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Contributions of tumor and stromal matrix metalloproteinases to tumor progression, invasion and metastasis

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Summary

The malignant progression of tumors is driven by the expression of oncogenes and loss of expression of tumor suppressor genes; factors that are intrinsic to cancer cells. The phenotypic changes brought about by the gain or loss of expression of oncogenes and tumor suppressor genes lead to the acquisition of malignant traits, namely, the ability to invade into and grow in ectopic tissue environments. Recently, however, focus in cancer research has widened from the cancer cell to include the surrounding tumor stroma as an integral player in the process of tumor progression. One of the areas in cancer research contributing to this enhanced appreciation of stromal involvement in tumor progression and metastasis is that of matrix metalloproteinases (MMPs).

This review provides an overview of the characteristics of MMPs and discusses their role in the progression and metastasis of tumors. Initially, attention will focus on the regulation of MMPs in tumor cells but will switch to discourse on stromal expression of MMPs in tumors and speculation on the functional consequences of stromal expression of MMPs.

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References

  1. Matrisian LM: The matrix-degrading metalloproteinases. BioEssays 14: 455–463, 1992

    Google Scholar 

  2. Birkedal-Hansen H, Moore WGI, Bodden MK, Windsor LJ, Birkedal-Hansen B, DeCarlo A, Engler JA: Matrix Metalloproteinases: A Review. Critical Reviews in Oral Biology and Medicine 4: 197–250, 1993

    Google Scholar 

  3. Alexander CM, Werb Z: Proteinases and extracellular matrix remodeling. Curr Op Cell Biol 1: 974–982, 1989

    Google Scholar 

  4. Gross J, Lapiere CM: Collagenolytic activity in amphibian tissues: a tissue culture assay. Proc Natl Acad Sci USA 54: 1197–1204, 1962

    Google Scholar 

  5. Sato H, Takino T, Okada Y, Cao J, Shinagawa A, Yamamoto E, Seiki M: A matrix metalloproteinase expressed on the surface of invasive tumour cells. Nature 370: 61–64, 1994

    Google Scholar 

  6. Springman E, Angleton E, Birkedal-Hansen H, Van Wart H: 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, 1990

    Google Scholar 

  7. Matrisian LM, Hogan BLM: Growth factor-regulated proteases and extracellular matrix remodeling during mammalian development. Curr Top Dev Biol 24: 219–259, 1990

    Google Scholar 

  8. Opdenakker G, Van Damme J: Cytokines and proteases in invasive processes: molecular similarities between inflammation and cancer. Cytokine 4: 251–258, 1995

    Google Scholar 

  9. Mauviel A: Cytokine regulation of metalloproteinase gene expression. J Cell Biochem 53: 288–295, 1993

    Google Scholar 

  10. Matrisian L, Leroy P, Ruhlmann C, Gesnel M, Breathnach R: Isolation of the oncogene and epidermal growth factorinduced transin gene: Complex control in rat fibroblasts. Mol Cell Biol 6: 1678–1686, 1986

    Google Scholar 

  11. Overall CM, Wrana JL, Sodek J: Transcriptional and posttranscriptional regulation of 72-kDa gelatinase/type IV collagenase by transforming growth factor-betal in human fibroblasts: Comparisons with collagenase and tissue inhibitor of matrix metalloproteinase gene expression. J Biol Chem 266: 14064–14071, 1991

    Google Scholar 

  12. Delany AM, Brinckerhoff CE: Post-transcriptional regulation of collagenase and stromelysin gene expression by epidermal growth factor and dexamethasone in cultured human fibroblasts. J Cell Biochem 50: 400–410, 1992

    Google Scholar 

  13. Powell WC, Matrisian LM: Complex roles of matrix metalloproteinases in tumor progression. In: Gunthert U, Schlag PM, Birchmeier W (eds) 1995, in press

  14. Hirose T, Patterson C, Pourmotabbed T, Mainardi CL, Hasty KA: Structure-function relationship of human neutrophil collagenase: Identification of regions responsible for substrate specificity and general proteinase activity. Proc Natl Acad Sci USA 90: 2569–2573, 1993

    Google Scholar 

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

    Google Scholar 

  16. Garbisa S, Pozzatti R, Muschel RJ, Saffiotti U, Ballin M, Goldfarb RH, Khoury G, Liotta LA: Secretion of type IV collagenolytic protease and metastatic phenotype: induction by transfection withc-Ha-ras but not c-Ha-ras plus Ad2-Ela. Cancer Res 47: 1523–1528, 1987

