Summary
There are several characteristics of stromelysin that suggest that expression of this enzyme may play an important role in tumor invasion and metastasis; the stromelysin gene is expressed in response to stimulation by oncogenes and tumor promoters, and the protein product of this gene is a metalloproteinase capable of degrading multiple components of the extracellular matrix. Experimental evidence to support this hypothesis has been derived from several animal model systems, in which a positive correlation has been observed between stromelysin expression and tumor progression and metastasis. In addition, in vivo experiments in which the levels of TIMP, the tissue inhibitor of metalloproteinases, were altered also strongly suggest a causal role for metalloproteinases in tumor metastases. The expression of active stromelysin in tumor cells requires the fulfillment of several criteria, and this multistep process is reminiscent of the molecular events that are currently understood to contribute to tumor progression and carcinogenesis. Expression of stromelysin mRNA requires both a stimulus, a step which may correspond to the activation of an oncogene in multistep carcinogenesis, as well as the lifting of transcriptional repression, which may correspond to the loss of tumor suppressor function. Both positive and negative modulation of stromelysin transcription appear to utilize pathways that involve the protooncogenes c-fos and/or c-jun. The expression of active stromelysin expression of inhibitors and the levels of active enzyme. The multiple levels of stromelysin regulation support the concept of multistep carcinogenesis and may provide a tool for further understanding of the molecular nature of the events that lead to tumor progression, invasion, and metastasis.
Similar content being viewed by others
References
Werb Z: Proteinases and matrix degradation. In: WNKelley, Ruddy S, Sledge CB (ed) Textbook of rheumatology. WB Saunders, Philadelphia, 1989, pp 300–321.
Matrisian LM: Metalloproteinases and their inhibitors in matrix remodeling. TIG 6: 121–125, 1990
Hasty KA, Pourmotabbed T, Goldberg GI, Thompson JP, Stevens R, Mainardi CL: The complete primary structure of human neutrophil collagenase (Abstract) FASEB J 4: A2158, 1990
Chin JR, Murphy G, Werb Z: Stromelysin, a connective tissue-degrading metalloproteinase secreted by stimulated rabbit synovial fibroblasts in parallel with collagenase. J Biol Chem 260: 12367–12376, 1985
Matrisian LM, Glaichenhaus N, Gesnel MC, Breathnach R: Epidermal growth factor and oncogenes induce transcription of the same cellular mRNA in rat fibroblasts. EMBO J 4: 1435–1440, 1985
Matrisian LM, Bowden GT, Krieg P, Furstenberger G, Briand J-P, Leroy P, Breathnach R: 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, 1986
Whitham SE, Murphy G, Angel P, Rahmsdorf HJ, Smith BJ, Lyons A, Harris TJR, Reynolds JJ, Herrlich P, Docherty AJP: Comparison of human stromelysin and collagenase by cloning and sequence analysis. Biochem J 240: 913–916, 1986.
Muller D, Quantin B, Gesnel MC, Millon-Collard R, Abecassis J, Breathnach R: The collagenase gene family in humans consists of at least four members. Biochem J 253: 187–192, 1987.
Fini ME, Karmilowicz MJ, Ruby PL, Beeman AM, Borges KA, Brinckerhoff CE: Cloning of a complementary DNA for rabbit proactivator. A metalloproteinase that activates synovial cell collagenases, shares homology with stromelysin and transin, and is coordinately regulated with collagenase. Arthritis Rheum 30: 1254–1264, 1987.
