Skip to main content

Matrix Metalloproteinases: Mediators of Tumour-Host Cell Interactions

  • Chapter
Integration/Interaction of Oncologic Growth

Part of the book series: Cancer Growth and Progression ((CAGP,volume 15))

Abstract

Matrix metalloproteinases (MMPs) are a family of metalloendopeptidases that induce remodelling of extracellular matrix (ECM) and differentially cleave many soluble mediators that regulate cell physiology. Due to their matrix-degrading capabilities and elevated expression levels in both neoplastic and host cells in human cancer, MMPs have acquired considerable attention as targets for anti-cancer therapy. This chapter summarizes two decades of research examining MMP biochemistry and biology utilizing in vitro cell-based and biochemical analyses, more recent examination of their functional significance in de novo mouse models of human cancer development and results from human clinical trials where MMP inhibitors were evaluated for efficacy as anti-cancer therapeutics.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 219.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

Similar content being viewed by others

References

  1. Knudson, A.G.J., 1977, Genetic predisposition to cancer. In Origins of Human Cancer, J.D.W. H.H. Hiatt, J.A. Wiunsted eds, Vol. 4:45–52. Cold Spring Harbor Lab, Cold Spring Harbor, NY.

    Google Scholar 

  2. Fearon, E. R., and Vogelstein, B., 1990, A genetic model for colorectal tumorigenesis. Cell, 61:759–767.

    Article  PubMed  Google Scholar 

  3. Knudson, A. G., 2001, Two genetic hits (more or less) to cancer. Nat Rev Cancer 1:157–162.

    Article  Google Scholar 

  4. Hanahan, D., and Weinberg, R. A., 2000, The hallmarks of cancer. Cell, 100:57–70.

    Article  PubMed  Google Scholar 

  5. Bissell, M. J., and Radisky, D., 2001, Putting tumours in context. Nat Rev Cancer, 1:46–54.

    Article  PubMed  Google Scholar 

  6. Coussens, L. M., and Werb, Z., 2002, Inflammation and cancer. Nature, 420:860–867.

    Article  PubMed  Google Scholar 

  7. Hahn, W. C., and Weinberg, R. A., 2002, Modelling the molecular circuitry of cancer, Nat Rev Cancer, 2:331–341.

    Article  PubMed  Google Scholar 

  8. Bergers, G., and Benjamin, L. E., 2003, Angiogenesis: Tumorigenesis and the angiogenic switch. Nat Rev Cancer, 3:401–410.

    Article  PubMed  Google Scholar 

  9. Hussain, S. P., Hofseth, L. J., and Harris, C. C., 2003, Radical causes of cancer. Nat Rev Cancer, 3:275–286.

    Article  Google Scholar 

  10. Fidler, I. J., 2003, Timeline: The pathogenesis of cancer metastasis: the 'seed and soil’ hypothesis revisited. Nat Rev Cancer, 3:453–458.

    Article  PubMed  Google Scholar 

  11. Nagase, H., and Woessner, J. F., 1999, Matrix metalloproteinases. J Biol Chem, 274:21491–21494.

    Article  PubMed  Google Scholar 

  12. Bergers, G., Brekken, R., McMahon, G., Vu, T. H., Itoh, T., Tamaki, K., Tanzawa, K., Thorpe, P., Itohara, S., Werb, Z., and Hanahan, D., 2000, Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis. Nat Cell Biol, 2:737–744.

    Article  PubMed  Google Scholar 

  13. McQuibban, G. A., Gong, J. H., Tam, E. M., McCulloch, C. A., Clark-Lewis, I., and Overall, C. M., 2000, Inflammation dampened by gelatinase A cleavage of monocyte chemoattractant protein-3. Science, 289:1202–1206.

    Article  Google Scholar 

  14. Powell, W. C., Fingleton, B., Wilson, C. L., Boothby, M., and Matrisian, L. M., 1999, The metalloproteinase matrilysin proteolytically generates active soluble Fas ligand and potentiates epithelial cell apoptosis. Curr Biol, 9:1441–7.

    Article  PubMed  Google Scholar 

  15. Manes, S., Llorente, M., Lacalle, R. A., Gomez-Mouton, C., Kremer, L., Mira, E., and Martinez, A. C., 1999, The matrix metalloproteinase-9 regulates the insulin-like growth factor-triggered autocrine response in DU-145 carcinoma cells. J Biol Chem, 274:6935–6945.

    Article  PubMed  Google Scholar 

  16. Sternlicht, M. D., and Bergers, G., 2000, Matrix metalloproteinases as emerging targets in anticancer therapy: status and prospects. Emerg Theurpeut Targets, 4:609–633.

    Article  Google Scholar 

  17. Egeblad, M., and Werb, Z., 2002, New functions for the matrix metalloproteinases in cancer progression. Nat Rev Cancer, 2:161–174.

    Article  PubMed  Google Scholar 

  18. Wilson, C. L., Heppner, K. J., Labosky, P. A., Hogan, B. L., and Matrisian, L. M., 1997, Intestinal tumorigenesis is suppressed in mice lacking the metalloproteinase matrilysin. Proc Natl Acad Sci USA, 94:1402–7.

    Article  PubMed  Google Scholar 

  19. Sternlicht, M. D., Lochter, A., Sympson, C. J., Huey, B., Rougier, J. P., Gray, J. W., Pinkel, D., Bissell, M. J., and Werb, Z., 1999, The stromal proteinase MMP3/stromelysin-1 promotes mammary carcinogenesis. Cell, 98:137–146.

    Article  PubMed  Google Scholar 

  20. Coussens, L. M., Tinkle, C. L., Hanahan, D., and Werb, Z., 2000, MMP-9 supplied by bone marrow-derived cells contributes to skin carcinogenesis. Cell, 103:481–490.

    Article  Google Scholar 

  21. Coussens, L. M., Shapiro, S. D., Soloway, P. D., and Werb, Z., 2001, Models for gain-of-function and loss-of-function of MMPs. Transgenic and gene targeted mice. Methods Mol Biol, 151:149–179.

    PubMed  Google Scholar 

  22. Rawlings, N. D., and Barrett, A. J., 1995, Evolutionary families of metallopeptidases. Methods Enzymol, 248:183–228.

    PubMed  Google Scholar 

  23. Stocker, W., Grams, F., Baumann, U., Reinemer, P., Gomis-Ruth, F. X., McKay, D. B., and Bode, W., 1995, The metzincins—topological and sequential relations between the astacins, adamalysins, serralysins, and matrixins (collagenases) define a superfamily of zinc-peptidases. Protein Sci, 4:823–40.

    PubMed  Google Scholar 

  24. Sternlicht, M.D., and Werb, Z., 1999, ECM Proteinases. In Guidebook to the Extracellular Matrix, Kries, T., and Vale, R., eds, 503–562. Oxford University Press, Oxford, UK.

    Google Scholar 

  25. Overall, C. M., 2002, Molecular determinants of metalloproteinase substrate specificity: matrix metalloproteinase substrate binding domains, modules, and exosites. Mol Biotechnol, 22:51–86.

    Article  PubMed  Google Scholar 

  26. Puente, X. S., Sanchez, L. M., Overall, C. M., and Lopez-Otin, C., 2003, Human and mouse proteases: a comparative genomic approach. Nat Rev Genet, 4:544–558.

    Article  Google Scholar 

  27. Lopez-Otin, C., and Overall, C. M., 2002, Protease degradomics: a new challenge for proteomics. Nat Rev Mol Cell Biol, 3:509–519.

    Article  PubMed  Google Scholar 

  28. Woessner, J. F., and Nagase, H., 2000, Matrix metalloproteinases and TIMPs. Oxford University Press, Oxford, UK.

    Google Scholar 

  29. Hirose, T., Patterson, C., Pourmotabbed, T., Mainardi, C. L., and Hasty, K. A., 1993, 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.

    PubMed  Google Scholar 

  30. Li, J., Brick, P., O'Hare, M. C., Skarzynski, T., Lloyd, L. F., Curry, V. A., Clark, I. M., Bigg, H. F., Hazleman, B. L., Cawston, T. E., and et al., 1995, Structure of full-length porcine synovial collagenase reveals a C-terminal domain containing a calcium-linked, four-bladed beta-propeller. Structure, 3:541–9.

    Article  PubMed  Google Scholar 

  31. Murphy, G., Nguyen, Q., Cockett, M. I., Atkinson, S. J., Allan, J. A., Knight, C. G., Willenbrock, F., and Docherty, A. J., 1994, Assessment of the role of the fibronectin-like domain of gelatinase A by analysis of a deletion mutant. J Biol Chem, 269:6632–6.

    PubMed  Google Scholar 

  32. Banyai, L., Tordai, H., and Patthy, L., 1994, The gelatin-binding site of human 72 kDa type IV collagenase (gelatinase A). Biochem J, 298(Pt 2):403–407.

    PubMed  Google Scholar 

  33. Itoh, Y., Kajita, M., Kinoh, H., Mori, H., Okada, A., and Seiki, M., 1999, Membrane type 4 matrix metalloproteinase (MT4-MMP, MMP-17) is a glycosylphosphatidylinositol-anchored proteinase. J Biol Chem, 274:34260–34266.

    Article  PubMed  Google Scholar 

  34. Pei, D., Kang, T., and Qi, H., 2000, Cysteine array matrix metalloproteinase (CA-MMP)/MMP-23 is a type II transmembrane matrix metalloproteinase regulated by a single cleavage for both secretion and activation. J Biol Chem, 275:33988–97.

    Article  PubMed  Google Scholar 

  35. Seidah, N. G., and Chretien, M., 1997, Eukaryotic protein processing: endoproteolysis of precursor proteins. Curr Opin Biotechnol, 8:602–607.

    Article  Google Scholar 

  36. Nagase, H., 1997, Activation mechanisms of matrix metalloproteinases. Biol Chem, 378:151–160.

    PubMed  Google Scholar 

  37. Lafleur, M. A., Handsley, M. M., and Edwards, D. R., 2003, Metalloproteinases and their inhibitors in angiogenesis. Expert Rev Mol Med, 5:1–39.

    Article  Google Scholar 

  38. Esteve, P. O., Chicoine, E., Robledo, O., Aoudjit, F., Descoteaux, A., Potworowski, E. F., and St Pierre, Y., 2002, Protein kinase C-zeta regulates transcription of the matrix metalloproteinase-9 gene induced by IL-1 and TNF-alpha in glioma cells via NF-kappa B. J Biol Chem, 277:35150–35155.

    Article  PubMed  Google Scholar 

  39. Troussard, A. A., Costello, P., Yoganathan, T. N., Kumagai, S., Roskelley, C. D., and Dedhar, S., 2000, The integrin linked kinase (ILK) induces an invasive phenotype via AP-1 transcription factor-dependent upregulation of matrix metalloproteinase 9 (MMP-9). Oncogene, 19:5444–5452.

    Article  PubMed  Google Scholar 

  40. Fini, M.E., Cook, J.R., Mohan, R., and Brinckerhoff, C.E., 1998, Regulation of matrix metalloproteinase gene expression. In Matrix Metalloproteinases, Parks, W.C., and Mecham, R.P., eds, 299–356. Academic Press, New York.

    Google Scholar 

  41. Hou, G., Vogel, W. F., and Bendeck, M. P., 2002, Tyrosine kinase activity of discoidin domain receptor 1 is necessary for smooth muscle cell migration and matrix metalloproteinase expression. Circ Res, 90:1147–1149.

    Article  PubMed  Google Scholar 

  42. Olaso, E., Labrador, J. P., Wang, L., Ikeda, K., Eng, F. J., Klein, R., Lovett, D. H., Lin, H. C., and Friedman, S. L., 2002, Discoidin domain receptor 2 regulates fibroblast proliferation and migration through the extracellular matrix in association with transcriptional activation of matrix metalloproteinase-2. J Biol Chem, 277:3606–3613.

    Article  PubMed  Google Scholar 

  43. Arnott, C. H., Scott, K. A., Moore, R. J., Hewer, A., Phillips, D. H., Parker, P., Balkwill, F. R., and Owens, D. M., 2002, Tumour necrosis factor-alpha mediates tumour promotion via a PKC alpha-and AP-1-dependent pathway. Oncogene, 21:4728–4738.

    Article  PubMed  Google Scholar 

  44. Ventura, J. J., Kennedy, N. J., Lamb, J. A., Flavell, R. A., and Davis, R. J., 2003, c-Jun NH(2)-terminal kinase is essential for the regulation of AP-1 by tumor necrosis factor. Mol Cell Biol, 23:2871–2882.

    Article  PubMed  Google Scholar 

  45. Gilbert, S. J., Duance, V. C., and Mason, D. J., 2004, Does protein kinase R mediate TNF-alpha-and ceramide-induced increases in expression and activation of matrix metalloproteinases in articular cartilage by a novel mechanism?. Arthritis Res Ther, 6:R46–R55.

    Article  PubMed  Google Scholar 

  46. Chen, N., Nomura, M., She, Q. B., Ma, W. Y., Bode, A. M., Wang, L., Flavell, R. A., and Dong, Z., 2001, Suppression of skin tumorigenesis in c-Jun NH(2)-terminal kinase-2-deficient mice. Cancer Res, 61:3908–3912.

    PubMed  Google Scholar 

  47. Vogel, W., Gish, G. D., Alves, F., and Pawson, T., 1997, The discoidin domain receptor tyrosine kinases are activated by collagen. Mol Cell, 1:13–23.

    Article  PubMed  Google Scholar 

  48. Vogel, W., 1999, Discoidin domain receptors: structural relations and functional implications. Faseb J, 13Suppl:S77–82.

    PubMed  Google Scholar 

  49. Johnson, J. D., Edman, J. C., and Rutter, W. J., 1993, A receptor tyrosine kinase found in breast carcinoma cells has an extracellular discoidin I-like domain. Proc Natl Acad Sci USA, 90:10891.

    PubMed  Google Scholar 

  50. Matsuyama, W., Wang, L., Farrar, W. L., Faure, M., and Yoshimura, T., 2004, Activation of discoidin domain receptor 1 isoform b with collagen up-regulates chemokine production in human macrophages: role of p38 mitogen-activated protein kinase and NF-kappaB. J Immunol, 172:2332–2340.

