figure 6

Similar content being viewed by others

References

  1. Kim SJ et al. Prognostic impact of urokinase-type plasminogen activator (PA), PA inhibitor type-1, and tissue-type PA antigen levels in node-negative breast cancer: a prospective study on multicenter basis. Clin Cancer Res 1998; 4: 177–182.

    CAS  PubMed  Google Scholar 

  2. Powell WC et al. Expression of the metalloproteinase matrilysin in DU-145 cells increases their invasive potential in severe combined immunodeficient mice. Cancer Res 1993; 53: 417–422.

    CAS  PubMed  Google Scholar 

  3. Shalinsky DR et al. Broad antitumor and antiangiogenic activities of AG3340, a potent and selective MMP inhibitor undergoing advanced oncology clinical trials. Ann NY Acad Sci 1999; 878: 236–270.

    Article  CAS  PubMed  Google Scholar 

  4. Van Veldhuizen PJ, Sadasivan R, Cherian R, Wyatt A . Urokinase-type plasminogen activator expression in human prostate carcinomas. Am J Med Sci 1996; 312: 8–11.

    Article  CAS  PubMed  Google Scholar 

  5. Bubley GJ et al. Eligibility and response guidelines for phase II clinical trials in androgen-independent prostate cancer: recommendations from the Prostate-Specific Antigen Working Group. J Clin Oncol 1999; 17: 3461–3467.

    Article  CAS  PubMed  Google Scholar 

  6. Doherty A et al. Correlation of the osteoblastic phenotype with prostate-specific antigen expression in metastatic prostate cancer: implications for paracrine growth. J Pathol 1999; 188: 278–281.

    Article  CAS  PubMed  Google Scholar 

  7. Rittenhouse HG, Finlay JA, Mikolajczyk SD, Partin AW . Human kallikrein 2 (hK2) and prostate-specific antigen (PSA): two closely related, but distinct, kallikreins in the prostate. Crit Rev Clin Lab Sci 1998; 35: 275–368.

    Article  CAS  PubMed  Google Scholar 

  8. Lin B et al. Prostate-localized and androgen-regulated expression of the membrane-bound serine protease TMPRSS2. Cancer Res 1999; 59: 4180–4184.

    CAS  PubMed  Google Scholar 

  9. Takeuchi T, Shuman MA, Craik CS . Reverse biochemistry: use of macromolecular protease inhibitors to dissect complex biological processes and identify a membrane-type serine protease in epithelial cancer and normal tissue. Proc Natl Acad Sci USA 1999; 96: 11054–11061.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Miyake H et al. Elevation of serum levels of urokinase-type plasminogen activator and its receptor is associated with disease progression and prognosis in patients with prostate cancer. Prostate 1999; 39: 123–129.

    Article  CAS  PubMed  Google Scholar 

  11. Crowley CW et al. Prevention of metastasis by inhibition of the urokinase receptor. Proc Natl Acad Sci USA 1993; 90: 5021–5025.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Wan XS et al. Treatment with soybean-derived Bowman Birk inhibitor increases serum prostate-specific antigen concentration while suppressing growth of human prostate cancer xenografts in nude mice. Prostate 1999; 41: 243–252.

    Article  CAS  PubMed  Google Scholar 

  13. Shepherd FA et al. Randomized double-blind pacebo-controlled trial of marimastat in patients with small cell lung cancer (SCLC) following response to first-line chemotherapy: an NCIC-CTG and EORTC study. Am Soc Clin Oncol 2001; 20: 4a.

    Google Scholar 

  14. Greenberg NM et al. Prostate cancer in a transgenic mouse. Proc Natl Acad Sci USA 1995; 92: 3439–3443.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Takeuchi T et al. Cellular localization of membrane-type serine protease 1 and identification of protease-activated receptor-2 and single-chain urokinase-type plasminogen activator as substrates. J Biol Chem 2000; 275: 26333–26342.

    Article  CAS  PubMed  Google Scholar 

  16. Furuya M et al. Clarification of the active gelatinolytic sites in human ovarian neoplasms using in situ zymography. Hum Pathol 2001; 32: 163–168.

    Article  CAS  PubMed  Google Scholar 

  17. Kristensen P, Eriksen J, Blasi F, Dano K . Two alternatively spliced mouse urokinase receptor mRNAs with different histological localization in the gastrointestinal tract. J Cell Biol 1991; 115: 1763–1771.

    Article  CAS  PubMed  Google Scholar 

  18. Unkeless JC et al. An enzymatic function associated with transformation of fibroblasts by oncogenic viruses. I. Chick embryo fibroblast cultures transformed by avian RNA tumor viruses. J Exp Med 1973; 137: 85–111.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Gururajan R, Grenet J, Lahti JM, Kidd VJ . Isolation and characterization of two novel metalloproteinase genes linked to the Cdc2L locus on human chromosome 1p36.3. Genomics 1998; 52: 101–106.

    Article  CAS  PubMed  Google Scholar 

  20. Sternlicht MD et al. The stromal proteinase MMP3/stromelysin-1 promotes mammary carcinogenesis. Cell 1999; 98: 137–146.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Upadhyay J et al. Membrane type 1-matrix metalloproteinase (MT1-MMP) and MMP-2 immunolocalization in human prostate: change in cellular localization associated with high-grade prostatic intraepithelial neoplasia. Clin Cancer Res 1999; 5: 4105–4110.

    CAS  PubMed  Google Scholar 

  22. Murphy G, Gavrilovic J . Proteolysis and cell migration: creating a path? Curr Opin Cell Biol 1999; 11: 614–621.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Drs Zena Werb and Mark Sternlicht for anti-MMP-2 and MMP-9 antibodies, Drs Charles Craik and Toshi Takeuchi for antibody to MT-SP1, and Dr Lynn Matrisian for the gift of anti-MMP-7 antibody. This publication was made possible by funds received from the Cancer Research Fund, under Interagency Agreement #97–12013 (University of California, Davis contract #98–00924V) with the Department of Health Services, Cancer Research Section, and from NIH/NHLBI P01 CA72006.

Author information

Authors and Affiliations

  1. Department of Medicine, University of California, San Francisco, California, USA

    R A Bok, T P Nguyen & M A Shuman

  2. Department of Pathology and Pharmaceutical Chemistry, University of California, San Francisco, California, USA

    E J Hansell & J H McKerrow

  3. Department of Cell Biology, Baylor College of Medicine, Houston, Texas, USA

    N M Greenberg

Authors
  1. R A Bok
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. E J Hansell
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. T P Nguyen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. N M Greenberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. J H McKerrow
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. M A Shuman
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to R A Bok.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bok, R., Hansell, E., Nguyen, T. et al. Patterns of protease production during prostate cancer progression: proteomic evidence for cascades in a transgenic model. Prostate Cancer Prostatic Dis 6, 272–280 (2003). https://doi.org/10.1038/sj.pcan.4500676

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.pcan.4500676

Keywords

This article is cited by

Search

Advanced search

Quick links