Okada Y, Nagase H, Harris ED: A metalloproteinase from human rheumatoid synovial fibroblasts that digests connective tissue matrix components. J Biol Chem 261: 14245–14255, 1986
Galloway WA, Murphy G, Sandy JD, Gavrilovic J, Cawston TE, Reynolds JJ: Purification and characterization of a rabbit bone metalloproteinase that degrades proteoglycan and other connective-tissue components. Biochem J 209: 741–752, 1983
Breathnach R, Matrisian LM, Gesnel MC, Staub A, Leroy P: Sequences coding for part of oncogene-induced transin are highly conserved in a related rat gene. Nucl Acids Res 15: 1139–1151, 1987
Birkedal-Hansen H, ed (1990) Proceedings of the matrix metalloproteinase conference, in press
Quantin B, Murphy G, Breathnach R: Pump-1 cDNA codes for a protein with characteristics similar to those of classical collagenase family members. Biochem 28: 5327–5333, 1989
Woessner JF, Taplin C: Purification and properties of a small latent matrix metalloproteinase of the rat uterus. J Biol Chem 263: 16918–16925, 1988
Wilhelm SM, Collier IE, Kronberger A, Eisen AZ, Marmer BL, Grant GA, Bauer EA, Goldberg GI: Human skin fibroblast stromelysin: structure, glycosylation, substrate specificity, and differential expression in normal and tumorigenic cells. Proc Natl Acad Sci USA 84: 6725–6729, 1987
Nicholson R, Murphy G, Breathnach R: Human and rat malignant-tumor-associated mRNAs encode stromelysin-like metalloproteinases. Biochemistry 28: 5195–5203, 1989
Murphy G, Reynolds JJ, Hembry RM: Metalloproteinases and cancer invasion and metastasis. Int J Cancer 44: 757–760, 1989
Vallee BL, Auld DS: Active-site zinc ligands and activated H2O of zinc enzymes. Proc Natl Acad Sci USA 87: 220–224, 1990
Sanchez-Lopez R, Nicholson R, Gesnel MC, Matrisian LM, Breathnach R: Structure-function relationships in the collagenase family member transin. J Biol Chem 263: 11892–11890, 1988
Stoppelli MP, Corti A, Soffientini A, Cassani G, Blasi F, Assoian RK: Differentiation-enhanced binding of the amino-terminal fragment of human urokinase plasminogen activator to a specific receptor on U937 monocytes. Proc Natl Acad Sci USA 82: 4939–4943, 1985
Goldberg GI, Wilhelm SM, Kronberger A, Bauer EA, Grant GA, Eisen AZ: Human fibroblast collagenase: complete primary structure and homology to an oncogene transformation-induced rat protein. J Biol Chem 261: 6600–6605, 1986
Stetler-Stevenson WG, Krutzsch HC, Wacher MP, Margulies IMK, Liotta LA: The activation of human type IV collagenase proenzyme: sequence identification of the major conversion product following organomercurial activation. J Biol Chem: 1353–1356, 1989
He C, Wilhelm SM, Pentland AP, Marmer BL, Grant GA, Eisen AZ, Goldberg GI: Tissue cooperation in a proteolytic cascade activating human interstitial collagenase. Proc Natl Acad Sci USA 86: 2632–2636, 1989
Springman EB, Angleton EL, Birkedal-Hansen H, VanWart H: Multiple modes of activation of latent human fibroblast collagenase: evidence for the role of a Cys73 active-site zinc complex in latency and a ‘cysteine switch’ mechanism for activation. Proc Natl Acad Sci USA 87: 364–368, 1990
Park AJ, Matrisian LM, Kells AF, Pearson R, Yuan Z, Navre M: Mutational analysis of the transin (rat stromelysin) autoinhibitor region suggests that it does not function as pseudosubstrate inhibitor. J Biol Chem (in press)
Herron GS, Banda MJ, Clark EJ, Gavrilovic J, Werb Z: Secretion of metalloproteinases by stimulated capillary endothelial cells. II. Expression of collagenase and stromelysin activities is regulated by endogenous inhibitors. J Biol Chem 261: 2814–2818, 1986
Welgus HG, Stricklin GP: Human skin fibroblast collagenase inhibitor: comparative studies in human connective tissues, serum, and amniotic fluid. J Biol Chem 258: 12259–12264, 1983