    PubMed  Google Scholar 

  51. Kamohara, H., Yamashiro, S., Galligan, C., and Yoshimura, T., 2001, Discoidin domain receptor 1 isoform-a (DDR1alpha) promotes migration of leukocytes in three-dimensional collagen lattices. Faseb J, 15:2724–2726.

    PubMed  Google Scholar 

  52. Alves, F., Vogel, W., Mossie, K., Millauer, B., Hofler, H., and Ullrich, A., 1995, Distinct structural characteristics of discoidin I subfamily receptor tyrosine kinases and complementary expression in human cancer. Oncogene, 10:609–618.

    PubMed  Google Scholar 

  53. Barker, K. T., Martindale, J. E., Mitchell, P. J., Kamalati, T., Page, M. J., Phippard, D. J., Dale, T. C., Gusterson, B. A., and Crompton, M. R., 1995, Expression patterns of the novel receptor-like tyrosine kinase, DDR, in human breast tumours. Oncogene, 10:569–575.

    PubMed  Google Scholar 

  54. Ye, S., 2000, Polymorphism in matrix metalloproteinase gene promoters: implication in regulation of gene expression and susceptibility of various diseases. Matrix Biol, 19:623–629.

    Article  PubMed  Google Scholar 

  55. Kanamori, Y., Matsushima, M., Minaguchi, T., Kobayashi, K., Sagae, S., Kudo, R., Terakawa, N., and Nakamura, Y., 1999, Correlation between expression of the matrix metalloproteinase-1 gene in ovarian cancers and an insertion/deletion polymorphism in its promoter region. Cancer Res, 59:4225–7.

    PubMed  Google Scholar 

  56. Ghilardi, G., Biondi, M. L., Mangoni, J., Leviti, S., DeMonti, M., Guagnellini, E., and Scorza, R., 2001, Matrix metalloproteinase-1 promoter polymorphism 1G/2G is correlated with colorectal cancer invasiveness. Clin Cancer Res, 7:2344–2346.

    PubMed  Google Scholar 

  57. Van Wart, H. E., and Birkedal-Hansen, H., 1990, The cysteine switch: a principle of regulation of metalloproteinase activity with potential applicability to the entire matrix metalloproteinase gene family. Proc Natl Acad Sci USA, 87:5578–82.

    PubMed  Google Scholar 

  58. Springman, E. B., Angleton, E. L., Birkedal-Hansen, H., and Van Wart, H. E., 1990, 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, 87:364–8.

    PubMed  Google Scholar 

  59. Sternlicht, M. D., and Werb, Z., 2001, How matrix metalloproteinases regulate cell behavior. Annu Rev Cell Dev Biol, 17:463–516.

    Article  PubMed  Google Scholar 

  60. O'Connell, J. P., Willenbrock, F., Docherty, A. J., Eaton, D., and Murphy, G., 1994, Analysis of the role of the COOH-terminal domain in the activation, proteolytic activity, and tissue inhibitor of metalloproteinase interactions of gelatinase B. J Biol Chem, 269:14967–73.

    PubMed  Google Scholar 

  61. Pei, D., 1999, CA-MMP: a matrix metalloproteinase with a novel cysteine array, but without the classic cysteine switch. FEBS Lett, 457:262–70.

    Article  PubMed  Google Scholar 

  62. Fridman, R., Toth, M., Pena, D., and Mobashery, S., 1995, Activation of progelatinase B (MMP-9) by gelatinase A (MMP-2). Cancer Res, 55:2548–2555.

    PubMed  Google Scholar 

  63. Knauper, V., Will, H., Lopez-Otin, C., Smith, B., Atkinson, S. J., Stanton, H., Hembry, R. M., and Murphy, G., 1996, Cellular mechanisms for human procollagenase-3 (MMP-13) activation. Evidence that MT1-MMP (MMP-14) and gelatinase a (MMP-2) are able to generate active enzyme. J Biol Chem, 271:17124–31.

    Article  PubMed  Google Scholar 

  64. Itoh, Y., Takamura, A., Ito, N., Maru, Y., Sato, H., Suenaga, N., Aoki, T., and Seiki, M., 2001, Homophilic complex formation of MT1-MMP facilitates proMMP-2 activation on the cell surface and promotes tumor cell invasion. Embo J, 20:4782–4793.

    Article  PubMed  Google Scholar 

  65. Ramos-DeSimone, N., Hahn-Dantona, E., Sipley, J., Nagase, H., French, D. L., and Quigley, J. P., 1999, Activation of matrix metalloproteinase-9 (MMP-9) via a converging plasmin/stromelysin-1 cascade enhances tumor cell invasion. J Biol Chem, 274:13066–76.

    Article  PubMed  Google Scholar 

  66. Overall, C. M., and Sodek, J., 1990, Concanavalin A produces a matrix-degradative phenotype in human fibroblasts. Induction and endogenous activation of collagenase, 72-kDa gelatinase, and Pump-1 is accompanied by the suppression of the tissue inhibitor of matrix metalloproteinases. J Biol Chem, 265:21141–21151.

    PubMed  Google Scholar 

  67. Strongin, A. Y., Collier, I., Bannikov, G., Marmer, B. L., Grant, G. A., and Goldberg, G. I., 1995, Mechanism of cell surface activation of 72-kDa type IV collagenase. Isolation of the activated form of the membrane metalloprotease. J Biol Chem, 270:5331–5338.

    Article  Google Scholar 

  68. Fang, K. C., Raymond, W. W., Lazarus, S. C., and Caughey, G. H., 1996, Dog mastocytoma cells secrete a 92-kD gelatinase activated extracellularly by mast cell chymase. J Clin Invest 97:1589–1596.

    PubMed  Google Scholar 

  69. Fang, K. C., Raymond, W. W., Blount, J. L., and Caughey, G. H., 1997, Dog mast cell alpha-chymase activates progelatinase B by cleaving the Phe88-Gln89 and Phe91-Glu92 bonds of the catalytic domain. J Biol Chem, 272:25628–25635.

    Article  PubMed  Google Scholar 

  70. Saarinen, J., Kalkkinen, N., Welgus, H. G., and Kovanen, P. T., 1994, Activation of human interstitial procollagenase through direct cleavage of the Leu83-Thr84 bond by mast cell chymase. J Biol Chem, 269:18134–18140.

    PubMed  Google Scholar 

  71. 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.

    Article  Google Scholar 

  72. Rice, A., and Banda, M. J., 1995, Neutrophil elastase processing of gelatinase A is mediated by extracellular matrix. Biochemistry, 34:9249–56.

    Article  PubMed  Google Scholar 

  73. Ferry, G., Lonchampt, M., Pennel, L., de Nanteuil, G., Canet, E., and Tucker, G. C., 1997, Activation of MMP-9 by neutrophil elastase in an in vivo model of acute lung injury. FEBS Lett, 402:111–115.

    Article  PubMed  Google Scholar 

  74. Shamamian, P., Schwartz, J. D., Pocock, B. J., Monea, S., Whiting, D., Marcus, S. G., and Mignatti, P., 2001, Activation of progelatinase A (MMP-2) by neutrophil elastase, cathepsin G, and proteinase-3: a role for inflammatory cells in tumor invasion and angiogenesis. J Cell Physiol, 189:197–206.

    Article  Google Scholar 

  75. Butler, G. S., Hutton, M., Wattam, B. A., Williamson, R. A., Knauper, V., Willenbrock, F., and Murphy, G., 1999, The specificity of TIMP-2 for matrix metalloproteinases can be modified by single amino acid mutations. J Biol Chem, 274:20391–20396.

    Article  Google Scholar 

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

    Article  PubMed  Google Scholar 

  77. Zhao, H., Bernardo, M. M., Osenkowski, P., Sohail, A., Pei, D., Nagase, H., Kashiwagi, M., Soloway, P. D., DeClerck, Y. A., and Fridman, R., 2004, Differential Inhibition of Membrane Type 3 (MT3)-Matrix Metalloproteinase (MMP) and MT1-MMP by Tissue Inhibitor of Metalloproteinase (TIMP)-2 and TIMP-3 Regulates Pro-MMP-2 Activation. J Biol Chem, 279:8592–8601.

    Article  PubMed  Google Scholar 

  78. Baker, A. H., Edwards, D. R., and Murphy, G., 2002, Metalloproteinase inhibitors: biological actions and therapeutic opportunities. J Cell Sci, 115:3719–3727.

    Article  PubMed  Google Scholar 

  79. Bein, K., and Simons, M., 2000, Thrombospondin type 1 repeats interact with matrix metalloproteinase 2. Regulation of metalloproteinase activity. J Biol Chem, 275:32167–32173.

    Article  PubMed  Google Scholar 

  80. Rodriguez-Manzaneque, J. C., Lane, T. F., Ortega, M. A., Hynes, R. O., Lawler, J., and Iruela-Arispe, M. L., 2001, Thrombospondin-1 suppresses spontaneous tumor growth and inhibits activation of matrix metalloproteinase-9 and mobilization of vascular endothelial growth factor. Proc Natl Acad Sci USA, 98:12485–12490.

    Article  PubMed  Google Scholar 

  81. Rhee, J., and Coussens, L., 2002, RECKing MMP function: implications for cancer development. Trends in Cell Bio, 12:209–211.

    Article  Google Scholar 

  82. Oh, J., Takahashi, R., Kondo, S., Mizoguchi, A., Adachi, E., Sasahara, R. M., Nishimura, S., Imamura, Y., Kitayama, H., Alexander, D. B., Ide, C., Horan, T. P., Arakawa, T., Yoshida, H., Nishikawa, S., Itoh, Y., Seiki, M., Itohara, S., Takahashi, C., and Noda, M., 2001, The Membrane-Anchored MMP Inhibitor RECK Is a Key Regulator of Extracellular Matrix Integrity and Angiogenesis. Cell, 107:789–800.

    Article  PubMed  Google Scholar 

  83. Brew, K., Dinakarpandian, D., and Nagase, H., 2000, Tissue inhibitors of metalloproteinases: evolution, structure and function. Biochim Biophys Acta, 1477:267–283.

    PubMed  Google Scholar 

  84. Amour, A., Slocombe, P. M., Webster, A., Butler, M., Knight, C. G., Smith, B. J., Stephens, P. E., Shelley, C., Hutton, M., Knauper, V., Docherty, A. J., and Murphy, G., 1998, TNF-alpha converting enzyme (TACE) is inhibited by TIMP-3. FEBS Lett, 435:39–44.

    Article  PubMed  Google Scholar 

  85. Liu, L., Rich, B. E., Inobe, J., Chen, W., and Weiner, H. L., 1997, A potential pathway of Th2 development during primary immune response. IL-10 pretreated dendritic cells can prime naive CD4+T cells to secrete IL-4. Adv Exp Med Biol, 417:375–81.

    PubMed  Google Scholar 

  86. Yang, Z., Strickland, D. K., and Bornstein, P., 2001, Extracellular matrix metalloproteinase 2 levels are regulated by the low density lipoprotein-related scavenger receptor and thrombospondin 2. J Biol Chem, 276:8403–8408.

    Article  Google Scholar 

  87. Sottrup-Jensen, L., Sand, O., Kristensen, L., and Fey, G. H., 1989, The alpha-macroglobulin bait region. Sequence diversity and localization of cleavage sites for proteinases in five mammalian alpha-macroglobulins. J Biol Chem, 264:15781–9.

    PubMed  Google Scholar 

  88. Takahashi, C., Sheng, Z., Horan, T. P., Kitayama, H., Maki, M., Hitomi, K., Kitaura, Y., Sasahara, R. M., Horimoto, A., and al., e., 1998, Regulation of matrix metalloproteinase-9 and inhibition of tumor invasion by the membrane-anchored glycoprotein RECK. Proc Nat Acad Sci USA, 95:13221–13226.

    Article  PubMed  Google Scholar 

  89. Welm, B., Mott, J. D., and Werb, Z., 2002, Vasculogenesis is a wreck without Reck: Regulating matrix metalloproteinase activity during embryogenesis is critical for development. Curr Biol, 12:209–211.

    Article  Google Scholar 

  90. Stamenkovic, I., 2003, Extracellular matrix remodelling: the role of matrix metalloproteinases. J Pathol, 200:448–464.

    Article  PubMed  Google Scholar 

  91. Giannelli, G., Falk-Marzillier, J., Schiraldi, O., Stetler-Stevenson, W. G., and Quaranta, V., 1997, Induction of cell migration by matrix metalloprotease-2 cleavage of laminin-5. Science, 277:225–228.

    Article  PubMed  Google Scholar 

  92. Bosman, F. T., and Stamenkovic, I., 2003, Functional structure and composition of the extracellular matrix. J Pathol, 200:423–428.

    Article  PubMed  Google Scholar 

  93. Dumin, J. A., Dickeson, S. K., Stricker, T. P., Bhattacharyya-Pakrasi, M., Roby, J. D., Santoro, S. A., and Parks, W. C., 2001, Pro-collagenase-1 (matrix metalloproteinase-1) binds the alpha(2)beta(1) integrin upon release from keratinocytes migrating on type I collagen. Journal of Biological Chemistry, 276:29368–29374.

    Article  PubMed  Google Scholar 

  94. Guo, H., Zucker, S., Gordon, M. K., Toole, B. P., and Biswas, C., 1997, Stimulation of matrix metalloproteinase production by recombinant extracellular matrix metalloproteinase inducer from transfected Chinese hamster ovary cells. J Biol Chem, 272:24–27.

    Article  Google Scholar 

  95. Guo, H., Li, R., Zucker, S., and Toole, B. P., 2000, EMMPRIN (CD147), an inducer of matrix metalloproteinase synthesis, also binds interstitial collagenase to the tumor cell surface. Cancer Res, 60:888–891.

    PubMed  Google Scholar 

  96. Brooks, P. C., Strömblad, S., Sanders, L. C., von Schalscha, T. L., Aimes, R. T., Stetler-Stevenson, W. G., Quigley, J. P., and Cheresh, D. A., 1996, Localization of matrix metalloproteinase MMP-2 to the surface of invasive cells by interaction with integrin alpha v beta 3. Cell, 85:683–693.

