Clinical & Experimental Metastasis

, Volume 17, Issue 2, pp 177–181

Experimental metastasis is suppressed in MMP-9-deficient mice

  • Takeshi Itoh
  • Masatoshi Tanioka
  • Hidetoshi Matsuda
  • Hirofumi Nishimoto
  • Takayuki Yoshioka
  • Ryuji Suzuki
  • Masahiro Uehira


Matrix metalloproteinases (MMPs) are thought to play a key role in tumor invasion and metastasis. The role of MMP-9 (gelatinase B) in tumor metastasis was examined in MMP-9-deficient mice produced by gene targeting using embryonic stem cells. MMP-9-deficient mice develop normally and are fertile. In these mice, the number of metastatic colonies of B16-BL6 melanoma cells or Lewis lung carcinoma cells that were implanted intravenously fell by 45% for B16-BL6 melanoma and 59% for Lewis lung carcinoma (p=0.03 and p=0.0043, respectively). Gelatin zymography showed that both tumor cell lines did not secrete MMP-9 by themselves but the host cells surrounding the tumor cells secrete MMP-9 in vivo. These results indicated that host-derived MMP-9 plays an important role in the process of tumor metastasis.

experimental tumor metastasis gelatinase knockout mice matrix metalloproteinase 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Woessner JF. Matrix metalloproteinases and their inhibitors in connective tissue remodeling. FASEB J. 1991; 5: 2145–2154.Google Scholar
  2. 2.
    Matrisian LM. Metalloproteinases and their inhibitors in matrix remodeling. Trends Genet 1990; 6: 121–125.Google Scholar
  3. 3.
    Stetler-Stevenson WG, Krutzsch HC, Wacher MP, Margulies IMK, Liotta LA. The activation of human type IV collagenase proenzyme. Biol Chem. 1989; 264: 1353–1356.Google Scholar
  4. 4.
    Docherty AJP, Lyons A, Smith BJ, et al. Sequence of human tissue inhibitor f metalloproteinases and its identity to erythroid-potentiating activity. Nature 1985; 318: 66–69.Google Scholar
  5. 5.
    Stetler-Stevenson WG, Krutzsch HC, Liotta LA. Tissue inhibitor of etalloproteinase (TIMP-2). J Biol Chem 1989 264: 17374–17378.Google Scholar
  6. 6.
    Liotta LA, Tryggvason K, Garbisa S et al. Metastatic potential correlates ith enzymatic degradation of basement membrane collagen. Nature 1980; 284: 67–68.Google Scholar
  7. 7.
    Himelstein BP, Canete-Soler R, Bernhard EJ, Dilks DW, Muschel RJ. Metalloproteinases in tumor progression: the contribution of MMP-9. Invasion & Metastasis 1995; 14: 246–258.Google Scholar
  8. 8.
    Stetler-Stevenson WG. Progelatinase A activation during tumor cell nvasion. Invasion & Metastasis 1995; 14: 259–268.Google Scholar
  9. 9.
    Sugiura Y, Shimada H, Seeger RC, Laug WE, DeClerck YA. Matrix etalloproteinases-2 and-9 are expressed in human neuroblastoma: ontribution of stromal cells to their production and correlation with metastasis. Cancer Res 1988; 58: 2209–2216.Google Scholar
  10. 10.
    Nielsen BS, Timshel S, Kjeldsen L et al. 92 kDa type IV collagenase (MMP-9) is expressed in neutrophils and macrophages but not in malignant epithelial cells in human colon cancer. Int J Cancer 1996; 65: 57–62.Google Scholar
  11. 11.
    Segain JP, Harb J, Grégoire M, Meflah K, Menanteau J. Induction of fibroblast gelatinase B expression by direct contact with cell lines derived from primary tumor but not from metastases. Cancer Res 1996; 56: 5506–5512.Google Scholar
  12. 12.
    Himelstein BP, Canete-Soler R, Bernhard EJ, Muschel RJ. Induction of fibroblast 92 kDa gelatinase/type IV collagenase expression by direct contact with metastatic tumor cells. J Cell Sci 1994; 107: 477–486.Google Scholar
  13. 13.
    Itoh T, Ikeda T, Gomi H et al. Unaltered secretion of β-amyloid precursor protein in gelatinase A (Matrix metalloproteinase 2)-deficient mice. J Biol Chem 1997; 272: 22389–22392.Google Scholar
  14. 14.
    Itoh T, Tanioka M, Yoshida H et al. Reduced angiogenesis and tumor progression in gelatinase A-deficient mice. Cancer Res 1998; 58: 1048–1051.Google Scholar
  15. 15.
    Yagi T, Ikawa Y, Yoshida K, et al. Homologous recombination at c-fyn locus of mouse embryonic stem cells with use of diphtheria toxin Afragment gene in negative selection. Proc Natl Acad Sci USA 1990; 87: 9918–9922.Google Scholar
  16. 16.
    Gomi H, Yokoyama T, Fujimoto K et al. Mice devoid of the glial fibrillary acidic protein develop normally and are susceptible to scrapie prions. Neuron 1995; 14: 29–41.Google Scholar
  17. 17.
    Hart IR. The selection and characterization of an invasive variant of the B16 melanoma. Am J Path 1979; 97: 587–600.Google Scholar
  18. 18.
    Uehira M, Matsuda H, Nakamura A, Nishimoto H. Immunologic abnormalities exhibited in IL-7 transgenic mice with dermatitis. J Invest Dermatol 1998; 110: 740–745.Google Scholar
  19. 19.
    Raz A, McLellan WL, Hart IR et al. Cell surface properties of B16 melanoma variants with differing metastatic potential. Cancer Res 1980; 40: 1645–1651.Google Scholar
  20. 20.
    Vu TH, Shipley JM, Bergers G et al. MMP-9/Gelatinase B is a key regulator of growth plate angiogenesis and apoptosis of hypertrophic chondrocytes. Cell 1998; 93: 411–422.Google Scholar

Copyright information

© Kluwer Academic Publishers 1999

Authors and Affiliations

  • Takeshi Itoh
    • 1
  • Masatoshi Tanioka
    • 1
  • Hidetoshi Matsuda
    • 1
  • Hirofumi Nishimoto
    • 1
  • Takayuki Yoshioka
    • 2
  • Ryuji Suzuki
    • 1
  • Masahiro Uehira
    • 1
  1. 1.Shionogi & Co., LtdShionogi Institute for Medical ScienceJapan
  2. 2.Discovery Research LaboratoriesShionogi & Co., LtdFukushima-ku, OsakaJapan

Personalised recommendations