Goldberg GI, Marmer BL, Gregory GA, Eisen AZ, Wilhelm S, He C: 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, 1989
Stetler-Stevenson WG, Krutzsch HC, Liotta LL: Tissue inhibitor of metalloproteinase (TIMP-2): a new member of the metalloproteinase inhibitor family. J Biol Chem 264: 17374–17378
DeClerk YA, Yenn T-D, Ratzkin BJ, Lu HS, Langley KE: Purification and characterization of two related but distinct metalloproteinase inhibitors secreted by bovine aortic endothelial cells. J Biol Chem 264: 17445–17453, 1989
Boone TC, Johnson ME, DeClerk YA, Langley KE: cDNA cloning and expression of a metalloproteinase inhibitor related to tissue inhibitor of metalloproteinases. Proc Natl Acad Sci USA 87: 2800–2804, 1990
Frisch SM, Clark EJ, Werb Z: Coordinate regulation of stromelysin and collagenase genes determined with cDNA probes. Proc Natl Acad Sci USA 84: 2600–2604, 1987
Brenner CA, Adler RR, Rappolee DA, Pedersen RA, Werb Z: Genes for extracellular-matrix-degrading metalloproteinases and their inhibitors, TIMP, are expressed during early mammalian development. Genes Dev 6: 848–859, 1989
Matrisian LM, Hogan BL: Growth factor-regulated proteases and extracellular matrix remodeling during mammalian development. In: Nielsen-Hamilton M (ed) Growth factors and development. Academic Press, NY, 1990, pp 219–250
Quaglino D, Nanney LB, Kennedy R, Davidson JM: Transforming growth factor-β stimulates wound healing and modulates extracellular matrix gene expression in pig skin. Lab Invest (in press)
Ito A, Nagase H, Mori Y: Characterization of metalloproteinases in rat gastric tissues with acetic acid-induced ulcers. Scand J Gastroenterol 24: 146–149, 1989
Case JP, Sano H, Lafyatis R, Remmers EF, Kumkumian GK, Wilder RL: Transin/stromelysin expression in the synovium of rats with experimental erosive arthritis. In situ localization and kinetics of expression of the transformation-associated metalloproteinase in euthymic and athymic lewis rats. J Clin Invest 84: 1731–1740, 1989
Hasty KA, Reife RA, Kang AH, Stuart JM: The role of stromelysin in the cartilage destruction that accompanies inflammatory arthritis. Arthritis Rheum 33: 388–397, 1990
Kerr LD, Olashaw NE, Matrisian LM: Transforming growth factor β1 and cAMP inhibit epidermal growth factor and oncogene-induced transin RNA. J Biol Chem 263: 16999–16705, 1988
Kerr LD, Holt JT, Matrisian LM: Growth factors regulate transin gene expression through c-fos dependent and c-fos independent pathways. Science 242: 1424–1428, 1988
Matrisian LM, Bowden GT: Stromelysin/transin and tumor progression. Seminars in Cancer Biol 1: 107–115, 1990
Ostrowski LE, Finch J, Krieg P, Matrisian L, Patskan G, O'Connell JF, Philips J, Slaga TJ, Breathnach R, Bowden GT: Expression pattern of a gene for a secreted metalloproteinase during late stages of tumor progression. Mol Carcinogenesis 1: 13–19, 1988
Krieg P, Finch J, Furstenberger G, Melber K, Matrisian LM, Bowden GT: Tumor promoters induce a transient expression of tumor-associated genes in both basal and differentiated cells of the mouse epidermis. Carcinogenesis 9: 95–100, 1988
Roop DR, Lowy DR, Tambourin PE, Strickland J, Harper JR, Balaschak M, Spangler EF, Yuspa SH: An activated Harvey ras oncogene produces benign tumors on mouse epidermal tissue. Nature 323: 822–824, 1986
Strickland JE, Greenhalgh DA, Koceva-Chylan A, Hennings H, Restrepo C, Balaschak M, Yuspa SH: Development of murine epidermal cell lines which contain an activated ras Ha oncogene and form papillomas in skin grafts on athymic nude mouse hosts. Cancer Res 48: 165–169, 1988
Greenhalgh DA, Yuspa SH: Malignant conversion of murine squamous papilloma cell lines by transfection with the fos oncogene. Mol Carcinogenesis 1: 134–143, 1989