    Article  PubMed  Google Scholar 

  97. Yu, W. H., Woessner, J. F., Jr., McNeish, J. D., and Stamenkovic, I., 2002, CD44 anchors the assembly of matrilysin/MMP-7 with heparin-binding epidermal growth factor precursor and ErbB4 and regulates female reproductive organ remodeling. Genes Dev, 16:307–323.

    Article  PubMed  Google Scholar 

  98. Yu, Q., and Stamenkovic, I., 1999, Localization of matrix metalloproteinase 9 to the cell surface provides a mechanism for CD44-mediated tumor invasion. Genes Dev, 13:35–48.

    PubMed  Google Scholar 

  99. Bourguignon, L. Y., Gunja-Smith, Z., Iida, N., Zhu, H. B., Young, L. J., Muller, W. J., and Cardiff, R. D., 1998, CD44v(3,8–10) is involved in cytoskeleton-mediated tumor cell migration and matrix metalloproteinase (MMP-9) association in metastatic breast cancer cells. J Cell Physiol, 176:206–215.

    Article  PubMed  Google Scholar 

  100. Fiore, E., Fusco, C., Romero, P., and Stamenkovic, I., 2002, Matrix metalloproteinase 9 (MMP-9/gelatinase B) proteolytically cleaves ICAM-1 and participates in tumor cell resistance to natural killer cell-mediated cytotoxicity. Oncogene, 21:5213–5223.

    Article  PubMed  Google Scholar 

  101. Olson, M. W., Toth, M., Gervasi, D. C., Sado, Y., Ninomiya, Y., and Fridman, R., 1998, High affinity binding of latent matrix metalloproteinase-9 to the alpha2(IV) chain of collagen IV. J Biol Chem, 273:10672–81.

    Article  PubMed  Google Scholar 

  102. Yu, Q., and Stamenkovic, I., 2000, Cell surface-localized matrix metalloproteinase-9 proteolytically activates TGF-beta and promotes tumor invasion and angiogenesis. Genes Dev, 14:163–176.

    PubMed  Google Scholar 

  103. Ruiter, D., Bogenrieder, T., Elder, D., and Herlyn, M., 2002, Melanoma-stroma interactions: structural and functional aspects, Lancet Oncol, 3:35–43.

    Article  Google Scholar 

  104. Martin, P., 1997, Wound healing—aiming for perfect skin regeneration. Science, 276:75–81.

    Article  PubMed  Google Scholar 

  105. Uitto, J., and Kouba, D., 2000, Cytokine modulation of extracellular matrix gene expression: relevance to fibrotic skin diseases. J Dermatol Sci, 24Suppl 1:S60–S69.

    Article  PubMed  Google Scholar 

  106. van Kempen, L. C., Ruiter, D. J., van Muijen, G. N., and Coussens, L. M., 2003, The tumor microenvironment: a critical determinant of neoplastic evolution. Eur J Cell Biol, 82:539–548.

    Article  PubMed  Google Scholar 

  107. Gheree-Kermani, M., and Phan, M., 2001, Role of Cytokines and cytokine therapy in wound healing and fibrotic disease. Curr Pharm Des:1083–1103.

    Google Scholar 

  108. Bergers, G., and Coussens, L. M., 2000, Extrinsic regulators of epithelial tumor progression: metalloproteinases. Curr Opin Genet Dev, 10:120–127.

    Article  PubMed  Google Scholar 

  109. Engbring, J. A., and Kleinman, H. K., 2003, The basement membrane matrix in malignancy. J Pathol, 200:465–470.

    Article  PubMed  Google Scholar 

  110. Colorado, P. C., Torre, A., Kamphaus, G., Maeshima, Y., Hopfer, H., Takahashi, K., Volk, R., Zamborsky, E. D., Herman, S., Sarkar, P. K., Ericksen, M. B., Dhanabal, M., Simons, M., Post, M., Kufe, D. W., Weichselbaum, R. R., Sukhatme, V. P., and Kalluri, R., 2000, Anti-angiogenic cues from vascular basement membrane collagen. Cancer Res, 60:2520–2526.

    PubMed  Google Scholar 

  111. McCawley, L. J., and Matrisian, L. M., 2001, Matrix metalloproteinases: they're not just for matrix anymore!. Curr Opin Cell Biol, 13:534–40.

    Article  Google Scholar 

  112. O'Reilly, M. S., Boehm, T., Shing, Y., Fukai, N., Vasios, G., Lane, W. S., Flynn, E., Birkhead, J. R., Olsen, B. R., and Folkman, J., 1997, Endostatin: an endogenous inhibitor of angiogenesis and tumor growth. Cell, 88:277–285.

    Article  PubMed  Google Scholar 

  113. Kamphaus, G. D., Colorado, P. C., Panka, D. J., Hopfer, H., Ramchandran, R., Torre, A., Maeshima, Y., Mier, J. W., Sukhatme, V. P., and Kalluri, R., 2000, Canstatin, a novel matrix-derived inhibitor of angiogenesis and tumor growth. J Biol Chem, 275:1209–1215.

    Article  PubMed  Google Scholar 

  114. Maeshima, Y., Colorado, P. C., and Kalluri, R., 2000, Two RGD-independent αvβ3 integrin binding sites on tumstatin regulate distinct anti-tumor properties. J Biol Chem, 275:23745–50.

    Article  PubMed  Google Scholar 

  115. Petitclerc, E., Boutaud, A., Prestayko, A., Xu, J., Sado, Y., Ninomiya, Y., Sarras, M. P., Jr., Hudson, B. G., and Brooks, P. C., 2000, New functions for non-collagenous domains of human collagen type IV. Novel integrin ligands inhibiting angiogenesis and tumor growth in vivo. J Biol Chem, 275:8051–8061.

    Article  PubMed  Google Scholar 

  116. Ramchandran, R., Dhanabal, M., Volk, R., Waterman, M. J., Segal, M., Lu, H., Knebelmann, B., and Sukhatme, V. P., 1999, Antiangiogenic activity of restin, NC10 domain of human collagen XV: comparison to endostatin. Biochem Biophys Res Commun, 255:735–739.

    Article  PubMed  Google Scholar 

  117. Hiraoka, N., Allen, E., Apel, I. J., Gyetko, M. R., and Weiss, S. J., 1998, Matrix metalloproteinases regulate neovascularization by acting as pericellular fibrinolysins. Cell, 95:365–377.

    Article  PubMed  Google Scholar 

  118. Cornelius, L. A., Nehring, L. C., Harding, E., Bolanowski, M., Welgus, H. G., Kobayashi, D. K., Pierce, R. A., and Shapiro, S. D., 1998, Matrix metalloproteinases generate angiostatin: effects on neovascularization. J Immunol, 161:6845–6852.

    PubMed  Google Scholar 

  119. Hiller, O., Lichte, A., Oberpichler, A., Kocourek, A., and Tschesche, H., 2000, Matrix metalloproteinases collagenase-2, macrophage elastase, collagenase-3, and membrane type 1-matrix metalloproteinase impair clotting by degradation of fibrinogen and factor XII, J Biol Chem 275:33008–33013.

    Article  Google Scholar 

  120. Vaisanen, A., Kallioinen, M., Taskinen, P. J., and Turpeenniemi-Hujanen, T., 1998, Prognostic value of MMP-2 immunoreactive protein (72 kD type IV collagenase) in primary skin melanoma. J Pathol, 186:51–58.

    Article  PubMed  Google Scholar 

  121. McQuibban, G. A., Butler, G. S., Gong, J. H., Bendall, L., Power, C., Clark-Lewis, I., and Overall, C. M., 2001, Matrix metalloproteinase activity inactivates the CXC chemokine stromal cell-derived factor-1. J Biol Chem, 276:43503–8.

    Article  PubMed  Google Scholar 

  122. McQuibban, G. A., Gong, J. H., Wong, J. P., Wallace, J. L., Clark-Lewis, I., and Overall, C. M., 2002, Matrix metalloproteinase processing of monocyte chemoattractant proteins generates CC chemokine receptor antagonists with anti-inflammatory properties in vivo. Blood, 100:1160–1167.

    PubMed  Google Scholar 

  123. Sheu, B. C., Hsu, S. M., Ho, H. N., Lien, H. C., Huang, S. C., and Lin, R. H., 2001, A novel role of metalloproteinase in cancer-mediated immunosuppression. Cancer Res, 61:237–242.

    PubMed  Google Scholar 

  124. Balbin, M., Fueyo, A., Tester, A. M., Pendas, A. M., Pitiot, A. S., Astudillo, A., Overall, C. M., Shapiro, S. D., and Lopez-Otin, C., 2003, Loss of collagenase-2 confers increased skin tumor susceptibility to male mice. Nat Genet, 35:252–257.

    Article  PubMed  Google Scholar 

  125. Coussens, L. M., and Werb, Z., 1996, Matrix metalloproteinases and the development of cancer. Chem Biol, 3:895–904.

    Article  PubMed  Google Scholar 

  126. Nelson, A. R., Fingleton, B., Rothenberg, M. L., and Matrisian, L. M., 2000, Matrix metalloproteinases: biologic activity and clinical implications, J Clin Oncol 18:1135–1149.

    PubMed  Google Scholar 

  127. McCawley, L. J., and Matrisian, L. M., 2001, Tumor progression: defining the soil round the tumor seed. Curr Biol, 11:R25–R27.

    Article  PubMed  Google Scholar 

  128. Coussens, L. M., Fingleton, B., and Matrisian, L. M., 2002, Matrix metalloproteinase inhibitors and cancer: trials and tribulations. Science, 295:2387–2392.

    Article  PubMed  Google Scholar 

  129. Iwata, H., Kobayashi, S., Iwase, H., Masaoka, A., Fujimoto, N., and Okada, Y., 1996, Production of matrix metalloproteinases and tissue inhibitors of metalloproteinases in human breast carcinomas, Jpn J Cancer Res 87:602–611.

    PubMed  Google Scholar 

  130. Brummer, O., Athar, S., Riethdorf, L., Loning, T., and Herbst, H., 1999, Matrix-metalloproteinases 1, 2, and 3 and their tissue inhibitors 1 and 2 in benign and malignant breast lesions: an in situ hybridization study. Virchows Arch, 435:566–573.

    Article  PubMed  Google Scholar 

  131. Heppner, K. J., Matrisian, L. M., Jensen, R. A., and Rodgers, W. H., 1996, Expression of most matrix metalloproteinase family members in breast cancer represents a tumor-induced host response. Am J Pathol, 149:273–282.

    PubMed  Google Scholar 

  132. Visscher, D. W., Hoyhtya, M., Ottosen, S. K., Liang, C. M., Sarkar, F. H., Crissman, J. D., and Fridman, R., 1994, Enhanced expression of tissue inhibitor of metalloproteinase-2 (TIMP-2) in the stroma of breast carcinomas correlates with tumor recurrence. Int J Cancer, 59:339–344.

    PubMed  Google Scholar 

  133. Lebeau, A., Nerlich, A. G., Sauer, U., Lichtinghagen, R., and Lohrs, U., 1999, Tissue distribution of major matrix metalloproteinases and their transcripts in human breast carcinomas. Anticancer Res, 19:4257–64.

    PubMed  Google Scholar 

  134. Jones, J. L., Glynn, P., and Walker, R. A., 1999, Expression of MMP-2 and MMP-9, their inhibitors, and the activator MT1-MMP in primary breast carcinomas. J Pathol, 189:161–168.

    Article  PubMed  Google Scholar 

  135. Remacle, A. G., Noel, A., Duggan, C., McDermott, E., O'Higgins, N., Foidart, J. M., and Duffy, M. J., 1998, Assay of matrix metalloproteinases types 1, 2, 3 and 9 in breast cancer. Br J Cancer, 77:926–31.

    PubMed  Google Scholar 

  136. Scorilas, A., Karameris, A., Arnogiannaki, N., Ardavanis, A., Bassilopoulos, P., Trangas, T., and Talieri, M., 2001, Overexpression of matrix-metalloproteinase-9 in human breast cancer: a potential favourable indicator in node-negative patients. Br J Cancer, 84:1488–1496.

    Article  PubMed  Google Scholar 

  137. Ahmad, A., Hanby, A., Dublin, E., Poulsom, R., Smith, P., Barnes, D., Rubens, R., Anglard, P., and Hart, I., 1998, Stromelysin 3: an independent prognostic factor for relapse-free survival in node-positive breast cancer and demonstration of novel breast carcinoma cell expression. Am J Pathol, 152:721–728.

    PubMed  Google Scholar 

  138. Nielsen, B. S., Rank, F., Lopez, J. M., Balbin, M., Vizoso, F., Lund, L. R., Dano, K., and Lopez-Otin, C., 2001, Collagenase-3 expression in breast myofibroblasts as a molecular marker of transition of ductal carcinoma in situ lesions to invasive ductal carcinomas. Cancer Res, 61:7091–7100.

    PubMed  Google Scholar 

  139. Nielsen, B. S., Sehested, M., Kjeldsen, L., Borregaard, N., Rygaard, J., and Dano, K., 1997, Expression of matrix metalloprotease-9 in vascular pericytes in human breast cancer. Lab Invest, 77:345–55.

    PubMed  Google Scholar 

  140. Nielsen, B. S., Timshel, S., Kjeldsen, L., Sehested, M., Pyke, C., Borregaard, N., and Dano, K., 1996, 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, 65:57–62.

    Article  PubMed  Google Scholar 

  141. Wright, J. H., McDonnell, S., Portella, G., Bowden, G. T., Balmain, A., and Matrisian, L. M., 1994, 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 Carcinog, 10:207–215.

    PubMed  Google Scholar 

  142. Coussens, L. M., Raymond, W. W., Bergers, G., Laig-Webster, M., Behrendtsen, O., Werb, Z., Caughey, G. H., and Hanahan, D., 1999, Inflammatory mast cells up-regulate angiogenesis during squamous epithelial carcinogenesis. Genes Dev, 13:1382–1397.

    PubMed  Google Scholar 

  143. Janeway, C. A., Travers, P., Walport, M., and Shlomchik, M., 2001, Immunobiology, 5th ed. Garland Publishing, New York and London.