    Google Scholar 

  17. Bernhard EJ, Muschel RJ, Hughes EN: Mr92,000 gelatinase release correlates with the metastatic phenotype in transformed rat embryo cells. Cancer Res 50 (13): 3872–3877, 1990

    Google Scholar 

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

    Google Scholar 

  19. MacDougall JR, Bani MR, Lin Y, Rak J, Kerbel RS: The 92 kDa gelatinase B is expressed by advanced stage melanoma cells: suppression by somatic cell hybridization with early stage melanoma cells. Cancer Res 55: 4174–4181, 1995

    Google Scholar 

  20. Yamamoto H, Itoh F, Hinoda Y, Senota A, Yoshimoto M, Nakamura H, Imai K, Yachi A: Expression of matrilysin mRNA in colorectal adenomas and its induction by truncated fibronectin. Biochem Biophys Res Commun 201: 657–664, 1994

    Google Scholar 

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

    Google Scholar 

  22. Newell KJ, Witty JP, Rodgers WH, Matrisian LM: Expression and localization of matrix-degrading metalloproteinases during colorectal tumorigenesis. Mol Carcinog 10: 199–206, 1994

    Google Scholar 

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

    Google Scholar 

  24. Azzam HS, Arand GA, Lippman ME, Thompson EW: MMP-2 activation potential associates with metastatic progression in human breast cancer cell lines, and is independent of MMP-2 production. J Natl Cancer Inst 85: 1758–1764, 1993

    Google Scholar 

  25. De Clerck YA, Perez N, Shimada H, Boone TC, Langley KE, Taylor SM: Inhibition of invasion and metastasis in cells transfected with an inhibitor of metalloproteinases. Cancer Res 52: 701–708, 1992

    Google Scholar 

  26. Khokha R, Zimmer MJ, Graham CH, Lala PK, Waterhouse P: Suppression of invasion by inducible expression of tissue inhibitor of metalloproteinase-1 (TIMP-1) in B16-F10 melanoma cells. JNCI 84: 1017–1022, 1992

    Google Scholar 

  27. Khokha R, Zimmer MJ, Wilson SM, Chambers AF: Up-regulation of TIMP-1 expression in B16-F10 melanoma cells suppresses their metastatic ability in chick embryo. Clin Exp Metastasis 10: 365–370, 1992

    Google Scholar 

  28. Schultz R, Silberman S, Persky B, Bajkowski A, Carmichael D: 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

    Google Scholar 

  29. Alvarez OA, Carmichael DF, DeClerck YA: Inhibition of collagenolytic activity and metastatic of tumor cells by a recombinant human tissue inhibitor of metalloproteinases. J Natl Cancer Inst 82: 589–595, 1990

    Google Scholar 

  30. Chirivi RG, Garofalo A, Crimmin MJ, Bawden LJ, Stoppacciaro A, Brown PD, Giavazzi R: Inhibition of the metastatic spread and growth of B16-BL6 murine melanoma by a synthetic matrix metalloproteinase inhibitor. Int J Cancer 58: 460–464, 1995

    Google Scholar 

  31. Khokha R, Waterhouse P, Yagel S, Lala P, Overall C, Norton G, Denhardt D: Antisense RNA-induced reduction in murine TIMP levels confers oncogenicity on Swiss 3T3 cells. Science 244: 947–950, 1989

    Google Scholar 

  32. Koop S, Khokha R, Schmidt EE, MacDonald IC, Morris VL, Chambers AF, Groom AC: Overexpression of metalloproteinase inhibitor in B16F10 cells does not affect extravasation but reduces tumor growth. Cancer Res 54: 4791–4797, 1994

    Google Scholar 

  33. Montgomery AMP, Mueller BM, Reisfeld RA, Taylor SM, DeClerck YA: Effect of tissue inhibitor of the matrix metalloproteinases-2 expression on the growth and spontaneous metastasis of a human melanoma cell line. Cancer Res 54: 5467–5473, 1994

    Google Scholar 

  34. Witty JP, McDonnell S, Newell K, Cannon P, Navre M, Tressler R, Matrisian LM: Modulation of matrilysin levels in colon carcinoma cell lines affects tumorigenicityin vivo. Cancer Res 54: 4805–4812, 1994

    Google Scholar 

  35. Wang X, Fu X, Brown PD, Crimmin MJ, Hoffman RJ: Matrix metalloproteinase inhibitor BB-94 (Batimastat) inhibits human colon tumor growth and spread in a patient-like orthotopic model in nude mice. Cancer Res 54: 4726–4728, 1995

