Abstract
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.
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Woessner JF. Matrix metalloproteinases and their inhibitors in connective tissue remodeling. FASEB J. 1991; 5: 2145–2154.
Matrisian LM. Metalloproteinases and their inhibitors in matrix remodeling. Trends Genet 1990; 6: 121–125.
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.
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.
Stetler-Stevenson WG, Krutzsch HC, Liotta LA. Tissue inhibitor of etalloproteinase (TIMP-2). J Biol Chem 1989 264: 17374–17378.
Liotta LA, Tryggvason K, Garbisa S et al. Metastatic potential correlates ith enzymatic degradation of basement membrane collagen. Nature 1980; 284: 67–68.
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.
Stetler-Stevenson WG. Progelatinase A activation during tumor cell nvasion. Invasion & Metastasis 1995; 14: 259–268.
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.
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.
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.
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.
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.
Itoh T, Tanioka M, Yoshida H et al. Reduced angiogenesis and tumor progression in gelatinase A-deficient mice. Cancer Res 1998; 58: 1048–1051.
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.
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.
Hart IR. The selection and characterization of an invasive variant of the B16 melanoma. Am J Path 1979; 97: 587–600.
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.
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.
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.
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Itoh, T., Tanioka, M., Matsuda, H. et al. Experimental metastasis is suppressed in MMP-9-deficient mice. Clin Exp Metastasis 17, 177–181 (1999). https://doi.org/10.1023/A:1006603723759
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DOI: https://doi.org/10.1023/A:1006603723759