    Google Scholar 

  144. Dranoff, G., 2002, Tumour immunology: Immune recognition and tumor protection. Curr Opin in Immunology, 14:161–164.

    Article  Google Scholar 

  145. Dranoff, G., 2003, Coordinated tumor immunity. J Clin Invest, 111:1116–1118.

    Article  PubMed  Google Scholar 

  146. Oshikiri, T., Miyamoto, M., Shichinohe, T., Suzuoki, M., Hiraoka, K., Nakakubo, Y., Shinohara, T., Itoh, T., Kondo, S., and Katoh, H., 2003, Prognostic value of intratumoral CD8+ T lymphocyte in extrahepatic bile duct carcinoma as essential immune response. J Surg Oncol, 84:224–228.

    Article  PubMed  Google Scholar 

  147. Abe, M., Kondo, S., Hirano, S., Ambo, Y., Tanaka, E., Morikawa, T., Okushiba, S., and Katoh, H., 2003, Long-term survival after radical resection of advanced pancreatic cancer: a case report with special reference to CD8+ T-cell infiltration. Int J Gastrointest Cancer, 33:107–110.

    Article  PubMed  Google Scholar 

  148. Wakabayashi, O., Yamazaki, K., Oizumi, S., Hommura, F., Kinoshita, I., Ogura, S., Dosaka-Akita, H., and Nishimura, M., 2003, CD4(+) T cells in cancer stroma, not CD8(+) T cells in cancer cell nests, are associated with favorable prognosis in human non-small cell lung cancers. Cancer Sci, 94:1003–1009.

    Article  PubMed  Google Scholar 

  149. Nakakubo, Y., Miyamoto, M., Cho, Y., Hida, Y., Oshikiri, T., Suzuoki, M., Hiraoka, K., Itoh, T., Kondo, S., and Katoh, H., 2003, Clinical significance of immune cell infiltration within gallbladder cancer. Br J Cancer, 89:1736–1742.

    Article  Google Scholar 

  150. Funada, Y., Noguchi, T., Kikuchi, R., Takeno, S., Uchida, Y., and Gabbert, H. E., 2003, Prognostic significance of CD8+ T cell and macrophage peritumoral infiltration in colorectal cancer. Oncol Rep, 10:309–313.

    PubMed  Google Scholar 

  151. Dunn, G. P., Bruce, A. T., Ikeda, H., Old, L. J., and Schreiber, R. D., 2002, Cancer immunoediting: from immunosurveillance to tumor escape. Nat Immunol, 3:991–998.

    Article  PubMed  Google Scholar 

  152. Dudley, M. E., and Rosenberg, S. A., 2003, Adoptive-cell-transfer therapy for the treatment of patients with cancer. Nat Rev Cancer, 3:666–675.

    Article  PubMed  Google Scholar 

  153. Balkwill, F., and Mantovani, A., 2001, Inflammation and cancer: back to Virchow?. Lancet, 357:539–545.

    Article  Google Scholar 

  154. Duncan, L. M., Richards, L. A., and Mihm, M. C., Jr., 1998, Increased mast cell density in invasive melanoma. J Cutan Pathol, 25:11–15.

    PubMed  Google Scholar 

  155. Imada, A., Shijubo, N., Kojima, H., and Abe, S., 2000, Mast cells correlate with angiogenesis and poor outcome in stage I lung adenocarcinoma. Eur Respir J, 15:1087–1093.

    Article  PubMed  Google Scholar 

  156. Takanami, I., Takeuchi, K., and Naruke, M., 2000, Mast cell density is associated with angiogenesis and poor prognosis in pulmonary adenocarcinoma. Cancer, 88:2686–2692.

    Article  PubMed  Google Scholar 

  157. Tomita, M., Matsuzaki, Y., and Onitsuka, T., 2000, Effect of mast cells on tumor angiogenesis in lung cancer. Ann Thorac Surg, 69:1686–1690.

    Article  PubMed  Google Scholar 

  158. Toth-Jakatics, R., Jimi, S., Takebayashi, S., and Kawamoto, N., 2000, Cutaneous malignant melanoma: correlation between neovascularization and peritumor accumulation of mast cells overexpressing vascular endothelial growth factor. Hum Pathol, 31:955–960.

    Article  PubMed  Google Scholar 

  159. Shea, C. R., and Prieto, V. G., 1994, Mast cells in angiolipomas and hemangiomas of human skin: are they important for angiogenesis?. J Cutan Pathol, 21:247–251.

    PubMed  Google Scholar 

  160. Benitez-Bribiesca, L., Wong, A., Utrera, D., and Castellanos, E., 2001, The role of mast cell tryptase in neoangiogenesis of premalignant and malignant lesions of the uterine cervix. J Histochem Cytochem, 49:1061–1062.

    PubMed  Google Scholar 

  161. Ness, R. B., and Cottreau, C., 1999, Possible role of ovarian epithelial inflammation in ovarian cancer. J Natl Cancer Inst, 91:1459–67.

    Article  PubMed  Google Scholar 

  162. Weitzman, S. A., and Gordon, L. I., 1990, Inflammation and cancer: role of phagocyte-generated oxidants in carcinogenesis. Blood, 76:655–663.

    PubMed  Google Scholar 

  163. Shacter, E., and Weitzman, S. A., 2002, Chronic inflammation and cancer. Oncology, 16:217–226.

    PubMed  Google Scholar 

  164. Ernst, P. B., and Gold, B. D., 2000, The disease spectrum of Helicobacter pylori: the immunopathogenesis of gastroduodenal ulcer and gastric cancer. Annu Rev Microbiol, 54:615–640.

    Article  PubMed  Google Scholar 

  165. Engle, S. J., Ormsby, I., Pawlowski, S., Boivin, G. P., Croft, J., Balish, E., and Doetschman, T., 2002, Elimination of Colon Cancer in Germ-free Transforming Growth Factor Beta 1-deficient Mice. Cancer Res, 62:6362–6366.

    PubMed  Google Scholar 

  166. Williams, C. S., Mann, M., and DuBois, R. N., 1999, The role of cyclooxygenases in inflammation, cancer, and development. Oncogene, 18:7908–7916.

    Article  PubMed  Google Scholar 

  167. Garcia-Rodriguez, L. A., and Huerta-Alvarez, C., 2001, Reduced risk of colorectal cancer among long-term users of aspirin and nonaspirin nonsteroidal antiinflammatory drugs. Epidemiology, 12:88–93.

    Article  PubMed  Google Scholar 

  168. Meier, C. R., Schmitz, S., and Jick, H., 2002, Association between acetaminophen or nonsteroidal antiinflammatory drugs and risk of developing ovarian, breast, or colon cancer. Pharmacotherapy, 22:303–309.

    Article  Google Scholar 

  169. Sharpe, C. R., Collet, J. P., McNutt, M., Belzile, E., Boivin, J. F., and Hanley, J. A., 2000, Nested case-control study of the effects of non-steroidal antiinflammatory drugs on breast cancer risk and stage. Br J Cancer, 83:112–120.

    Article  PubMed  Google Scholar 

  170. Cotterchio, M., Kreiger, N., Sloan, M., and Steingart, A., 2001, Nonsteroidal anti-inflammatory drug use and breast cancer risk. Cancer Epidemiol Biomarkers Prev, 10:1213–1217.

    PubMed  Google Scholar 

  171. Akre, K., Ekstrom, A. M., Signorello, L. B., Hansson, L. E., and Nyren, O., 2001, Aspirin and risk for gastric cancer: a population-based case-control study in Sweden. Br J Cancer, 84:965–968.

    Article  PubMed  Google Scholar 

  172. Bashkin, P., Razin, E., Eldor, A., and Vlodavsky, I., 1990, Degranulating mast cells secrete an endoglycosidase that degrades heparan sulfate in subendothelial extracellular matrix. Blood, 75:2204–2212.

    PubMed  Google Scholar 

  173. Inuzuka, K., Ogata, Y., Nagase, H., and Shirouzu, K., 2000, Significance of coexpression of urokinase-type plasminogen activator, and matrix metalloproteinase 3 (stromelysin) and 9 (gelatinase B) in colorectal carcinoma. J Surg Res, 93:211–218.

    Article  PubMed  Google Scholar 

  174. Stahle-Backdahl, M., Sudbeck, B. D., Eisen, A. Z., Welgus, H. G., and Parks, W. C., 1992, Expression of 92-kDa type IV collagenase mRNA by eosinophils associated with basal cell carcinoma. J Invest Dermatol, 99:497–503.

    Article  PubMed  Google Scholar 

  175. Zeng, Z. S., and Guillem, J. G., 1996, Colocalisation of matrix metalloproteinase-9-mRNA and protein in human colorectal cancer stromal cells. Br J Cancer, 74:1161–1167.

    PubMed  Google Scholar 

  176. Coussens, L. M., Hanahan, D., and Arbeit, J., 1996, Genetic predisposition and parameters of malignant progression in K14-HPV16 transgenic mice. Am J Path, 149:1899–1917.

    PubMed  Google Scholar 

  177. van Kempen, L. C. L., Rhee, J. S., Dehne, K., Lee, J., Edwards, D. R., and Coussens, L. M., 2002, Epithelial carcinogenesis: dynamic interplay between neoplastic cells and their microenvironment. Differentiation, 70:501–623.

    Google Scholar 

  178. Huang, S., Van Arsdall, M., Tedjarati, S., McCarty, M., Wu, W., Langley, R., and Fidler, I. J., 2002, Contributions of stromal metalloproteinase-9 to angiogenesis and growth of human ovarian carcinoma in mice. J Natl Cancer Inst, 94:1134–1142.

    PubMed  Google Scholar 

  179. Hiratsuka, S., Nakamura, K., Iwai, S., Murakami, M., Itoh, T., Kijima, H., Shipley, J. M., Senior, R. M., and Shibuya, M., 2002, MMP9 induction by vascular endothelial growth factor receptor-1 is involved in lung-specific metastasis. Cancer Cell, 2:289–300.

    Article  PubMed  Google Scholar 

  180. van Kempen, L. C., and Coussens, L. M., 2002, MMP9 potentiates pulmonary metastasis formation. Cancer Cell, 2:251–252.

    Article  PubMed  Google Scholar 

  181. Biggs, J. R., and Kraft, A. S., 1995, Inhibitors of cyclin-dependent kinase and cancer. J Mol Med, 73:509–614.

    Article  PubMed  Google Scholar 

  182. Lin, P., Buxton, J. A., Acheson, A., Radziejewski, C., Maisonpierre, P. C., Yancopoulos, G. D., Channon, K. M., Hale, L. P., Dewhirst, M. W., George, S. E., and Peters, K. G., 1998, Antiangiogenic gene therapy targeting the endothelium-specific receptor tyrosine kinase Tie2. Proc Natl Acad Sci USA, 95:8829–8834.

    Article  PubMed  Google Scholar 

  183. Fong, T. A., Shawver, L. K., Sun, L., Tang, C., App, H., Powell, T. J., Kim, Y. H., Schreck, R., Wang, X., Risau, W., Ullrich, A., Hirth, K. P., and McMahon, G., 1999, SU5416 is a potent and selective inhibitor of the vascular endothelial growth factor receptor (Flk-1/KDR) that inhibits tyrosine kinase catalysis, tumor vascularization, and growth of multiple tumor types. Cancer Res, 59:99–106.

    PubMed  Google Scholar 

  184. Noonberg, S. B., and Benz, C. C., 2000, Tyrosine kinase inhibitors targeted to the epidermal growth factor receptor subfamily: role as anticancer agents. Drugs, 59:753–67.

    PubMed  Google Scholar 

  185. Attoub, S., Rivat, C., Rodrigues, S., Van Bocxlaer, S., Bedin, M., Bruyneel, E., Louvet, C., Kornprobst, M., Andre, T., Mareel, M., Mester, J., and Gespach, C., 2002, The c-kit Tyrosine Kinase Inhibitor STI571 for Colorectal Cancer Therapy. Cancer Res, 62:4879–4883.

    PubMed  Google Scholar 

  186. Somlyo, A. V., Phelps, C., Dipierro, C., Eto, M., Read, P., Barrett, M., Gibson, J. J., Burnitz, M. C., Myers, C., and Somlyo, A. P., 2003, Rho kinase and matrix metalloproteinase inhibitors cooperate to inhibit angiogenesis and growth of human prostate cancer xenotransplants. Faseb J, 17:223–234.

    Article  PubMed  Google Scholar 

  187. Bergers, G., Song, S., Meyer-Morse, N., Bergsland, E., and Hanahan, D., 2003, Benefits of targeting both pericytes and endothelial cells in the tumor vasculature with kinase inhibitors. J Clin Invest, 111:1287–1295.

    Article  PubMed  Google Scholar 

  188. Fowlkes, J. L., and Winkler, M. K., 2002, Exploring the interface between metallo-proteinase activity and growth factor and cytokine bioavailability. Cytokine Growth Factor Rev, 13:277–287.

    Article  PubMed  Google Scholar 

  189. Stamenkovic, I., 2000, Matrix metalloproteinases in tumor invasion and metastasis. Semin Cancer Biol, 10:415–33.

    Article  PubMed  Google Scholar 

  190. Lynch, C. C., and Matrisian, L. M., 2002, Matrix metalloproteinases in tumor-host cell communication. Differentiation, 70:561–573.

    Article  PubMed  Google Scholar 

  191. D'Armiento, J., DiColandrea, T., Dalal, S. S., Okada, Y., Huang, M. T., Conney, A. H., and Chada, K., 1995, Collagenase expression in transgenic mouse skin causes hyperkeratosis and acanthosis and increases susceptibility to tumorigenesis. Mol Cell Biol, 15:5732–5739.

    PubMed  Google Scholar 

  192. Martin, D. C., Sanchez-Sweatman, O. H., Ho, A. T., Inderdeo, D. S., Tsao, M. S., and Khokha, R., 1999, Transgenic TIMP-1 inhibits simian virus 40 T antigen-induced hepatocarcinogenesis by impairment of hepatocellular proliferation and tumor angiogenesis. Lab Invest, 79:225–234.

