Experimental metastasis is suppressed in MMP-9-deficient mice

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.

[1]  W. Stetler-Stevenson Progelatinase A activation during tumor cell invasion. , 1994, Invasion & metastasis.

[2]  S. Itohara,et al.  Reduced angiogenesis and tumor progression in gelatinase A-deficient mice. , 1998, Cancer research.

[3]  Stetler-Stevenson Wg Progelatinase A activation during tumor cell invasion. , 1994 .

[4]  L. Liotta,et al.  Metastatic potential correlates with enzymatic degradation of basement membrane collagen , 1980, Nature.

[5]  L. Liotta,et al.  The activation of human type IV collagenase proenzyme. Sequence identification of the major conversion product following organomercurial activation. , 1989, The Journal of biological chemistry.

[6]  S. Itohara,et al.  Mice devoid of the glial fibrillary acidic protein develop normally and are susceptible to scrapie prions , 1995, Neuron.

[7]  S. Itohara,et al.  Unaltered Secretion of β-Amyloid Precursor Protein in Gelatinase A (Matrix Metalloproteinase 2)-deficient Mice* , 1997, The Journal of Biological Chemistry.

[8]  J. Woessner,et al.  Matrix metalloproteinases and their inhibitors in connective tissue remodeling , 1991, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[9]  T. Yagi,et al.  Homologous recombination at c-fyn locus of mouse embryonic stem cells with use of diphtheria toxin A-fragment gene in negative selection. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[10]  L. Liotta,et al.  Tissue inhibitor of metalloproteinase (TIMP-2). A new member of the metalloproteinase inhibitor family. , 1989, The Journal of biological chemistry.

[11]  L. Matrisian,et al.  Metalloproteinases and their inhibitors in matrix remodeling. , 1990, Trends in genetics : TIG.

[12]  H. Shimada,et al.  Matrix metalloproteinases-2 and -9 are expressed in human neuroblastoma: contribution of stromal cells to their production and correlation with metastasis. , 1998, Cancer research.

[13]  R. Muschel,et al.  Metalloproteinases in tumor progression: the contribution of MMP-9. , 1994, Invasion & metastasis.

[14]  C. Bucana,et al.  Cell surface properties of B16 melanoma variants with differing metastatic potential. , 1980, Cancer research.

[15]  A. Nakamura,et al.  Immunologic abnormalities exhibited in IL-7 transgenic mice with dermatitis. , 1998, The Journal of investigative dermatology.

[16]  J. Harb,et al.  Induction of fibroblast gelatinase B expression by direct contact with cell lines derived from primary tumor but not from metastases. , 1996, Cancer research.

[17]  B. Nielsen,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 , 1996, International journal of cancer.

[18]  I. Hart The selection and characterization of an invasive variant of the B16 melanoma. , 1979, The American journal of pathology.

[19]  R. Muschel,et al.  Induction of fibroblast 92 kDa gelatinase/type IV collagenase expression by direct contact with metastatic tumor cells. , 1994, Journal of cell science.

[20]  P. Stephens,et al.  Sequence of human tissue inhibitor of metalloproteinases and its identity to erythroid-potentiating activity , 1985, Nature.

[21]  Gabriele Bergers,et al.  MMP-9/Gelatinase B Is a Key Regulator of Growth Plate Angiogenesis and Apoptosis of Hypertrophic Chondrocytes , 1998, Cell.