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Role of matrix metalloproteinases in invasion, and metastasis: biology, diagnosis and inhibitors

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Abstract

The processes of tumor invasion and subsequent metastasis are the most lethal, aspects of cancer. Whilst many factors are involved, the matrix metalloproteinases (MMPs) have been implicated as key-rate limiting enzymes in the invasive process. This family consisting of eight members of similar structure, can be roughly divided into three groups based on substrate specificity. All are secreted in a latent form and require proteolytic cleavage for activation. The expression of these enzymes is regulated at the transcriptional level by a variety of growth factors and oncogenes. They are also regulated at the protein level by a family of specific inhibitors called the tissue inhibitors of metalloproteinases (TIMPs). Studies, in human tumour samples have shown a positive correlation between metalloproteinase expression and metastatic potential. The levels of metalloproteinase expression, have been manipulated using molecular biology techniques in several cell lines and shown a similar correlation. These results suggest that an understanding of metalloproteinase expression and proteolytic activity may lead to the development of effective therapeutic agents with the potential, to reduce the incidence of metastatic cancer.

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Abbreviations

MMP:

matrix metalloproteinase

TIMP:

tissue inhibitor of metalloproteinase

rTIMP:

recombinant tissue inhibitor of metalloproteinase

TPA:

12-O-tetradecanoyl phorbol-13-acetate

TRE:

TPA responsive element

EGF:

epidermal growth factor

TGF-β:

transforming growth factor β

ELISA:

enzyme-linked immunosorbent assay

bp:

base pair

PCR:

polymerase chain reaction

RT-PCR:

reverse transcription polymerase chain reaction

References

  • Angel P, Imagawa M, Chiu R, Stein B, Imbra RJ, Rahmsdorf HJ, Jonat C, Herrlich P & Karin M (1987) Phorbol esterinducible genes contain a common cis element recognized by a TPA-modulated transacting factor. Cell 49:729–739.

    Google Scholar 

  • Albini A, Melchiori A, Santi L, Liotta, LA, Brown PD and Stetler-Stevenson WG (1991) Tumor cell invasion inhibited by TIMP-2. J Natl Cancer Inst 83:775–779.

    Google Scholar 

  • Alvarez OA, Carmichael DF, and De Clerck YA (1990) Inhibition of collagenolytic activity and metastasis of tumor cells by a recombinant human tissue inhibitor of metalloproteinases. J Natl Cancer Inst 82:589–595.

    Google Scholar 

  • Auble DT and Brinckerhoff CE (1991) The AP-1 sequence is necessary but not sufficient for phorbol induction of collagenase in fibroblasts. Biochemistry 30:4629–4635.

    Google Scholar 

  • Banda MJ, Howard EW, Herron GS and Apodeca G (1992) Secreted inhibitor of metalloproteinases (IMPs) that are distinct from TIMP. Matrix (Germany) Suppl 1: 294–298.

    Google Scholar 

  • Basset P, Bellocq JP, Wolf C, Stoll I, Hutin P, Limacher JM, Podhajcer OL, Chenard MP, Rio MC and Chambon P (1990) A novel metalloproteinase gene specifically expressed in stromal cells of breast carcinomas. Nature (Lond) 348: 699–704.

    Google Scholar 

  • Bevilacqua G, Sobel ME, Liotta LA and Steeg PS (1989) Association of low nm23 RNA levels in human primary infiltrating ductal breast carcinoma with lymph node involvement and other histopathological indicators of high metastatic potential. Cancer Res 49:5185–5190.

    Google Scholar 

  • Boone TC, Johnson MJ, DeClerck YA and Langley KE (1990) cDNA cloning and expression of a metalloproteinase inhibitor related to tissue inhibitor of metalloproteinases. Proc Natl Acad Sci (USA) 87:2800–2804.

    Google Scholar 

  • Brenner DA, O'Hara M, Chojkier M and Karin M (1989) Prolonged activation of c-jun and collagenase genes by tumour necrosis factor-α. Nature 337:661–663.

    Google Scholar 

  • Busiek DF, Ross FP, McDonnell S, Murphy G, Matrisian LM and Welgus HG (1992) The matrix metalloproteinase matrilysin (PUMP) is expressed in developing human mononuclear phagocytes. J Biol Chem 267:9087–9092.