    PubMed  Google Scholar 

  193. Martin, D. C., Ruther, U., Sanchez-Sweatman, O. H., Orr, F. W., and Khokha, R., 1996, Inhibition of SV40 T antigen-induced hepatocellular carcinoma in TIMP-1 transgenic mice. Oncogene, 13:569–576.

    PubMed  Google Scholar 

  194. Dong, J., Opresko, L. K., Dempsey, P. J., Lauffenburger, D. A., Coffey, R. J., and Wiley, H. S., 1999, Metalloprotease-mediated ligand release regulates autocrine signaling through the epidermal growth factor receptor. Proc Natl Acad Sci USA, 96:6235–6240.

    Article  PubMed  Google Scholar 

  195. Suzuki, M., Raab, G., Moses, M. A., Fernandez, C. A., and Klagsbrun, M., 1997, Matrix metalloproteinase-3 releases active heparin-binding EGF-like growth factor by cleavage at a specific juxtamembrane site. J Biol Chem, 272:31730–31737.

    Article  PubMed  Google Scholar 

  196. Arribas, J., Coodly, L., Vollmer, P., Kishimoto, T. K., Rose-John, S., and Massague, J., 1996, Diverse cell surface protein ectodomains are shed by a system sensitive to metalloprotease inhibitors. J Biol Chem, 271:11376–11382.

    Article  PubMed  Google Scholar 

  197. Werb, Z., 1997, ECM and cell surface proteolysis: regulating cellular ecology. Cell, 91:439–442.

    Article  PubMed  Google Scholar 

  198. Werb, Z., and Yan, Y., 1998, A cellular striptease act. Science, 282:1279–1280.

    Article  PubMed  Google Scholar 

  199. Yu, W. H., and Woessner, J. F., Jr., 2000, Heparan sulfate proteoglycans as extracellular docking molecules for matrilysin (matrix metalloproteinase 7). J Biol Chem, 275:4183–4191.

    Article  PubMed  Google Scholar 

  200. Kaya, G., Rodriguez, I., Jorcano, J. L., Vassalli, P., and Stamenkovic, I., 1997, Selective suppression of CD44 in keratinocytes of mice bearing an antisense CD44 transgene driven by a tissue-specific promoter disrupts hyaluronate metabolism in the skin and impairs keratinocyte proliferation. Genes Dev, 11:996–1007.

    PubMed  Google Scholar 

  201. Gallea-Robache, S., Morand, V., Millet, S., Bruneau, J. M., Bhatnagar, N., Chouaib, S., and Roman-Roman, S., 1997, A metalloproteinase inhibitor blocks the shedding of soluble cytokine receptors and processing of transmembrane cytokine precursors in human monocytic cells. Cytokine, 9:340–346.

    Article  PubMed  Google Scholar 

  202. Lombard, M. A., Wallace, T. L., Kubicek, M. F., Petzold, G. L., Mitchell, M. A., Hendges, S. K., and Wilks, J. W., 1998, Synthetic matrix metalloproteinase inhibitors and tissue inhibitor of metalloproteinase (TIMP)-2, but not TIMP-1, inhibit shedding of tumor necrosis factor-alpha receptors in a human colon adenocarcinoma (Colo 205) cell line. Cancer Res, 58:4001–7.

    PubMed  Google Scholar 

  203. McCusker, R. H., Busby, W. H., Dehoff, M. H., Camacho-Hubner, C., and Clemmons, D. R., 1991, Insulin-like growth factor (IGF) binding to cell monolayers is directly modulated by the addition of IGF-binding proteins. Endocrinology, 129:939–949.

    PubMed  Google Scholar 

  204. Osborne, C. K., Coronado, E. B., Kitten, L. J., Arteaga, C. I., Fuqua, S. A., and Ramaharma, K., 1989, Insulin-like growth factor-II (IGF-II): a potential autocrine/paracrine growth factor for human breast cancer acting via the IGF-I receptor. Mol Endocrinol, 3:1701–1709.

    PubMed  Google Scholar 

  205. Shimasaki, S., Shimonaka, M., Zhang, H. P., and Ling, N., 1991, Identification of five different insulin-like growth factor binding proteins (IGFBPs) from adult rat serum and molecular cloning of a novel IGFBP-5 in rat and human. J Biol Chem, 266:10646–10653.

    PubMed  Google Scholar 

  206. Fowlkes, J. L., Enghild, J. J., Suzuki, K., and Nagase, H., 1994, Matrix metalloproteinases degrade insulin-like growth factor-binding protein-3 in dermal fibroblast cultures. J Biol Chem, 269:25742–25746.

    PubMed  Google Scholar 

  207. Fowlkes, J. L., Serra, D. M., Nagase, H., and Thrailkill, K. M., 1999, MMPs are IGFBP-degrading proteinases: implications for cell proliferation and tissue growth. Ann N Y Acad Sci, 878:696–699.

    PubMed  Google Scholar 

  208. Fowlkes, J. L., Serra, D. M., Bunn, R. C., Thrailkill, K. M., Enghild, J. J., and Nagase, H., 2003, Regulation of Insulin-Like Growth Factor-I (Igf-I) Action by Matrix Metalloproteinase-3 (Mmp-3) Involves Selective Disruption of Igf-I/Igf-Binding Protein-3 (Igfbp-3) Complexes. Endocrinology.

    Google Scholar 

  209. Conover, C. A., Durham, S. K., Zapf, J., Masiarz, F. R., and Kiefer, M. C., 1995, Cleavage analysis of insulin-like growth factor (IGF)-dependent IGF-binding protein-4 proteolysis and expression of protease-resistant IGF-binding protein-4 mutants. J Biol Chem, 270:4395–4400.

    Article  PubMed  Google Scholar 

  210. Manes, S., Mira, E., Barbacid, M. M., Cipres, A., Fernandez-Resa, P., Buesa, J. M., Merida, I., Aracil, M., Marquez, G., and Martinez, A. C., 1997, Identification of insulin-like growth factor-binding protein-1 as a potential physiological substrate for human stromelysin-3. J Biol Chem, 272:25706–12.

    Article  PubMed  Google Scholar 

  211. Martin, D. C., Fowlkes, J.L., Babic, B., and Khokha, R., 1999, Insulin-like growth factor II signaling in neoplastic proliferation is blocked by transgenic expression of the metalloproteinase inhibitor TIMP-1. J Cell Biol, 146:881–892.

    Article  PubMed  Google Scholar 

  212. Tennant, M. K., Thrasher, J. B., Twomey, P. A., Drivdahl, R. H., Birnbaum, R. S., and Plymate, S. R., 1996, Protein and messenger ribonucleic acid (mRNA) for the type 1 insulin-like growth factor (IGF) receptor is decreased and IGF-II mRNA is increased in human prostate carcinoma compared to benign prostate epithelium. J Clin Endocrinol Metab, 81:3774–3782.

    Article  PubMed  Google Scholar 

  213. D'Errico, A., Grigioni, W. F., Fiorentino, M., Baccarini, P., Lamas, E., De Mitri, S., Gozzetti, G., Mancini, A. M., and Brechot, C., 1994, Expression of insulin-like growth factor II (IGF-II) in human hepatocellular carcinomas: an immunohistochemical study. Pathol Int, 44:131–137.

    PubMed  Google Scholar 

  214. Chan, J. M., Stampfer, M. J., Giovannucci, E., Gann, P. H., Ma, J., Wilkinson, P., Hennekens, C. H., and Pollak, M., 1998, Plasma insulin-like growth factor-I and prostate cancer risk: a prospective study. Science, 279:563–566.

    Article  PubMed  Google Scholar 

  215. Hankinson, S. E., Willett, W. C., Colditz, G. A., Hunter, D. J., Michaud, D. S., Deroo, B., Rosner, B., Speizer, F. E., and Pollak, M., 1998, Circulating concentrations of insulin-like growth factor-I and risk of breast cancer. Lancet, 351:1393–1396.

    Article  PubMed  Google Scholar 

  216. Whitelock, J. M., Murdoch, A. D., Iozzo, R. V., and Underwood, P. A., 1996, The degradation of human endothelial cell-derived perlecan and release of bound basic fibroblast growth factor by stromelysin, collagenase, plasmin, and heparanases. J Biol Chem, 271:10079–10086.

    Article  PubMed  Google Scholar 

  217. Friedl, A., Chang, Z., Tierney, A., and Rapraeger, A. C., 1997, Differential binding of fibroblast growth factor-2 and-7 to basement membrane heparan sulfate: comparison of normal and abnormal human tissues. Am J Pathol, 150:1443–1455.

    PubMed  Google Scholar 

  218. Levi, E., Fridman, R., Miao, H. Q., Ma, Y. S., Yayon, A., and Vlodavsky, I., 1996, Matrix metalloproteinase 2 releases active soluble ectodomain of fibroblast growth factor receptor 1, Proc Natl Acad Sci U S A 93:7069–74.

    Article  PubMed  Google Scholar 

  219. Czubayko, F., Liaudet-Coopman, E. D., Aigner, A., Tuveson, A. T., Berchem, G. J., and Wellstein, A., 1997, A secreted FGF-binding protein can serve as the angiogenic switch in human cancer. Nat Med, 3:1137–1140.

    Article  Google Scholar 

  220. Annes, J. P., Munger, J. S., and Rifkin, D. B., 2003, Making sense of latent TGFbeta activation. J Cell Sci, 116:217–224.

    Article  PubMed  Google Scholar 

  221. Massague, J., Blain, S. W., and Lo, R. S., 2000, TGFbeta signaling in growth control, cancer, and heritable disorders. Cell, 103:295–309.

    Article  PubMed  Google Scholar 

  222. Derynck, R., Akhurst, R. J., and Balmain, A., 2001, TGF-beta signaling in tumor suppression and cancer progression. Nat Genet, 29:117–129.

    Article  PubMed  Google Scholar 

  223. Akhurst, R. J., 2002, TGF-beta antagonists: why suppress a tumor suppressor?. J Clin Invest, 109:1533–1536.

    Article  PubMed  Google Scholar 

  224. Moustakas, A., Pardali, K., Gaal, A., and Heldin, C. H., 2002, Mechanisms of TGF-beta signaling in regulation of cell growth and differentiation. Immunol Lett, 82:85–91.

    Article  PubMed  Google Scholar 

  225. Markowitz, S. D., and Roberts, A. B., 1996, Tumor suppressor activity of the TGF-beta pathway in human cancers. Cytokine Growth Factor Rev, 7:93–102.

    Article  PubMed  Google Scholar 

  226. Alexandrow, M. G., and Moses, H. L., 1995, Transforming growth factor beta 1 inhibits mouse keratinocytes late in G1 independent of effects on gene transcription. Cancer Res, 55:3928–3932.

    PubMed  Google Scholar 

  227. Taipale, J., Saharinen, J., and Keski-Oja, J., 1998, Extracellular matrix-associated transforming growth factor-beta: role in cancer cell growth and invasion. Adv Cancer Res, 75:87–134.

    PubMed  Google Scholar 

  228. Miyazono, K., Ichijo, H., and Heldin, C. H., 1993, Transforming growth factor-beta: latent forms, binding proteins and receptors. Growth Factors, 8:11–22.

    PubMed  Google Scholar 

  229. Munger, J. S., Harpel, J. G., Gleizes, P. E., Mazzieri, R., Nunes, I., and Rifkin, D. B., 1997, Latent transforming growth factor-beta: structural features and mechanisms of activation. Kidney Int, 51:1376–1382.

    PubMed  Google Scholar 

  230. Oklu, R., and Hesketh, R., 2000, The latent transforming growth factor beta binding protein (LTBP) family. Biochem J, 352 Pt 3:601–610.

    Article  PubMed  Google Scholar 

  231. Imai, K., Hiramatsu, A., Fukushima, D., Pierschbacher, M. D., and Okada, Y., 1997, Degradation of decorin by matrix metalloproteinases: identification of the cleavage sites, kinetic analyses and transforming growth factor-beta1 release. Biochem J, 322:809–814.

    PubMed  Google Scholar 

  232. Hildebrand, A., Romaris, M., Rasmussen, L. M., Heinegard, D., Twardzik, D. R., Border, W. A., and Ruoslahti, E., 1994, Interaction of the small interstitial proteoglycans biglycan, decorin and fibromodulin with transforming growth factor beta. Biochem J, 302(Pt 2):527–534.

    PubMed  Google Scholar 

  233. Kresse, H., Hausser, H., Schonherr, E., and Bittner, K., 1994, Biosynthesis and interactions of small chondroitin/dermatan sulphate proteoglycans. Eur J Clin Chem Clin Biochem, 32:259–264.

    PubMed  Google Scholar 

  234. Velasco-Loyden, G., Arribas, J., and Lopez-Casillas, F., 2003, The shedding of betaglycan is regulated by pervanadate and mediated by MT1-MMP. J Biol Chem.

    Google Scholar 

  235. Damsky, C., 2002, Cell-cell and cell-extracellular matrix adhesion receptors. Ann NY Acad Sci, 961:154–155.

    PubMed  Google Scholar 

  236. Noe, V., Fingleton, B., Jacobs, K., Crawford, H. C., Vermeulen, S., Steelant, W., Bruyneel, E., Matrisian, L. M., and Mareel, M., 2001, Release of an invasion promoter E-cadherin fragment by matrilysin and stromelysin-1. J Cell Sci, 114:111–118.

    PubMed  Google Scholar 

  237. Kajita, M., Itoh, Y., Chiba, T., Mori, H., Okada, A., Kinoh, H., and Seiki, M., 2001, Membrane-type 1 matrix metalloproteinase cleaves CD44 and promotes cell migration. J Cell Biol, 153:893–904.

    Article  PubMed  Google Scholar 

  238. Deryugina, E. I., Soroceanu, L., and Strongin, A. Y., 2002, Up-regulation of vascular endothelial growth factor by membrane-type 1 matrix metalloproteinase stimulates human glioma xenograft growth and angiogenesis. Cancer Res, 62:580–588.

    PubMed  Google Scholar 

  239. Hynes, R. O., 2002, A reevaluation of integrins as regulators of angiogenesis. Nat Med, 8:918–921.

    Article  PubMed  Google Scholar 

  240. Hynes, R. O., 2002, Integrins: bidirectional, allosteric signaling machines. Cell, 110:673–687.

    PubMed  Google Scholar 

  241. Zamir, E., and Geiger, B., 2001, Molecular complexity and dynamics of cell-matrix adhesions. J Cell Sci, 114:3583–3590.