    Google Scholar 

  36. Davies B, Brown PD, East N, Crimmin MJ, Balkwill FR: A synthetic matrix metalloproteinase inhibitor decreases tumor burden and prolongs survival of mice bearing human ovarian carcinoma xenografts. Cancer Res 53: 2087–2091, 1993

    Google Scholar 

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

    Google Scholar 

  38. Muller D, Wolf C, Abecassis J, Millon R, Engelmann A, Bronner G, Rouyer N, Rio M-C, Eber M, Methlin G, Chambon P, Basset P: Increased stromelysin 3 gene expression is associated with increased local invasiveness in head and neck squamous cell carcinomas. Cancer Res 53: 165–169, 1993

    Google Scholar 

  39. Wolf C, Chenard M-P, De Grossouvre PD, Bellocq J-P, Chambon P, Basset P: Breast-cancer-associated stromelysin-3 gene is expressed in basal cell carcinoma and during cutaneous wound healing. J Invest Dermatol 99: 870–872, 1992

    Google Scholar 

  40. Pyke C, Ralfki!ae!r E, Tryggvason K, Dano K: Messenger RNA for two type IV collagenases is located in stromal cells in human colon cancer. Am J Pathol 142: 359–365, 1993

    Google Scholar 

  41. Okada A, Bellocq J, Chenard M, Rio M, Chambon P, Basset P: Membrane-type matrix metalloproteinase (MT-MMP) gene is expressed in stromal cells of human colon, breast and head and neck carcinomas. Proc Natl Acad Sci USA 92: 2730–2734. PNAS 92: 2730–2734, 1995

    Google Scholar 

  42. Majmudar G, Nelson BR, Jensen TC, Johnson TM: Increased expression of matrix metalloproteinase-3 (stromelysin-1) in cultured fibroblasts and basal cell carcinomas of nevoid basal cell carcinoma syndrome. Mol Carcinog 11: 29–33, 1994

    Google Scholar 

  43. Pyke C, Ralfki!ae!r E, Huhtala P, Hurskainen T, Tryggvason K: Localization of messenger RNA for Mr 72,000 and 92,000 type IV collagenases in human skin cancers byin situ hybridization. Cancer Res 52: 1336–1341, 1992

    Google Scholar 

  44. Canete-Soler R, Litzky L, Lubensky I, Muschel RJ: Localization of the 92 kd gelatinase mRNA in squamous cell and adenocarcinomas of the lung usingin situ hybridization. Am J Pathol 144: 518–527, 1994

    Google Scholar 

  45. Kossakowska AE, Urbanski SJ, Watson A, Hayden LJ, Edwards DR: Patterns of expression of metalloproteinases and their inhibitors in human malignant lymphomas. Oncology Research 5: 19–28, 1993

    Google Scholar 

  46. Wolf C, Rouyer N, Lutz Y, Adida C, Loriot M, Bellocq J-P, Chambon P, Basset P: Stromelysin 3 belongs to a subgroup of proteinases expressed in breast carcinoma fibroblastic cells and possibly implicated in tumor progression. Proc Natl Acad Sci USA 90: 1843–1847, 1993

    Google Scholar 

  47. Pajouh M, Nagle R, Breathnach R, Finch J, Brawer M, Bowden G: Expression of metalloproteinase genes in human prostate cancer. J Cancer Res Clin Oncol 117: 144–150, 1991

    Google Scholar 

  48. Wilson CL, Heppner KJ, Rudolph LA, Matrisian LM: The metalloproteinase matrilysin is preferentially expressed in epithelial cells in a tissue-restricted pattern in the mouse. Mol Biol Cell 6: 851–869, 1995

    Google Scholar 

  49. Saarialho-Kere UK, Crouch EC, Parks WC: The matrix metalloproteinase matrilysin is constitutively expressed in adult human exocrine epithelium. J Invest Dermatology (in press): 1995

  50. Okada Y, Shinmei M, Tanaka O, Naka K, Kimura A, Nakanishi I, Bayliss MT, Iwata K, Nagase H: Localization of matrix metalloproteinase 3 (stromelysin) in osteoarthritic cartilage and synovium. Lab Invest 66: 680–690, 1992

    Google Scholar 

  51. Goldberg G, Wilhelm S, Kronberger A, Bauer E, Grant G, Eisen A: Human fibroblast collagenase; complete primary structure and homology to an oncogene transformation-induced rat protein. J Biol Chem 261: 6600–6605, 1986