    Google Scholar 

  • Campbell CE, Flenniken AM, Skup D and Williams BRG (1991) Identification of a serum-and phorbol ester-responsive element in the murine tissue inhibitor of metalloproteinase gene. J Biol Chem 266:7199–7206.

    Google Scholar 

  • Carmichael DF, Sommer A, Thompson RC, Anderson DC, Smith CG, Welgus HG and Stricklin GP (1986) Primary sequence and cDNA cloning of human fibroblast collagenase inhibitor. Proc Natl Acad Sci USA 83:2407–2411.

    Google Scholar 

  • Carmichael, DF, Stricklin GP and Stuart JM (1989) Systemic administration of TIMP in the treatment, of collagen-induced arthritis in mice. Agents Actions 3:378–379.

    Google Scholar 

  • Cawston TE, Galloway WA, Mercer E, Murphy G and Reynolds JJ (1981) Purification of rabbit bone inhibitor of collagenase. Biochem J 195:159–165.

    Google Scholar 

  • Clark IM and Cawston TE (1989) Fragments of human fibroblast collagenase. Purification and characterization. Biochem J 263:201–206.

    Google Scholar 

  • Cohn KH, Wang F, De Soto-LaPaix F, Solomon WB, Patterson LG, Arnold MR, Weimar J, Feldman JG, Levy AT, Leone A and Steeg PS (1991) Association of nm23 Hi allelic deletion with distant metastasis in colorectal carcinoma. Lancet 338: 722–724.

    Google Scholar 

  • Collier IE, Wilhelm SM, Eisen AZ, Marmer BL, Grant GA, Seltzer JL, Kronherger A, He C, Bauer EA and Goldberg GI (1988) H-ras oncongene-transformed human bronchial epithelial cells (TBE-1) secrete a single metalloproteinase capable of degrading basement membrane collagen. J Biol Chem 263: 6579–6587.

    Google Scholar 

  • Dano K, Andreasen PA, Hansen-Grondahl J, Kristensen P, Nielsen LS and Skriver L (1985) Plasminogen activators, tissue degradation and cancer. Adv Cancer Res 44: 139–266.

    Google Scholar 

  • DeClerck YA, Yean TD, Ratzkin BJ, Lu HS and Langley KE (1989) Purification and characterization of two related but distinct metalloproteinase inhibitors secreted by bovine aortic endothetial cells. J Biol Chem 264: 17445–17453.

    Google Scholar 

  • DeClerck YA, Yean T, Lu HS, Ting J and Langley KE (1991a) Inhibition of autoproteolytic activation of interstitial procollagenase by recombinant metalloproteinase inhibitor MI/TIMP-2. J Biol Chem 266: 3893–3899.

    Google Scholar 

  • DeClerck YA, Yean TD, Chan D, Shimada H and Langley KE (1991b) Inhibition of tumor invasion of smooth muscle cell layers by recombinant human metalloprotinases inhibitor. Cancer Res 51: 2151–2157.

    Google Scholar 

  • Docherty AJP Lyons A, Smith BJ, Wright EM Stephen PE, Harris TJR, Murphy G and Reynolds JJ (1985) Sequence of human tissue inhibitor of metalloproteinases and its identity to erythroid-potentiating activity. Nature 318: 66–69.

    Google Scholar 

  • Fearon EJ and Vogelstein B (1990) A genetic model of colorectal tumorigenesis. Cell 61: 759–767.

    Google Scholar 

  • Frisch SM and Ruley HE (1987) Transcription from the stromelysin promoter is induced by interleukin-1 and repressed by dexamethasone. J Biol Chem 262: 16300–16304.

    Google Scholar 

  • Frisch SM, Reich R, Collier IE, Genrich LT, Martin G and Goldberg GI (1990) Adenovirus E1A represses protease gene expression and inhibits metastasis of human tumor cells. Oncogene 5: 75–83.

    Google Scholar 

  • Goldberg GI, Marmer BL, Gregory GA, Eisen AZ Wilhelm S and He C (1989) Human 72-kilodalton type IV collagenase forms a complex with a tissue inhibitor of metalloproteases designated TIMP-2. Proc Natl Acad Sci USA 86: 8207–8211.