    PubMed  Google Scholar 

  242. Kassis, J., Lauffenburger, D. A., Turner, T., and Wells, A., 2001, Tumor invasion as dysregulated cell motility. Semin Cancer Biol, 11:105–117.

    Article  PubMed  Google Scholar 

  243. Monsky, W. L., Kelly, T., Lin, C. Y., Yeh, Y., Stetler-Stevenson, W. G., Mueller, S. C., and Chen, W. T., 1993, Binding and localization of M(r) 72,000 matrix metalloproteinase at cell surface invadopodia. Cancer Res, 53:3159–3164.

    PubMed  Google Scholar 

  244. Chen, W. T., and Wang, J. Y., 1999, Specialized surface protrusions of invasive cells, invadopodia and lamellipodia, have differential MT1-MMP, MMP-2, and TIMP-2 localization. Ann NY Acad Sci, 878:361–371.

    PubMed  Google Scholar 

  245. Riikonen, T., Westermarck, J., Koivisto, L., Broberg, A., Kahari, V. M., and Heino, J., 1995, Integrin alpha 2 beta 1 is a positive regulator of collagenase (MMP-1) and collagen alpha 1(I) gene expression. J Biol Chem, 270:13548–13552.

    Article  PubMed  Google Scholar 

  246. von Bredow, D. C., Nagle, R. B., Bowden, G. T., and Cress, A. E., 1997, Cleavage of beta 4 integrin by matrilysin. Exp Cell Res, 236:341–345.

    Article  PubMed  Google Scholar 

  247. Akimov, S. S., Krylov, D., Fleischman, L. F., and Belkin, A. M., 2000, Tissue transglutaminase is an integrin-binding adhesion coreceptor for fibronectin. J Cell Biol, 148:825–838.

    Article  PubMed  Google Scholar 

  248. Belkin, A. M., Akimov, S. S., Zaritskaya, L. S., Ratnikov, B. I., Deryugina, E. I., and Strongin, A. Y., 2001, Matrix-dependent proteolysis of surface transglutaminase by membrane-type metalloproteinase regulates cancer cell adhesion and locomotion. J Biol Chem, 276:18415–18422.

    Article  PubMed  Google Scholar 

  249. Van Aken, E., De Wever, O., Correia da Rocha, A., and Mareel, M., 2001, Defective E-cadherin/catenin complexes in human cancer. Virchows Arch, 439:725–751.

    PubMed  Google Scholar 

  250. Bracke, M. E., Van Roy, F. M., and Mareel, M. M., 1996, The E-cadherin/catenin complex in invasion and metastasis. Curr Top Microbiol Immunol, 213:123–161.

    PubMed  Google Scholar 

  251. De Leeuw, W. J., Berx, G., Vos, C. B., Peterse, J. L., Van de Vijver, M. J., Litvinov, S., Van Roy, F., Cornelisse, C. J., and Cleton-Jansen, A. M., 1997, Simultaneous loss of E-cadherin and catenins in invasive lobular breast cancer and lobular carcinoma in situ. J Pathol, 183:404–411.

    Article  PubMed  Google Scholar 

  252. Llorens, A., Rodrigo, I., Lopez-Barcons, L., Gonzalez-Garrigues, M., Lozano, E., Vinyals, A., Quintanilla, M., Cano, A., and Fabra, A., 1998, Down-regulation of E-cadherin in mouse skin carcinoma cells enhances a migratory and invasive phenotype linked to matrix metalloproteinase-9 gelatinase expression. Lab Invest, 78:1131–42.

    PubMed  Google Scholar 

  253. Beavon, I. R., 2000, The E-cadherin-catenin complex in tumour metastasis: structure, function and regulation. Eur J Cancer, 36:1607–1620.

    Article  PubMed  Google Scholar 

  254. Christofori, G., and Semb, H., 1999, The role of the cell-adhesion molecule E-cadherin as a tumoursuppressor gene. Trends Biochem Sci, 24:73–76.

    Article  PubMed  Google Scholar 

  255. Perl, A. K., Wilgenbus, P., Dahl, U., Semb, H., and Christofori, G., 1998, A causal role for E-cadherin in the transition from adenoma to carcinoma. Nature, 392:190–3.

    Article  PubMed  Google Scholar 

  256. Perl, A. K., Dahl, U., Wilgenbus, P., Cremer, H., Semb, H., and Christofori, G., 1999, Reduced expression of neural cell adhesion molecule induces metastatic dissemination of pancreatic beta tumor cells. Nat Med, 5:286–91.

    Article  PubMed  Google Scholar 

  257. Lochter, A., Galosy, S., Muschler, J., Freedman, N., Werb, Z., and Bissell, M. J., 1997, Matrix metalloproteinase stromelysin-1 triggers a cascade of molecular alterations that leads to stable epithelial-to-mesenchymal conversion and a premalignant phenotype in mammary epithelial cells. J Cell Biol, 139:1861–1872.

    Article  PubMed  Google Scholar 

  258. Nikkola, J., Vihinen, P., Vlaykova, T., Hahka-Kemppinen, M., Kahari, V. M., and Pyrhonen, S., 2002, High expression levels of collagenase-1 and stromelysin-1 correlate with shorter disease-free survival in human metastatic melanoma. Int J Cancer. 97:432–438.

    Article  PubMed  Google Scholar 

  259. Sympson, C. J., Bissell, M. J., and Werb, Z., 1995, Mammary gland tumor formation in transgenic mice overexpressing stromelysin-1. Semin Cancer Biol, 6:159–163.

    Article  PubMed  Google Scholar 

  260. Thomasset, N., Lochter, A., Sympson, C. J., Lund, L. R., Williams, D. R., Behrendtsen, O., Werb, Z., and Bissell, M. J., 1998, Expression of autoactivated stromelysin-1 in mammary glands of transgenic mice leads to a reactive stroma during early development. Am J Pathol, 153:457–467.

    PubMed  Google Scholar 

  261. Lochter, A., Werb, Z., and Bissell, M. J., 1999, Transcriptional regulation of stromelysin-1 gene expression is altered during progression of mouse mammary epithelial cells from functionally normal to malignant. Matrix Biol, 18:455–467.

    Article  PubMed  Google Scholar 

  262. Rudolph-Owen, L. A., Chan, R., Muller, W. J., and Matrisian, L. M., 1998, The matrix metalloproteinase matrilysin influences early-stage mammary tumorigenesis. Cancer Res, 58:5500–5506.

    PubMed  Google Scholar 

  263. Vargo-Gogola, T., Fingleton, B., Crawford, H. C., and Matrisian, L. M., 2002, Matrilysin (matrix metalloproteinase-7) selects for apoptosis-resistant mammary cells in vivo. Cancer Res, 62:5559–5563.

    PubMed  Google Scholar 

  264. McGuire, J. K., Li, Q., and Parks, W. C., 2003, Matrilysin (matrix metalloproteinase-7) mediates Ecadherin ectodomain shedding in injured lung epithelium. Am J Pathol, 162:1831–1843.

    PubMed  Google Scholar 

  265. Naot, D., Sionov, R. V., and Ish-Shalom, D., 1997, CD44: structure, function, and association with the malignant process. Adv Cancer Res, 71:241–319.

    PubMed  Google Scholar 

  266. Pohl, M., Sakurai, H., Stuart, R. O., and Nigam, S. K., 2000, Role of hyaluronan and CD44 in in vitro branching morphogenesis of ureteric bud cells. Dev Biol, 224:312–325.

    Article  PubMed  Google Scholar 

  267. Okamoto, I., Kawano, Y., Murakami, D., Sasayama, T., Araki, N., Miki, T., Wong, A. J., and Saya, H., 2001, Proteolytic release of CD44 intracellular domain and its role in the CD44 signaling pathway. J Cell Biol, 155:755–62.

    Article  PubMed  Google Scholar 

  268. Cichy, J., and Pure, E., 2003, The liberation of CD44. J Cell Biol, 161:839–843.

    Article  PubMed  Google Scholar 

  269. Jalkanen, S., Joensuu, H., Soderstrom, K. O., and Klemi, P., 1991, Lymphocyte homing and clinical behavior of non-Hodgkin's lymphoma. J Clin Invest, 87:1835–1840.

    PubMed  Google Scholar 

  270. Mori, H., Tomari, T., Koshikawa, N., Kajita, M., Itoh, Y., Sato, H., Tojo, H., Yana, I., and Seiki, M., 2002, CD44 directs membrane-type 1 matrix metalloproteinase to lamellipodia by associating with its hemopexin-like domain. Embo J, 21:3949–3959.

    Article  PubMed  Google Scholar 

  271. Li, R., Huang, L., Guo, H., and Toole, B. P., 2001, Basigin (murine EMMPRIN) stimulates matrix metalloproteinase production by fibroblasts. J Cell Physiol, 186:371–9.

    Article  PubMed  Google Scholar 

  272. Folkman, J., 1990, What is the evidence that tumors are angiogenesis dependent?. J Nat Cancer Inst, 82:4–6.

    PubMed  Google Scholar 

  273. Folkman, J., and Shing, Y., 1992, Angiogenesis. J Biol Chem, 267:10931–10934.

    PubMed  Google Scholar 

  274. Weidner, N., Folkman, J., Pozza, F., Bevilacqua, P., Allred, E. N., Moore, D. H., Meli, S., and Gasparini, G., 1992, Tumor angiogenesis: a new significant and independent prognostic indicator in early-stage breast carcinoma. J Natl Cancer Inst, 84:1875–1887.

    PubMed  Google Scholar 

  275. Folkman, J., 1994, Tumor angiogenesis. Nature Medicine, 1:206–232.

    Google Scholar 

  276. Folkman, J., 1995, Tumor Angiogenesis. In The Molecular Basis of Cancer, Mendelsohn, J., Howley, P. M., Israel, M. A., and Liotta L. A., eds, Vol. 9:206–232. W. B. Saunders Company, Philadelphia.

    Google Scholar 

  277. Folkman, J., and D'Amore, P. A., 1996, Blood vessel formation: what is its molecular basis. Cell, 87:1153–1155.

    Article  PubMed  Google Scholar 

  278. Carmeliet, P., and Jain, R. K., 2000, Angiogenesis in cancer and other diseases. Nature, 407:249–257.

    PubMed  Google Scholar 

  279. Carmeliet, P., 2003, Angiogenesis in health and disease. Nat Med, 9:653–60.

    Article  PubMed  Google Scholar 

  280. Hanahan, D., and Folkman, J., 1996, Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell, 86:353–364.

    Article  PubMed  Google Scholar 

  281. Nagy, J. A., Brown, L. F., Senger, D. R., Lanir, N., Van de Water, L., Dvorak, A. M., and Dvorak, H. F., 1989, Pathogenesis of tumor stroma generation: a critical role for leaky blood vessels and fibrin deposition. Biochim Biophys Acta, 948:305–326.

    PubMed  Google Scholar 

  282. Lindahl, P., Johansson, B. R., Leveen, P., and Betsholtz, C., 1997, Pericyte loss and microaneurysm formation in PDGF-B-deficient mice. Science, 277:242–245.

    Article  PubMed  Google Scholar 

  283. Paku, S., and Paweletz, N., 1991, First steps of tumor-related angiogenesis. Lab Invest, 65:334–346.

    PubMed  Google Scholar 

  284. Giordano, F. J., and Johnson, R. S., 2001, Angiogenesis: the role of the microenvironment in flipping the switch. Curr Opin Genet Dev, 11:35–40.

    Article  PubMed  Google Scholar 

  285. Seandel, M., Noack-Kunnmann, K., Zhu, D., Aimes, R. T., and Quigley, J. P., 2001, Growth factor-induced angiogenesis in vivo requires specific cleavage of fibrillar type I collagen. Blood, 97:2323–2332.

    Article  PubMed  Google Scholar 

  286. Liu, X., Wu, H., Byrne, M., Jeffrey, J., Krane, S., and Jaenisch, R., 1995, A targeted mutation at the known collagenase cleavage site in mouse type I collagen impairs tissue remodeling. J Cell Biol, 130:227–237.

    Article  PubMed  Google Scholar 

  287. Xu, J., Rodriguez, D., Petitclerc, E., Kim, J. J., Hangai, M., Moon, Y. S., Davis, G. E., Brooks, P. C., and Yuen, S. M., 2001, Proteolytic exposure of a cryptic site within collagen type IV is required for angiogenesis and tumor growth in vivo. J Cell Biol, 154:1069–1079.

    Article  PubMed  Google Scholar 

  288. DiPietro, L. A., Burdick, M., Low, Q. E., Kunkel, S. L., and Strieter, R. M., 1998, MIP-1alpha as a critical macrophage chemoattractant in murine wound repair. J Clin Invest, 101:1693–1698.

    PubMed  Google Scholar 

  289. Ferreras, M., Felbor, U., Lenhard, T., Olsen, B. R., and Delaisse, J., 2000, Generation and degradation of human endostatin proteins by various proteinases. FEBS Lett, 486:247–251.

    Article  PubMed  Google Scholar 

  290. O'Reilly, M. S., Holmgren, L., Shing, Y., Chen, C., Rosenthal, R. A., Moses, M., Lane, W. S., Cao, Y., Sage, E. H., and Folkman, J., 1994, Angiostatin: a novel angiogenesis inhibitor that mediates the suppression of metastases by a Lewis lung carcinoma. Cell, 79:315–328.

    Article  PubMed  Google Scholar 

  291. Maeshima, Y., Colorado, P. C., Torre, A., Holthaus, K. A., Grunkemeyer, J. A., Ericksen, M. B., Hopfer, H., Xiao, Y., Stillman, I. E., and Kalluri, R., 2000, Distinct antitumor properties of a type IV collagen domain derived from basement membrane. J Biol Chem, 275:21340–8.

    Article  PubMed  Google Scholar 

  292. Petitclerc, E., Stromblad, S., von Schalscha, T. L., Mitjans, F., Piulats, J., Montgomery, A. M., Cheresh, D. A., and Brooks, P. C., 1999, Integrin αvβ3 promotes M21 melanoma growth in human skin by regulating tumor cell survival. Cancer Res, 59:2724–30.