    Google Scholar 

  52. Rodgers WH, Matrisian LM, Giudice LC, Dsupin B, Cannon P, Svitek C, Gorstein F, Osteen KG: Patterns of matrix metalloproteinase expression in cycling endometrium imply differential functions and regulation by steroid hormones. J Clin Invest 94: 946–953, 1994

    Google Scholar 

  53. Klein-Szanto AJ, Larcher F, Bonfil RD, Conti CJ: Multistage chemical carcinogenesis protocols produce spindle cell carcinomas of the mouse skin. Carcinogenesis 10: 2169–2172, 1989

    Google Scholar 

  54. Stoler AB, Stenback F, Balmain A: The conversion of mouse skin squamous cell carcinomas to spindle cell carcinomas is a recessive event. J Cell Biol 122: 1103–1117, 1993

    Google Scholar 

  55. Wright JH, McDonnell S, Portella G, Bowden GT, Balmain A, Matrisian LM: A switch from stromal to tumor cell expression of stromelysin-1 mRNA associated with the conversion of squamous to spindle carcinomas during mouse skin tumor progression. Mol Carinog 10: 207–215, 1994

    Google Scholar 

  56. Killary AM, Fournier REK: A genetic analysis of extinction: trans-dominant loci regulate expression of liver-specific traits in hepatoma hybrid cells. Cell 38: 523–534, 1984

    Google Scholar 

  57. Boshart M, Nitsch D, Schutz G: Extinction of gene expression in somatic cell hybrids - a reflection of important regulatory mechanisms? TIG 9: 240–245, 1995

    Google Scholar 

  58. McDonnell SE, Kerr LD, Matrisian LM: 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, 1990

    Google Scholar 

  59. Kataoka H, DeCastro R, Zucker S, Biswas C: Tumor cellderived collagenase-stimulatory factor increases expression of interstitial collagenase, stromelysin, and 72-kDa gelatinase. Cancer Res 53: 3154–3158, 1993

    Google Scholar 

  60. 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 107: 477–486, 1994

    Google Scholar 

  61. Ito A, Nakajima S, Sasaguri Y, Nagase H, Mori Y: Co-culture of human breast adenocarcinoma MCF-7 cells and human dermal fibroblasts enhances the production of matrix metalloproteinases 1, 2 and 3 in fibroblasts. British Journal of Cancer 71: 1039–1045, 1995

    Google Scholar 

  62. Borchers AH, Powell MB, Fusenig NE, Bowden GT: Paracrine factor and cell-cell contact-mediated induction of protease and c-ets gene expression in malignant keratinocyte/dermal fibroblast cocultures. Exp Cell Res 213: 143–147, 1994

    Google Scholar 

  63. Clark W: Tumor progression and the nature of cancer. British Journal of Cancer 64: 631–644, 1991

    Google Scholar 

  64. Werb Z, Tremble PM, Behrendtsen O, Crowley E, Damsky CH: Signal transduction through the fibronectin receptor induces collagenase and stromelysin gene expression. J Cell Biol 109: 877–889, 1989

    Google Scholar 

  65. Unemori EN, Werb Z: Reorganization of polymerized actin: a possible trigger for induction of procollagenase in fibroblasts cultured in or on collagen gels. J Cell Biol 102: 1021–1031, 1986

    Google Scholar 

  66. Aggeler J, Frisch SM, Werb Z: Changes in cell shape correlate with collagenase gene expression in rabbit synovial fibroblasts. J Cell Biol 98: 1662–1671, 1984

    Google Scholar 

  67. MacDougall JR, Kerbel RS: Constitutive production of 92 kDa gelatinase B can be suppressed by alterations in cell shape. Exp Cell Res 218: 508–515, 1995

    Google Scholar 

  68. Edvardsen K, Chen W, Rucklidge G, Walsh FS, Öbrink B, Bock E: Transmembrane neural cell-adhesion molecule (NCAM), but not glycosyl-phosphatidylinositol-anchored NCAM, down-regulates secretion of matrix metalloproteinases. Proc Natl Acad Sci USA 90: 11463–11467, 1993

    Google Scholar 

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

    Google Scholar 

  70. Bernhard EJ, Gruber SB, Muschel RJ: Direct evidence linking expression of matrix metalloproteinase 9 (92-kDa gelatinase/collagenase) to the metastatic phenotype in transformed rat embryo cells. Proc Natl Acad Sci USA 91: 4293–4297, 1994

    Google Scholar 

  71. Docherty A, Lyons A, Smith B, Wright E, Stephens P, Harris T, Murphy G, Reynolds J: Sequence of human tissue inhibitor of metalloproteinases and its identity to erythroid-potentiating activity. Nature 315: 761–768, 1985