    Google Scholar 

  • Gottesman MM (1993) How cancer cells evade chemotherapy: Sixteenth Richard and Linda Rosenthal foundation award lecture. Cancer Res 53: 747–754.

    Google Scholar 

  • Grant GA, Eisen AZ, Marmer BL Roswit WT and Goldberg GI (1987) The activation of human skin fibroblast procollagenase. Sequence identification of the major conversion products. J Biol Chem 262: 5886–5889.

    Google Scholar 

  • Gray ST, Wilkins RJ and Yun K (1992) Interstitial collagenase gene expression in oral squamous cell carcinoma. Am J Pathol 141: 301–306.

    Google Scholar 

  • Halaka AN, Bunning RAD, Bird CC, Gibson M and Reynolds JJ (1983) Production of collagenase and inhibitor (TIMP) by intracranial tumours and durain vitro. J Neurosurg 59: 461–466.

    Google Scholar 

  • Hasty KA, Pourmotabbed TF, Goldberg GI, Thompson JP, Spinella DG, Stevens RM and Mainardi CL (1990a). Human neutrophil collagenase. A distinct gene product with homology to other matrix metalloproteinases. J Biol Chem 265: 11421–11424.

    Google Scholar 

  • Hasty KA, Reife RA, Kang AH and Stuart JM (1990b) The role of stromelysin in the cartilage destruction that accompanies inflammatory arthritis. Arthritis Rheum 33: 388–397.

    Google Scholar 

  • He C, Wilhelm SM, Pentland AP, Marmer BL, Grant GA, Eisen AZ and Goldberg GI (1989) Tissue cooperation in a proteolytic cascade activating human interstitial collagenase. Proc Natl Acad Sci USA 86: 2632–2636.

    Google Scholar 

  • Hendrix MJC, Seftor EA, Seftor REB and Fidler I (1987) A simple quantitative assay for studying the invasive potential of high and low metastatic variants. Cancer Lett 38: 137–147.

    Google Scholar 

  • Hennessy C, Henry JA, May FEB, Wesley BR, Angus B and Lennard TWJ (1991) Expression of the anti-metastatic gene nm23 in human breast cancer: association with good prognosis. J Natl Cancer Inst 83: 281–285.

    Google Scholar 

  • Hicks NJ, Ward RV and Reynolds JJ (1984). A fibrosarcoma model derived from mouse embryo cells: growth properties and secretion of collagenase and metalloproteinase inhibitor (TIMP) by tumor cell lines. Int J Cancer 33: 835–844.

    Google Scholar 

  • Howard EW, Bullen EC and Banda MJ (1991) Regulation of the autoactivation of human 72-kDa progelatinase by tissue inhibitor of metalloproteinases-2. J Biol Chem 266: 13061–13069.

    Google Scholar 

  • Huhtala P, Chow LT and Tryggvason K (1990) Structure of the human type IV collagenase gene. J Biol Chem 265: 11077–11082.

    Google Scholar 

  • Hunt LT, Barker WC and Chen HR (1987) A domain structure common to hemopexin, vitronectin, interstitial collagenase and a collagenase homolog. Protein Seq Data Anal 1: 21–26.

    Google Scholar 

  • Jonat C, Rahmsdorf HJ, Park K-K, Cato ACB, Gebel S, Ponta H and Herrlich P (1990) Anti-tumor promotion and anti-inflammation: Down modulation of AP-1 (Fos/Jun) activity by glucocorticoid hormone. Cell 62: 1189–1204.

    Google Scholar 

  • Kerr LD, Holt JT and Matrisian LM (1988) Growth factors regulate transin gene expression by c-fos dependent and c-fos independent pathways. Science 242: 1424–1427.

    Google Scholar 

  • Kerr LD, Miller DB and Matrisian LM (1990) TGF-β1 inhibition of transin'stromelysin gene expression is mediated through a c-fos binding sequence. Cell 61: 267–278.

    Google Scholar 

  • Khokha R, Waterhouse P, Yagel S, Lala PK, Overall CM, Norton G and Denhardt DT (1989) Antisense RNA-induced reduction in murine TIMP levels confers concogenity on Swiss 3T3 cells. Science 244: 947–950.