    PubMed  Google Scholar 

  293. Hamano, Y., Zeisberg, M., Sugimoto, H., Lively, J. C., Maeshima, Y., Changqing, Y., R.O., H., Werb, Z., Sudhakar, A., and Kalluri, R., 2003, Physiological levels of tumstatin, a fragment of collagen IV alpha3 chain, are generated by MMP-9 protelysis and suppress angioenesis via alphaVbeta3 integrin. Cancer Cell, 3:589–601.

    Article  PubMed  Google Scholar 

  294. Patterson, B. C., and Sang, Q. A., 1997, Angiostatin-converting enzyme activities of human matrilysin (MMP-7) and gelatinase B/type IV collagenase (MMP-9). J Biol Chem, 272:28823–5.

    Article  PubMed  Google Scholar 

  295. Sobrin, L., Liu, Z., Monroy, D. C., Solomon, A., Selzer, M. G., Lokeshwar, B. L., and Pflugfelder, S. C., 2000, Regulation of MMP-9 activity in human tear fluid and corneal epithelial culture supernatant. Invest Ophthalmol Vis Sci, 41:1703–1709.

    PubMed  Google Scholar 

  296. Pozzi, A., LeVine, W. F., and Gardner, H. A., 2002, Low plasma levels of matrix metalloproteinase 9 permit increased tumor angiogenesis. Oncogene, 21:272–281.

    Article  Google Scholar 

  297. Grunert, S., Jechlinger, M., and Beug, H., 2003, Diverse cellular and molecular mechanisms contribute to epithelial plasticity and metastasis. Mol Cell Biol, 4:657–665.

    Google Scholar 

  298. Birchmeier, C., Birchmeier, W., Gherardi, E., and Vande Woude, G., 2003, Met, metastasis, motility and more. Nat Med, 4:915–925.

    Google Scholar 

  299. Woodhouse, E. C., Chuaqui, R. F., and Liotta, L. A., 1997, General mechanisms of metastasis. Cancer, 80:1529–37.

    Article  PubMed  Google Scholar 

  300. Yokota, J., 2000, Tumor progression and metastasis. Carcinogenesis, 21:497–503.

    Article  PubMed  Google Scholar 

  301. Fidler, I. J., 2001, Seed and soil revisited: contribution of the organ microenvironment to cancer metastasis. Surg Oncol Clin N Am, 10:257–269.

    PubMed  Google Scholar 

  302. Fidler, I. J., 2002, Critical determinants of metastasis. Semin Cancer Biol, 12:89–96.

    Article  PubMed  Google Scholar 

  303. Comoglio, P. M., and Trusolino, L., 2002, Invasive growth: from development to metastasis, J Clin Invest 109:857–62.

    Article  PubMed  Google Scholar 

  304. Jussila, L., and Alitalo, K., 2002, Vascular growth factors and lymphangiogenesis. Physiol Rev, 82:673–700.

    PubMed  Google Scholar 

  305. Engers, R., and Gabbert, H. E., 2000, Mechanisms of tumor metastasis: cell biological aspects and clinical implications. J Cancer Res Clin Oncol, 126:682–692.

    PubMed  Google Scholar 

  306. Moser, P. L., Kieback, D. G., Hefler, L., Tempfer, C., Neunteufel, W., and Gitsch, G., 1999, Immunohistochemical detection of matrix metalloproteinases (MMP) 1 and 2, and tissue inhibitor of metalloproteinase 2 (TIMP 2) in stage IB cervical cancer. Anticancer Res, 19:4391–4393.

    PubMed  Google Scholar 

  307. Inoue, T., Yashiro, M., Nishimura, S., Maeda, K., Sawada, T., Ogawa, Y., Sowa, M., and Chung, K. H., 1999, Matrix metalloproteinase-1 expression is a prognostic factor for patients with advanced gastric cancer. Int J Mol Med, 4:73–77.

    PubMed  Google Scholar 

  308. Yamashita, K., Azumano, I., Mai, M., and Okada, Y., 1998, Expression and tissue localization of matrix metalloproteinase 7 (matrilysin) in human gastric carcinomas. Implications for vessel invasion and metastasis. Int J Cancer, 79:187–194.

    Article  PubMed  Google Scholar 

  309. Gokaslan, Z. L., Chintala, S. K., York, J. E., Boyapati, V., Jasti, S., Sawaya, R., Fuller, G., Wildrick, D. M., Nicolson, G. L., and Rao, J. S., 1998, Expression and role of matrix metalloproteinases MMP-2 and MMP-9 in human spinal column tumors. Clin Exp Metastasis, 16:721–728.

    Article  PubMed  Google Scholar 

  310. Garbisa, S., Scagliotti, G., Masiero, L., Di Francesco, C., Caenazzo, C., Onisto, M., Micela, M., Stetler-Stevenson, W. G., and Liotta, L. A., 1992, Correlation of serum metalloproteinase levels with lung cancer metastasis and response to therapy. Cancer Res, 52:4548–4549.

    PubMed  Google Scholar 

  311. Nyormoi, O., Mills, L., and Bar-Eli, M., 2003, An MMP-2/MMP-9 inhibitor, 5a, enhances apoptosis induced by ligands of the TNF receptor superfamily in cancer cells. Cell Death Differ, 10:558–569.

    Article  PubMed  Google Scholar 

  312. Hotz, H. G., Hines, O. J., Hotz, B., Foitzik, T., Buhr, H. J., and Reber, H. A., 2003, Evaluation of vascular endothelial growth factor blockade and matrix metalloproteinase inhibition as a combination therapy for experimental human pancreatic cancer. J Gastrointest Surg, 7:220–227.

    Article  PubMed  Google Scholar 

  313. Shinoda, K., Shibuya, M., Hibino, S., Ono, Y., Matsuda, K., Takemura, A., Zou, D., Kokubo, Y., Takechi, A., and Kudoh, S., 2003, A novel matrix metalloproteinase inhibitor, FYK-1388 suppresses tumor growth, metastasis and angiogenesis by human fibrosarcoma cell line. Int J Oncol, 22:281–288.

    PubMed  Google Scholar 

  314. Winding, B., NicAmhlaoibh, R., Misander, H., Hoegh-Andersen, P., Andersen, T. L., Holst-Hansen, C., Heegaard, A. M., Foged, N. T., Brunner, N., and Delaisse, J. M., 2002, Synthetic matrix metalloproteinase inhibitors inhibit growth of established breast cancer osteolytic lesions and prolong survival in mice. Clin Cancer Res, 8:1932–1939.

    PubMed  Google Scholar 

  315. Katori, H., Baba, Y., Imagawa, Y., Nishimura, G., Kagesato, Y., Takagi, E., Ishii, A., Yanoma, S., Maekawa, R., Yoshioka, T., Nagashima, Y., Kato, Y., and Tsukuda, M., 2002, Reduction of in vivo tumor growth by MMI-166, a selective matrix metalloproteinase inhibitor, through inhibition of tumor angiogenesis in squamous cell carcinoma cell lines of head and neck. Cancer Lett, 178:151–159.

    Article  PubMed  Google Scholar 

  316. Weber, M. H., Lee, J., and Orr, F. W., 2002, The effect of Neovastat (AE-941) on an experimental metastatic bone tumor model. Int J Oncol, 20:299–303.

    PubMed  Google Scholar 

  317. Naglich, J. G., Jure-Kunkel, M., Gupta, E., Fargnoli, J., Henderson, A. J., Lewin, A. C., Talbott, R., Baxter, A., Bird, J., Savopoulos, R., Wills, R., Kramer, R. A., and Trail, P. A., 2001, Inhibition of angiogenesis and metastasis in two murine models by the matrix metalloproteinase inhibitor, BMS-275291. Cancer Res, 61:8480–8485.

    PubMed  Google Scholar 

  318. Brown, P. D., 1999, Clinical studies with matrix metalloproteinase inhibitors. APMIS, 107:174–180.

    PubMed  Google Scholar 

  319. Drummond, A. H., Beckett, P., Brown, P. D., Bone, E. A., Davidson, A. H., Galloway, W. A., Gearing, A. J., Huxley, P., Laber, D., McCourt, M., Whittaker, M., Wood, L. M., and Wright, A., 1999, Preclinical and clinical studies of MMP inhibitors in cancer. Ann N Y Acad Sci, 878:228–235.

    PubMed  Google Scholar 

  320. Whittaker, M., Floyd, C. D., Brown, P., and Gearing, A. J., 1999, Design and therapeutic application of matrix metalloproteinase inhibitors. Chem Rev, 99:2735–76.

    Article  PubMed  Google Scholar 

  321. Brown, P. D., 2000, Ongoing trials with matrix metalloproteinase inhibitors. Expert Opin Investig Drugs, 9:2167–2177.

    PubMed  Google Scholar 

  322. Opdenakker, G., Van den Steen, P. E., and Van Damme, J., 2001, Gelatinase B: a tuner and amplifier of immune functions. Trends Immunol, 22:571–579.

    Article  PubMed  Google Scholar 

  323. Müller, A., Homey, B., Soto, H., Ge, N., Catron, D., Buchanan, M. E., McClanahan, T., Murphy, E., Yuan, W., Wagner, S. N., Barrera, J. L., Mohar, A., Verastegui, E., and Zlotnik, A., 2001, Involvement of chemokine receptors in breast cancer metastasis. Nature, 410:50–56.

    Article  PubMed  Google Scholar 

  324. Van den Steen, P. E., Proost, P., Wuyts, A., Van Damme, J., and Opdenakker, G., 2000, Neutrophil gelatinase B potentiates interleukin-8 tenfold by aminoterminal processing, whereas it degrades CTAP-III, PF-4, and GRO-alpha and leaves RANTES and MCP-2 intact. Blood, 96:2673–2681.

    PubMed  Google Scholar 

  325. Ramjeesingh, R., Leung, R., and Siu, C. H., 2003, Interleukin-8 secreted by endothelial cells induces chemotaxis of melanoma cells through the chemokine receptor CXCR1. Faseb J, 17:1292–1294.

    PubMed  Google Scholar 

  326. Varney, M. L., Li, A., Dave, B. J., Bucana, C. D., Johansson, S. L., and Singh, R. K., 2003, Expression of CXCR1 and CXCR2 receptors in malignant melanoma with different metastatic potential and their role in interleukin-8 (CXCL-8)-mediated modulation of metastatic phenotype. Clin Exp Metastasis, 20:723–731.

    Article  PubMed  Google Scholar 

  327. Kawamata, H., Kawai, K., Kameyama, S., Johnson, M. D., Stetler-Stevenson, W. G., and Oyasu, R., 1995, Over-expression of tissue inhibitor of matrix metalloproteinases (TIMP1 and TIMP2) suppresses extravasation of pulmonary metastasis of a rat bladder carcinoma. Int J Cancer, 63:680–687.

    PubMed  Google Scholar 

  328. Onisto, M., Riccio, M. P., Scannapieco, P., Caenazzo, C., Griggio, L., Spina, M., Stetler-Stevenson, W. G., and Garbisa, S., 1995, Gelatinase A/TIMP-2 imbalance in lymph-node-positive breast carcinomas, as measured by RT-PCR. Int J Cancer, 63:621–6.

    PubMed  Google Scholar 

  329. Bian, J., Wang, Y., Smith, M. R., Kim, H., Jacobs, C., Jackman, J., Kung, H. F., Colburn, N. H., and Sun, Y., 1996, Suppression of in vivo tumor growth and induction of suspension cell death by tissue inhibitor of metalloproteinases (TIMP)-3. Carcinogenesis, 17:1805–1811.

    PubMed  Google Scholar 

  330. Fong, K. M., Kida, Y., Zimmerman, P. V., and Smith, P. J., 1996, TIMP1 and adverse prognosis in non-small cell lung cancer. Clin Cancer Res, 2:1369–1372.

    PubMed  Google Scholar 

  331. Grignon, D. J., Sakr, W., Toth, M., Ravery, V., Angulo, J., Shamsa, F., Pontes, J. E., Crissman, J. C., and Fridman, R., 1996, High levels of tissue inhibitor of metalloproteinase-2 (TIMP-2) expression are associated with poor outcome in invasive bladder cancer. Cancer Res, 56:1654–1659.

    PubMed  Google Scholar 

  332. Martin, D. C., Rüther, U., Sanchez-Sweatman, O. H., Orr, F. W., and Khokha, R., 1996, Inhibition of SV40 T antigen-induced hepatocellular carcinoma in TIMP-1 transgenic mice. Oncogene, 13:569–576.

    PubMed  Google Scholar 

  333. Matsuzawa, K., Fukuyama, K., Hubbard, S. L., Dirks, P. B., and Rutka, J. T., 1996, Transfection of an invasive human astrocytoma cell line with a TIMP-1 cDNA: modulation of astrocytoma invasive potential. J Neuropathol Exp Neurol, 55:88–96.

    PubMed  Google Scholar 

  334. Soloway, P. D., Alexander, C. M., Werb, Z., and Jaenisch, R., 1996, Targeted mutagenesis of Timp-1 reveals that lung tumor invasion is influenced by Timp-1 genotype of the tumor but not by that of the host. Oncogene, 13:2307–14.

    PubMed  Google Scholar 

  335. Thorgeirsson, U. P., Yoshiji, H., Sinha, C. C., and Gomez, D. E., 1996, Breast cancer; tumor neovasculature and the effect of tissue inhibitor of metalloproteinases-1 (TIMP-1) on angiogenesis. In Vivo, 10:137–144.

    PubMed  Google Scholar 

  336. Kruger, A., Fata, J. E., and Khokha, R., 1997, Altered tumor growth and metastasis of a T-cell lymphoma in Timp-1 transgenic mice. Blood, 90:1993–2000.

    PubMed  Google Scholar 

  337. Shoji, A., Sakamoto, Y., Tsuchiya, T., Moriyama, K., Kaneko, T., Okubo, T., Umeda, M., and Miyazaki, K., 1997, Inhibition of tumor promoter activity toward mouse fibroblasts and their in vitro transformation by tissue inhibitor of metalloproteinases-1 (TIMP-1). Carcinogenesis, 18:2093–100.