    Google Scholar 

  72. Murate T, Yamashita K, Ohashi H, Kagami Y, Tsushita K, Kinoshita T, Hotta T, Saito H, Yoshida S, Mori KJ, Hayakawa T: Erythroid potentiating activity of tissue inhibitor of metalloproteinases on the differentiation of erythropoietin-responsive mouse erythroleukemia cell line, ELM-I-1-3, is closely related to its cell growth potentiating activity. Exp Hematol 21: 169–176, 1993

    Google Scholar 

  73. Hayakawa T, Yamashita K, Ohuchi E, Shinagawa A: Cell growth-promoting activity of tissue inhibitor of metalloproteinases-2 (TIMP-2). J Cell Sci 107: 2373–2379, 1994

    Google Scholar 

  74. Emonard HP, Remacle AG, Noël AC, Grimaud J-A, Stetler-Stevenson WG, Foidart J-M: Tumor cell surface-associated binding site for theM r 72,000 type IV collagenase. Cancer Res 52: 5845–5848, 1992

    Google Scholar 

  75. Yu M, Sato H, Seiki M, Thompson EW: Complex regulation of membrane-type matrix metalloproteinase expression and matrix metalloproteinase-2 activation by concanavalin A in MDA-MB-231 human breast cancer cells. Cancer Res 55: 3272–3277, 1995

    Google Scholar 

  76. Okada A, Bellocq J, Rouyer N, Chenard M, Rio M, Chambon P, Basset P: Membrane-type matrix metalloproteinase (MT-MMP) gene is expressed in stromal cells of human colon, breast, and head and neck carcinomas. Proceedings of the National Academy of Sciences of the United States of America: 2730–2734, 1995

  77. Witty JP, Lempka T, Coffey RJ Jr, Matrisian LM: Decreased tumor formation in 7,12-dimethylbenzanthracene-treated stromelysin-1 transgenic mice is associated with alterations in mammary epithelial cell apoptosis. Cancer Res 55: 1401–1406, 1995

    Google Scholar 

  78. Johnson MD, Kim H-RC, Chesler L, Tsao-Wu G, Bouck N, Polverini PJ: Inhibition of angiogenesis by tissue inhibitor of metalloproteinase. J Cell Physiol 160: 194–202, 1994

    Google Scholar 

  79. Albini A, Fontanini G, Masiello L, Tacchetti C, Bigini D, Luzzi P, Noonan DM, Stetler-Stevenson WG: Angiogenic potentialin vivo by Kaposi's sarcoma cell-free supernatants and HIV-1tat product: Inhibition of KS-like lesions by tissue inhibitor of metalloproteinase-2. AIDS 8: 1237–1244, 1994

    Google Scholar 

  80. Taraboletti G, Garofalo A, Belotti D, Drudis T, Borsotti P, Scanziani E, Brown PD, Giavazzi R: Inhibition of angiogenesis and murine hemangioma growth by batimastat, a synthetic inhibitor of matrix metalloproteinases. J Natl Cancer Inst 87: 293–298, 1995

    Google Scholar 

  81. Galardy RE, Grobelny D, Foellmer HG, Fernandez LA: Inhibition of angiogenesis by the matrix metalloprotease inhibitorN-[2R-2-(hydroxamidocarbonymethyl)-4-methylpentanoyl)]-L-tryptophan methylamide. Cancer Res 54: 4715–4718, 1994

    Google Scholar 

  82. Moses MA, Langer R: A metalloproteinase inhibitor as an inhibitor of neovascularization. J Cell Biochem 47: 230–235, 1991

    Google Scholar 

  83. Takahashi K, Mulliken JB, Kozakewich HP, Rogers RA, Folkman J, Ezekowitz RA: Cellular markers that distinguish the phases of hemangioma during infancy and childhood. J Clin Invest 93: 2357–2364, 1994

    Google Scholar 

  84. Benelli R, Adatia R, Ensoli B, Stetler-Stevenson WG, Santi L, Albini A: Inhibition of AIDS-Kaposi's sarcoma cell induced endothelial cell invasion by TIMP-2 and a synthetic peptide from the metalloproteinase propeptide: implications for an anti-angiogenic therapy. Oncology Research 6: 251–257, 1994

    Google Scholar 

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MacDougall, J.R., Matrisian, L.M. Contributions of tumor and stromal matrix metalloproteinases to tumor progression, invasion and metastasis. Cancer Metast Rev 14, 351–362 (1995). https://doi.org/10.1007/BF00690603

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