    Google Scholar 

  • Kolkenbrock H, Orgel D, Hecker-Kia A, Noack W and Ulbrich N (1991) Complex between a tissue inhibitor of metalloproteinases (TIMP-2) and 72 kDa progelatinase is a metalloproteinase inhibitor. Eur J Biochem 198: 775–781.

    Google Scholar 

  • Komminoth P (1992) Digoxigenin as an alternative probe labeling forin situ hybridization. Diagnostic Mol Pathol 1: 142–150.

    Google Scholar 

  • Lala PK and Graham CH (1990) Mechanisms of trophoblast invasiveness and their control: the role of proteases and proteases inhibitors. Cancer Met Rev 9: 369–379.

    Google Scholar 

  • Leone A, Flaton U, Richter-King C, Sandeen MA, Margulies IMK, Liotta LA and Steeg PS (1991) Reduced tumor incidence, metastatic potential and cytokine responsiveness of nm23-transfected melanoma cells. Cell 65: 25–35.

    Google Scholar 

  • Levy AT, Cioce V, Sobel ME, Garbisa S, Grigioni WF, Liotta LA and Stetler-Stevenson WG (1991) Increased expression of the Mr 72,000 type IV collagenase in human colonic adenocarcinoma. Cancer Res 51: 439–444.

    Google Scholar 

  • Linder ME and Gilman AG (1992) G proteins. Sci Amer 267: 36–43.

    Google Scholar 

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

    Google Scholar 

  • Liotta LA, Rao CN and Barsky SH (1983) Tumour invasion and the extracellular matrix. Lab Invest 49: 636–649.

    Google Scholar 

  • Liotta LA (1986) Tumor invasion and metastases — role of the extracellular matrix. Cancer Res 46: 1–7.

    Google Scholar 

  • Liotta LA, Steeg PS and Stetler-Stevenson WG (1991a) Cancer metastasis and angiogenesis: an imbalance of positive and negative regulation. Cell 64: 327–336.

    Google Scholar 

  • Liotta LA, Stetler-Stevenson WG and Steeg PS (1991b) Metastasis suppressor genes. Import Adv Oncol 85–100.

  • Machida CM, Rodland KD, Matrisian LM, Magun BE and Ciment G (1989) NGF induction of the gene encoding the protease transin accompanies neuronal differentiation in PC 12 cells. Neuron 2: 1587–1596.

    Google Scholar 

  • Matrisian LM, Glaischenhaus N, Gesnel MC and Brethnach R (1985) Epidermal growth factor and oncogenes induce transcription of the same cellular mRNA in rat fibroblasts. EMBO J 4: 1435–1440.

    Google Scholar 

  • Matrisian LM, Bowden GT, Krieg P, Furstenberger G, Briand JP Leroy P and Breathnach R (1986) The mRNA coding for the secreted protease transin is expressed more abundantly in malignant than in benign tumors. Proc Natl Acad Sci USA 83: 9413–9417.

    Google Scholar 

  • Matrisian LM (1990) Metalloproteinases and their inhibitors in matrix remodeling. Trends Genet 6: 121–125.

    Google Scholar 

  • Matrisian LM, McDonnell S, Miller DB, Navre M, Seftor EA and Hendrix MJC (1991) The role of the matrix metalloproteinase stromelysin in the progression of squamous cell careinomas Am J Med Sci 302: 157–162.

    Google Scholar 

  • Matrisian LM (1992) The matrix-degrading metalloproteinases. Bioessays 14: 455–463.

    Google Scholar 

  • McDonnell S and Matrisian LM (1990a) Stromelysin in tumour progression and metastasis. Cancer Metast Rev 9: 305–319.

    Google Scholar 

  • McDonnell SE, Kerr LD and Matrisian LM (1990b) Epidermal growth factor stimulation of stromelysin mRNA in rat fibroblasts requires induction of proto-oncogenes c-fos and c-jun and activation of protein kinase C. Mol Cell Biol 10: 4284–4293.

    Google Scholar 

  • McDonnell S Navre M, Coffey RJ and Matrisian LM (1991) Expression and localization of the matrix metalloproteinase Pump-1 (MMP-7) in human gastric and colon carcinomas. Mol Carcinogenesis 4: 527–533.