Pozzatti R, Muschel R, Williams J, Padmanabhan R, Howard B, Liotta L, Khoury G: Primary rat embryo cells transformed by one or two oncogenes show different metastatic potentials. Science 232: 223–227, 1986
Balmain A, Ramsden M, Bowden GT, Smith J: Activation of the mouse cellular Harvey-ras gene in chemically induced benign skin papillomas. Nature 307: 658–660, 1984
Bonham K, Embry T, Gibson D, Jaffe DR, Roberts R, Cress AE, Bowden GT: Activation of the cellular Harvey ras gene in mouse skin tumors initiated with urethane. Mol Carcinogenesis 2: 34–39, 1989
Bremner R, Balmain A: Genetic changes in skin tumor progression: Correlation between presence of a mutant ras gene and loss of heterozygosity on mouse chromosome 7. Cell 61: 407–417, 1990
Khokha R, Waterhouse P, Yagel S, Lala PK, Overall CM, Norton G, Denhardt DT: Antisense RNA-induced reduction in murine TIMP levels confers oncogenicity on Swiss 3T3 cells. Science 244: 947–950, 1989
Schultz RM, Silberman S, Persky B, Bajkowski AS, Carmichael DF: 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, 1988
Alvarez OA, Carmichael DF, DeClerk YA: Inhibition of collagenolytic activity and metastasis of tumor cells by a recombinant human tissue inhibitor of metalloproteinases. J Natl Cancer Inst 82: 589–595, 1990
Carmichel DF, Stricklin GP, Stuart JM: Systemic administration of TIMP in the treatment of collagen-induced arthritis in mice. Agents Actions 3: 378–379, 1989
Docherty AJP, Lyons A, Smith BJ, Wright EM, Stephens PE, Harris TJR, Murphy G, Reynolds JJ: Sequence of human tissue inhibitor of metalloproteinases and its identity to erythroid-potentiating activity. Nature 315: 768–761, 1985
McDonnell SE, Kerr LD, Matrisian LM: Epidermal growth factor stimulation of stromelysin mRNA in rat fibroblasts requires induction of proto-oncogene c-fos and c-jun and activation of protein kinase C. Mol Cell Biol 10: 4284–4293, 1990
Schonthal A, Herrlich P, Rahmsdorf HJ, Ponta H: Requirement for fos gene expression in the transcriptional activation of collagenase by other oncogenes and phorbol esters. Cell 35: 325–334, 1988
Brenner DA, O'Hara M, Chojkier M, Karin M: Prolonged activation of c-jun and collagenase genes by tumor necrosis factor-α. Nature 337: 661–663, 1989
Machida CM, Rodland KD, Matrisian L, Magun BE, Ciment G: NGF induction of the gene encoding the protease transin accompanies neuronal differentiation in PC12 cells. Neuron 2: 1587–1596, 1989
Frisch SM, Ruley HE: Transcription from the stromelysin promoter is induced by interleukin-1 and repressed by dexamethasone. J Biol Chem 262: 16300–16304, 1987
Sirum KL, Brinckerhoff CE: Cloning of the genes for human stromelysin and stromelysin-2: Differential expression in rheumatoid synovial fibroblasts. Biochemistry 28: 8691–8698, 1989
Quinones S, Saus J, Otani Y, Harris EDJ, Kurkinen M: Transcriptional regulation of human stromelysin. J Biol Chem 264: 8339–8344, 1989
Machida CM, Muldoon LL, Rodland KD, Magun BE: Transcriptional modulation of transin gene expression by epidermal growth factor and transforming growth factor beta. Mol Cell Biol 8: 2479–2483, 1988
Kerr LD, Miller DB, Matrisian LM: TGF-β1 inhibition of transin/stromelysin gene expression is mediated through a c-fos binding sequence. Cell 61: 267–278, 1990
Jonat C, Rahmsdorf HJ, Park K-K, Cato ACB, Gebel S, Ponta H, Herrlich P: Anti-tumor promotion and anti-inflammation: Down-modulation of AP-1 (Fos/Jun) activity by glucocorticoid hormone. Cell 62: 1189–1204, 1990
Klein G: The approaching era of the tumor suppressor genes. Science 238: 1539–1545, 1987
Fearon EJ, Vogelstein B: A genetic model for colorectal tumorigenesis. Cell 61: 759–767, 1990
Lyons RM, Moses HL: Transforming growth factors and the regulation of cell proliferation. Eur J Biochem 187: 467–473, 1990