    Google Scholar 

  • Mignatti P, Robbins E, and Rifkin DB (1986) Tumor invasion through the human amniotic membrane: requirement for a proteolytic cascade. Cell 47: 487–498.

    Google Scholar 

  • Monteagudo C, Merino MJ, San-Juan J, Liotta LA and Steler-Stevenson WG (1990) Immunohistochemical distribution of type IV collagenase in normal, benign and malignant breast tissue. Am J Pathol 136: 585–592.

    Google Scholar 

  • Muller D, Quantin B, Gesnel MC, Millon-Collard R and Breathnach R (1988) The collagenase gene family in humans consists of at least four members. Biochem J 253: 187–192.

    Google Scholar 

  • Muller D, Breathnach R Engelmann A, Millon R, Broner G, Flesch H, Dumont P, Eber M and Abecassis J (1991) Expression of collagenase-related metalloproteinase genes in human lung or head and neck tumours. Int J Cancer 48: 550–556.

    Google Scholar 

  • Murphy G, Cawston TE and Reynolds JJ (1981) An inhibitor of collagenase from human amniotic fluid. Biochem J 195: 167–170.

    Google Scholar 

  • Murphy G, Cockett MI, Ward RV and Docherty AJP (1991) Matrix metalloproteinase degradation of elastin, type IV collagen and proteoglycan. A quantitative comparison of the activities of 95 kDa and 72 kDa gelatinases, stromelysin-1 and-2 and punctuated metalloproteinase (pump) Biochem J 277: 277–279.

    Google Scholar 

  • Murphy G, Allan JA, Willenbrock F, O'Connell JP and Docherty AJP (1992) The role of the C-terminal domain in collagenase and stromelysin specificity. J Biol Chem 267: 9612–9618.

    Google Scholar 

  • Nagase H, Enghild JJ Suzuki K and Salvesen G (1990) Stepwise activation mechanisms of the precursor of matrix metalloproteinase (stromelysin) by proteinases and (4-aminophenyl) mercuric acetate. Biochemistry 29: 5783–5789.

    Google Scholar 

  • Newell K, McDonnell S, Witty JP, Gaire M, Rodgers WH and Matrisian LM (1993) The stromelysin subclass of metalloproteinases in tumor progression and metastasis. In: Barrett AJ and Bond J (eds) Proceedings of the 9th International ICOP Conference, Proteolysis and Protein Turnover.

  • Obata K, Iwata K, Okada Y, Kohrin Y, Ohuchi E Yoshida S, Shinmei M and Hayakawa T (1992) A one step sandwich enzyme immunoassay for human matrix metalloproteinase 3 (stromelysin- 1) using monoclonal antibodies. Clin Chim Acta 211: 59–72.

    Google Scholar 

  • Okada Y and Nakanishi I (1989) Activation of matrix metalloproteinase 3 (stromelysin) and matrix metalloproteinase 2 (gelatinase) by human neutrophil elastase and cathepsin G. FEBS Lett 249: 353–356.

    Google Scholar 

  • Overall CM, Wrans JL and Sodek J (1989) Independent regulation of collagenase 72 kDa progelatinase and metalloendoproteinase inhibitor expression in human fibroblasts by transforming growth factor β. J Biol Chem 264: 1860–1869.

    Google Scholar 

  • Pajouh MS, Nagle RB, Breathnach R, Finch JS Brawer MK and Bowden GT (1991) Expression of metalloproteinase genes in human prostate cancer. J Cancer Res Clin Oncol 117: 144–150.

    Google Scholar 

  • Park AJ, Matrisian LM, Kells AF, Pearson R, Yuan Z and Navre M (1991) Mutational analysis of the transin (rat stromelysin) auto-inhibitor region demonstrates a role for residues surrounding the “cysteine switch”. J Biol Chem 266: 1584–1590.

    Google Scholar 

  • Poulsom R, Pignatelli M, Stetler-Stevenson WG, Liotta LA, Wright PA, Jeffrey RE, Longcroft JA, Rogers L and Stamp GW (1992) Stromal expression of 72 kDa type IV collagenase (MMP-2) and TIMP-2 mRNAs in colorectal neoplasia. Am J Pathol 141: 389–396.

    Google Scholar 

  • Powell WC, Knox JD, Navre M, Grogan TM, Kittelson J, Nagle RB and Bowden GT (1993) Expression of the metalloproteinase matrilysin in DU-145 cells increases their invasive potential in severe combined immunodeficient mice. Cancer Res 53: 417–422.

    Google Scholar 

  • Rappolee DA, Wang A, Mark D and Werb Z (1989) Developmental expression of PDGF, TGF-α and TFG-β genes in preimplantation mouse embryos. Science 241: 1823–1825.

    Google Scholar 

  • Rodgers WH, Osteen KG, Matrisian LM, Navre M, Giudice LC and Gorstein F (1993) Expression and localization of matrilysin, a matrix metalloproteinase in human endometrium during the reproductive cycle. Am J Obstet Gynecol 168: 253–260.

    Google Scholar 

  • Schonthal A, Herrlich P, Rahmsdorf HJ and Ponta H (1988) Requirement for fos gene expression in the transcriptional activation of collagenase by other oncogenes and phorbol esters. Cell 35: 325–334.

    Google Scholar 

  • Schultz RM, Silberman S, Persky B, Bajkowski WS and Carmichael DF (1988) Inhibition by human recombinant tissue inhibitor of metalloproteinases of human amnion invasion and lung colonization by murine B16-F10 melanoma cells. Cancer Res 48: 5539–5545.

    Google Scholar 

  • Shapiro SD, Griffin GL, Gilbert DJ, Jenkins NA, Copeland NG, Senior RM and Ley TJ (1992) Molecular cloning, chromosomal location, and bacterial expression of a novel murine macrophage metalloelastase. J Biol Chem 267: 4664–4671.

    Google Scholar 

  • Shi YE, Torri J, Yieh L, Wellstein A, Lippman M and Dickson RB (1993) Identification and characterization of a novel matrix-degrading protease from hormone-dependent human breast cancer cells. Cancer Res 53: 1409–1415.

    Google Scholar 

  • Shibata DK, Arnhem M and Martin WJ (1988) Detection of human papillomavirus in paraffin embedded tissue using the polymerase chain reaction. J Exp Med 167: 225–230.

    Google Scholar 

  • Shima I, Sasaguri Y, Kusukawa J, Yamana H, Fujita H, Kakegawa T and Morimatsu M (1992) Production of matrix metalloproteinase-2 and metalloproteinase-3 related to malignant behavior of oesophageal carcinoma. A clinopathologic study. Cancer 70: 2747–2753.

    Google Scholar 

  • Sidebottom E and Clark SR (1983) Cell fusion segregates progressive growth from metastasis. Br J Cancer 47: 399–405.

    Google Scholar 

  • Sires UI, Griffin GL, Broekelmann TJ, Mecham RP, Murphy G, Chung AE, Welgus HG and Senior RM (1993) Degradation of entactin by matrix metalloproteinases, susceptibility to matrilysin and identification of cleavage sites. J Biol Chem 268: 2069–2074.

    Google Scholar 

  • Sirum KL and Brinckerhoff CE (1989) Cloning of the genes for human stromelysin and stromelysin-2: differential expression in rheumatoid synovial fibroblasts. Biochemistry 28: 8691–8698.

    Google Scholar 

  • Sloane BF and Honn KV (1984) Cysteine proteinases and metastasis. Cancer Metast Rev 3: 249–263.

    Google Scholar 

  • Springman EB, Angleton EL, Birkedal-Hansen H and Van Wart H (1990) Multiple modes of activation of latent human fibroblast collagenase: evidence for the role of a Cys 73 active-site zinc complex in latency and a ‘cysteine switch’ mechanism for activation. Proc Natl Acad Sci USA 87: 364–368.

    Google Scholar 

  • Sreenath T, Matrisian LM, Stetler-Stevenson WG, Gattoni-Celli S and Pozzatti RO (1992) Expression of matrix metalloproteinase genes in transformed rat cell lines of high and low metastatic potential. Cancer Res 52: 4942–4947.

    Google Scholar 

  • Steeg PS, Bevilacqua G, Kopper L, Thorgeirsson UP, Talmadge JE, Liotta LA and Sobel MF (1988) Evidence for a novel gene associated with low tumor metastatic potential. J Natl Cancer Inst 80: 200–204.