Parkinson K, Balmain A: Chalones revisited — a possible role for transforming growth factor β in tumour promotion. Carcinogenesis 11: 195–198, 1990
Takahashi T, Nau M, Chiba I, Birrer MJ, Rosenberg RK, Vinocour M, Levitt M, Pass H, Gazdar AF, Minna JD: p53: a frequent target for genetic abnormalities in lung cancer. Science 246: 491–494, 1989
Huang HJ, Yee JK, Shew JY, Chen PL, Bookstein R, Friedmann T, Lee EY, Lee WH: Suppression of the neoplastic phenotype by replacement of the RB gene in human cancers. Science 242: 1563–1566, 1988
Bookstein R, Lee EY, To H, Young LJ, Sery TW, Hayes RC, Friedmann T, Lee WH: Human retinoblastoma susceptibility gene: genomic organization and analysis of heterozygous intragenic deletion mutants. Proc Natl Acad Sci USA 85: 2210–2214, 1988
Dunn JM, Phillips RA, Becker AJ, Gallie BL: Identification of germline and somatic mutations affecting the retinoblastoma gene. Science 241: 1797–1800, 1988
Friend SH, Bernards R, Rogelj S, Weinberg RA, Rapaport JM, Dryja TP: A human DNA segment with properties of the gene that predisposes to retinoblastoma and osteosarcoma. Nature 323: 643–646, 1986
Weismann BE, Saxon PJ, Pasquale SR, Jones GR, Geiser AG, Stanbridge EJ: Introduction of a normal human chromosome 11 into a Wilms' tumor cell line controls its tumorigenic expression. Science 236: 175–180, 1987
Call KM, Glaser T, Ito CY, Buckler AJ, Pelletier J, Haber DA, Rose EA, Kral A, Yeger H, Lewis WH, Jones C, Housman DE: Isolation and characterization of a zinc finger polypeptide gene at the human chromosome 11 Wilms' tumor locus. Cell 60: 509–520, 1990
Baker SJ, Fearon ER, Nigro JM, Hamilton SR, Preisinger AC, Jessup JM, vanTuinen P, Ledbetter DH, Barker DF, Nakamura Y: Chromosome 17 deletions and p53 gene mutations on colorectal carcinomas. Science 244: 217–221, 1989
Pietenpol JA, Stein RW, Moran E, Yaciuk P, Schlegel R, Lyons RM, Pittelkow MR, Munger K, Howley PM, Moses HL: TGF-β1 inhibition of c-myc transcription and growth in keratinocytes is abrogated by viral transforming proteins with pRB binding domains. Cell 61: 777–785, 1990
Akhurst RJ, Fee F, Balmain A: Localized production of TGF-β mRNA in tumor promoter-stimulated mouse epidermis. Nature 231: 363–365, 1988
Hicks NJ, Ward RV, Reynolds JJ: 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: 834–844, 1984
Halaka AN, Bunning RAD, Bird CC, Gibson M, Reynolds JJ: Production of collagenase and inhibitor (TIMP) by intracranial tumors and dura in vitro. J Neurosurg 59: 461–444, 1983
Edwards DR, Parfett CLJ, Denhardt DT: Transcriptional regulation of two serum-induced RNAs in mouse fibroblasts. Mol Cell Biol 5: 3280–3288, 1985
Edwards DR, Waterhouse P, Holman ML, Denhardt DT: A growth-responsive gene (16C8) in normal mouse fibroblasts homologous to a human collagenase inhibitor with erythroid-potentiating activity: evidence for constitutive and inducible transcripts. Nuc Acids Res 14: 8863–8878, 1986
Edwards DR, Murphy G, Reynolds JJ, Whitham SE, Docherty AJP, Angel P, Heath JK: Transforming growth factor beta modulates the expression of collagenase and metalloproteinase inhibitor. EMBO 6: 1899–1904, 1987
Coulombe B, Ponton A, Daigneault T, Williams BR, Skup D: Presence of transcription regulatory elements within an intron of the virus-inducible murine TIMP gene. Mol Cell Biol 8: 3227–3234, 1988
Murphy G, Reynolds JJ, Werb Z: Biosynthesis of tissue inhibitor of metalloproteinases by human fibroblasts in culture. Stimulation by 12–0-tetradecanoylphorbol 13-acetate and interleukin 1 in parallel with collagenase. J Biol Chem 260: 3079–3083, 1985
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Donnell, S.M., Matrisian, L.M. Stromelysin in tumor progression and metastasis. Cancer Metast Rev 9, 305–319 (1990). https://doi.org/10.1007/BF00049521
Issue Date:
DOI: https://doi.org/10.1007/BF00049521