    Google Scholar 

  • Stetler-Stevenson WG, Krutzsch HC, Wacher MP, Margulies IMK and Liotta LA (1989a) The activation of type IV collagenase proenzyme: sequence identification of the major conversion product following organomercurial activation. J Biol Chem 264: 1353–1356.

    Google Scholar 

  • Stetler-Stevenson WG, Krutzsch HC and Liotta LA (1989b) Tissue inhibitor of metalloproteinase (TIMP-2): a new member of the metalloproteinase inhibitor family. J Biol Chem 264: 17374–17378.

    Google Scholar 

  • Stetler-Stevenson WG, Brown PD, Ohisto M, Levy AT and Liotta LA (1990) Tissue inhibitor of metalloproteinases-2 (TIMP-2) mRNA expression in tumor cell lines and human tumor tissues. J Biol Chem 265: 13933–13938.

    Google Scholar 

  • Stetler-Stevenson WG, Bersch N and Golde DW (1992) Tissue inhibitor of metalloproteinase-2 (TIMP-2) has erythroid-potentiating activity. FEBS Lett 296: 231–234.

    Google Scholar 

  • Urbanski SJ, Edwards DR, Maitland A, Leco KJ, Watson A and Kossakowska AE (1992) Expression of metalloproteinases and their inhibitors in primary pulmonary carcinomas. Br J Cancer 66: 1188–1194.

    Google Scholar 

  • Vogelstein B and Kinzler KW (1993) The multistep nature of cancer. Trends Genet 9: 138–141.

    Google Scholar 

  • Wallet V, Mutzel R, Troll H, Barzu O, Wurster B, Vernon M and Lacombe MA (1990) Dictyostelium nucleoside diphosphate kinase highly homologous in nm23 andawd proteins involved in mammalian tumour metastasis and Drosophila development. J Natl Cancer Inst 18: 1199–1202.

    Google Scholar 

  • Wang F, Patel U, Ghosh L, Chen H and Banergee S (1993) Mutation in nm23 gene is associated with metastasis in colorectal cancer. Cancer Res 53: 717–720.

    Google Scholar 

  • Wasylyk B, Wasylyk C, Flores P, Begue A, Leprince and Stehelin D (1990) The c-ets proto-oncogenes encode transcription factors that co-operate with c-fos and c-jun for transcriptional activation. Nature 346: 191–193.

    Google Scholar 

  • Wasylyk C, Gutman A, Nicholson R and Wasylyk B (1991) The c-ets oncoprotein activates the stromelysin promoter through the same elements as several nonnuclear oncoproteins. EMBO J 10: 1127–1134.

    Google Scholar 

  • Welgus HG and Stricklin GP (1983) Human skin fibroblast inhibitor. J Biol Chem 258: 12259–12264.

    Google Scholar 

  • Welgus HG, Senior PM, Parks WC, Kahn AJ, Ley TJ, Shapiro SD and Campbell EJ (1992) Neutral proteinase expression by human mononuclear phagocytes: a prominent role of cellular differentiation. Matrix (Germany) Suppl 1: 363–367.

    Google Scholar 

  • Wilhelm SM, Collier IE, Kronberger A, Eisen AZ, Marmer BL, Grant GA, Bauer EA and Goldberg GI (1987) Human skin fibroblast stromelysin: structure, glycosylation, substrate specificity, and differential expression in normal and tumorigenic cells. Proc Natl Acad Sci USA 84: 6725–6729.

    Google Scholar 

  • Wilhelm SM, Collier IE, Marmer BL, Eisen AZ, Grant GA and Goldberg GI (1989) SV40-transformed human lung fibroblasts secrete a 94-kDa type IV collagenase which is identical to that secreted by normal human macrophages. J Biol Chem 264: 17213–17221.

    Google Scholar 

  • Zucker S, Lysik RM, Zarrabi M and Moll T (1993) Mr 92,000 type IV collagenase is increased in plasma of patients with colon cancer and breast cancer. Cancer Res 53: 140–146.

    Google Scholar 

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McDonnell, S., Fingleton, B. Role of matrix metalloproteinases in invasion, and metastasis: biology, diagnosis and inhibitors. Cytotechnology 12, 367–384 (1993). https://doi.org/10.1007/BF00744674

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