    Article  PubMed  Google Scholar 

  338. Kruger, A., Sanchez-Sweatman, O. H., Martin, D. C., Fata, J. E., Ho, A. T., Orr, F. W., Ruther, U., and Khokha, R., 1998, Host TIMP-1 overexpression confers resistance to experimental brain metastasis of a fibrosarcoma cell line. Oncogene, 16:2419–23.

    Article  PubMed  Google Scholar 

  339. Baker, A. H., George, S. J., Zaltsman, A. B., Murphy, G., and Newby, A. C., 1999, Inhibition of invasion and induction of apoptotic cell death of cancer cell lines by overexpression of TIMP-3. Br J Cancer, 79:1347–1355.

    Article  PubMed  Google Scholar 

  340. Brown, P. D., 1995, Matrix metalloproteinase inhibitors: a novel class of anticancer agents. Adv Enzyme Regul, 35:293–301.

    Article  PubMed  Google Scholar 

  341. Brown, P. D., 1997, Matrix metalloproteinase inhibitors in the treatment of cancer. Med Oncol, 14:1–10.

    PubMed  Google Scholar 

  342. Hidalgo, M., and Eckhardt, S. G., 2001, Development of matrix metalloproteinase inhibitors in cancer therapy. J Natl Cancer Inst, 93:178–193.

    Article  PubMed  Google Scholar 

  343. Bernardo, M. M., Brown, S., Li, Z. H., Fridman, R., and Mobashery, S., 2002, Design, Synthesis, and Characterization of Potent, Slow-binding Inhibitors That Are Selective for Gelatinases. J Biol Chem, 277:11201–11207.

    Article  PubMed  Google Scholar 

  344. Coussens, L. M., B. Fingleton, B., and Matrisian, L. M., 2002, Matrix metalloproteinase inhibitors and cancer: trials and tribulations. Science, 295:2387–2392.

    Article  PubMed  Google Scholar 

  345. Brown, S., Bernardo, M. M., Li, Z. H., Kotra, L. P., Tanaka, Y., Fridman, R., and Mobashery, S., 2000, Potent and Selective Mechanism-Based Inhibition of Gelatinases. Journal of American Chemical Society, 122:6799–6800.

    Article  Google Scholar 

  346. Brown, P. D., 2001, New hope for matrix metalloproteinase inhibitors in cancer therapy. Drug Discov Today, 6:615.

    Article  Google Scholar 

  347. Koivunen, E., Arap, W., Valtanen, H., Rainisalo, A., Medina, O. P., Heikkila, P., Kantor, C., Gahmberg, C. G., Salo, T., Konttinen, Y. T., Sorsa, T., Ruoslahti, E., and Pasqualini, R., 1999, Tumor targeting with a selective gelatinase inhibitor. Nat Biotechnol, 17:768–774.

    Article  PubMed  Google Scholar 

  348. Garbisa, S., Biggin, S., Cavallarin, N., Sartor, L., Benelli, R., and Albini, A., 1999, Tumor invasion: molecular shears blunted by green tea. Nat Med, 5:1216.

    Article  PubMed  Google Scholar 

  349. Falardeau, P., Champagne, P., Poyet, P., Hariton, C., and Dupont, E., 2001, Neovastat, a naturally occurring multifunctional antiangiogenic drug, in phase III clinical trials. Semin Oncol, 28:620–625.

    Article  Google Scholar 

  350. Reich, R., Thompson, E. W., Iwamoto, Y., Martin, G. R., Deason, J. R., Fuller, G. C., and Miskin, R., 1988, Effects of inhibitors of plasminogen activator, serine proteinases, and collagenase IV on the invasion of basement membranes by metastatic cells. Cancer Res, 48:3307–12.

    PubMed  Google Scholar 

  351. Davies, B., Brown, P. D., East, N., Crimmin, M. J., and Balkwill, F. R., 1993, A synthetic matrix metalloproteinase inhibitor decreases tumor burden and prolongs survival of mice bearing human ovarian carcinoma xenografts. Cancer Res, 53:2087–2091.

    PubMed  Google Scholar 

  352. Wang, X., Fu, X., Brown, P. D., Crimmin, M. J., and Hoffman, R. M., 1994, Matrix metalloproteinase inhibitor BB-94 (batimastat) inhibits human colon tumor growth and spread in a patient-like orthotopic model in nude mice. Cancer Res, 54:4726–8.

    PubMed  Google Scholar 

  353. Eccles, S. A., Box, G. M., Court, W. J., Bone, E. A., Thomas, W., and Brown, P. D., 1996, Control of lymphatic and hematogenous metastasis of a rat mammary carcinoma by the matrix metalloproteinase inhibitor batimastat (BB-94). Cancer Res, 56:2815–2822.

    PubMed  Google Scholar 

  354. Goss, K. J., Brown, P. D., and Matrisian, L. M., 1998, Differing effects of endogenous and synthetic inhibitors of metalloproteinases on intestinal tumorigenesis. Int J Cancer, 78:629–635.

    Article  PubMed  Google Scholar 

  355. Bergers, G., Javaherian, K., Lo, K. M., Folkman, J., and Hanahan, D., 1999, Effects of angiogenesis inhibitors on multistage carcinogenesis in mice. Science, 284:808–812.

    Article  PubMed  Google Scholar 

  356. Sledge, G. W., Jr., Qulali, M., Goulet, R., Bone, E. A., and Fife, R., 1995, Effect of matrix metalloproteinase inhibitor batimastat on breast cancer regrowth and metastasis in athymic mice. J Natl Cancer Inst, 87:1546–50.

    PubMed  Google Scholar 

  357. Wagenaar-Miller, R. A., Gorden, L., and Matrisian, L. M., 2004, Matrix metalloproteinases in colorectal cancer: is it worth talking about?. Cancer Metastasis Rev, 23:119–135.

    Article  PubMed  Google Scholar 

  358. Oba, K., Konno, H., Tanaka, T., Baba, M., Kamiya, K., Ohta, M., Kaneko, T., Shouji, T., Igarashi, A., and Nakamura, S., 2002, Prevention of liver metastasis of human colon cancer by selective matrix metalloproteinase inhibitor MMI-166. Cancer Lett, 175:45–51.

    Article  PubMed  Google Scholar 

  359. An, Z., Wang, X., Willmott, N., Chander, S. K., Tickle, S., Docherty, A. J., Mountain, A., Millican, A. T., Morphy, R., Porter, J. R., Epemolu, R. O., Kubota, T., Moossa, A. R., and Hoffman, R. M., 1997, Conversion of highly malignant colon cancer from an aggressive to a controlled disease by oral administration of a metalloproteinase inhibitor. Clin Exp Metastasis, 15:184–195.

    Article  PubMed  Google Scholar 

  360. Bramhall, S. R., Rosemurgy, A., Brown, P. D., Bowry, C., and Buckels, J. A., 2001, Marimastat as first-line therapy for patients with unresectable pancreatic cancer: a randomized trial. J Clin Oncol, 19:3447–3455.

    PubMed  Google Scholar 

  361. Rao, J. S., 2003, Molecular mechanisms of glioma invasiveness: the role of proteases. Nat Rev Cancer, 3:489–501.

    Article  PubMed  Google Scholar 

  362. Fielding, J., Scholefield, J., Stuart, R., Hawkins, R., McCulloch, P., Maughan, T., Seymour, M., Cutsem, E.V., Thorlacius-Ussing, O., and Hovendal, C., 2000, Presented at the American Society of Clinical Oncology (ASCO)'s 36th Annual Meeting, New Orleans.

    Google Scholar 

  363. Moore, M.J., Eisenberg, J.H., Dagenais, M., Hagan, K., Fields, A., Greenberg, B., Schwartz, B., Ottaway, J., Zee, B., and Seymour, L., posting date 2000, A Comparison Between Gemcitabine (GEM) and the Matrix Metalloproteinase (MMP) Inhibitor BAY12-9566 (9566) in Patients (PTS) with Advanced Pancreatic Cancer. Published Online.

    Google Scholar 

  364. McIntyre, J. O., Fingleton, B., Wells, K. S., Piston, D. W., Lynch, C. C., Gautam, S., and Matrisian, L. M., 2004, Development of a novel fluorogenic proteolytic beacon for in vivo detection and imaging of tumour-associated matrix metalloproteinase-7 activity. Biochem J, 377:617–628.

    PubMed  Google Scholar 

  365. Wang, Z., Juttermann, R., and Soloway, P. D., 2000, TIMP-2 is required for efficient activation of proMMP-2 in vivo. J Biol Chem, 275:26411–5.

    Article  PubMed  Google Scholar 

  366. Ward, R. V., Hembry, R. M., Reynolds, J. J., and Murphy, G., 1991, The purification of tissue inhibitor of metalloproteinases-2 from its 72 kDa progelatinase complex. Demonstration of the biochemical similarities of tissue inhibitor of metalloproteinases-2 and tissue inhibitor of metalloproteinases-1. Biochem J, 278:179–87.

    PubMed  Google Scholar 

  367. Howard, E. W., Bullen, E. C., and Banda, M. J., 1991, Preferential inhibition of 72-and 92-kDa gelatinases by tissue inhibitor of metalloproteinases-2. J Biol Chem, 266:13070–13075.

    PubMed  Google Scholar 

  368. Quantin, B., Murphy, G., and Breathnach, R., 1989, Pump-1 cDNA codes for a protein with characteristics similar to those of classical collagenase family members. Biochemistry, 28:5327–34.

    Article  Google Scholar 

  369. Knauper, V., Wilhelm, S. M., Seperack, P. K., DeClerck, Y. A., Langley, K. E., Osthues, A., and Tschesche, H., 1993, Direct activation of human neutrophil procollagenase by recombinant stromelysin. Biochem J, 295:581–6.

    PubMed  Google Scholar 

  370. Murphy, G., Segain, J. P., O'shea, M., Cockett, M., Ioannou, C., Lefebvre, O., Chambon, P., and Basset, P., 1993, The 28-kDa N-terminal domain of mouse stromelysin-3 has the general properties of a weak metalloproteinase. J Biol Chem, 268:15435–41.

    PubMed  Google Scholar 

  371. Knauper, V., Lopez-Otin, C., Smith, B., Knight, G., and Murphy, G., 1996, Biochemical characterization of human collagenase-3. J Biol Chem, 271:1544–50.

    Article  PubMed  Google Scholar 

  372. English, W. R., Puente, X. S., Freije, J. M., Knauper, V., Amour, A., Merryweather, A., Lopez-Otin, C., and Murphy, G., 2000, Membrane type 4 matrix metalloproteinase (MMP17) has tumor necrosis factor-alpha convertase activity but does not activate pro-MMP2. J Biol Chem, 275:14046–14055.

    Article  PubMed  Google Scholar 

  373. Stracke, J. O., Hutton, M., Stewart, M., Pendas, A. M., Smith, B., Lopez-Otin, C., Murphy, G., and Knauper, V., 2000, Biochemical characterization of the catalytic domain of human matrix metalloproteinase 19. Evidence for a role as a potent basement membrane degrading enzyme. J Biol Chem, 275:14809–14816.

    Article  PubMed  Google Scholar 

  374. English, W. R., Velasco, G., Stracke, J. O., Knauper, V., and Murphy, G., 2001, Catalytic activities of membrane-type 6 matrix metalloproteinase (MMP25). FEBS Lett, 491:137–142.

    Article  PubMed  Google Scholar 

  375. Uria, J. A., and Lopez-Otin, C., 2000, Matrilysin-2, a new matrix metalloproteinase expressed in human tumors and showing the minimal domain organization required for secretion, latency, and activity. Cancer Res, 60:4745–4751.

    PubMed  Google Scholar 

  376. DeClerck, Y. A., Yean, T. D., Chan, D., Shimada, H., and Langley, K. E., 1991, Inhibition of tumor invasion of smooth muscle cell layers by recombinant human metalloproteinase inhibitor. Cancer Res, 51:2151–2157.

    PubMed  Google Scholar 

  377. Quesada, A. R., Barbacid, M. M., Mira, E., Fernandez-Resa, P., Marquez, G., and Aracil, M., 1997, Evaluation of fluorometric and zymographic methods as activity assays for stromelysins and gelatinases. Clin Exp Metastasis. 15:26–32.

    Article  PubMed  Google Scholar 

  378. Knauper, V., Osthues, A., DeClerck, Y. A., Langley, K. E., Blaser, J., and Tschesche, H., 1993, Fragmentation of human polymorphonuclear-leucocyte collagenase. Biochem J, 291 (Pt 3):847–854.

    PubMed  Google Scholar 

  379. Will, H., Atkinson, S. J., Butler, G. S., Smith, B., and Murphy, G., 1996, The soluble catalytic domain of membrane type 1 matrix metalloproteinase cleaves the propeptide of progelatinase A and initiates autoproteolytic activation. Regulation by TIMP-2 and TIMP-3. J Biol Chem, 271:17119–17123.

    Article  PubMed  Google Scholar 

  380. Shimada, T., Nakamura, H., Ohuchi, E., Fujii, Y., Murakami, Y., Sato, H., Seiki, M., and Okada, Y., 1999, Characterization of a truncated recombinant form of human membrane type 3 matrix metalloproteinase. Eur J Biochem, 262:907–914.

    Article  PubMed  Google Scholar 

  381. Llano, E., Pendas, A. M., Freije, J. P., Nakano, A., Knauper, V., Murphy, G., and Lopez-Otin, C., 1999, Identification and characterization of human MT5-MMP, a new membrane-bound activator of progelatinase a overexpressed in brain tumors. Cancer Res, 59:2570–2576.

    PubMed  Google Scholar 

  382. Zhao, Y. G., Xiao, A. Z., Park, H. I., Newcomer, R. G., Yan, M., Man, Y. G., Heffelfinger, S. C., and Sang, Q. X., 2004, Endometase/matrilysin-2 in human breast ductal carcinoma in situ and its inhibition by tissue inhibitors of metalloproteinases-2 and-4: a putative role in the initiation of breast cancer invasion. Cancer Res, 64:590–598.

    Article  PubMed  Google Scholar 

  383. Apte, S. S., Olsen, B. R., and Murphy, G., 1995, The gene structure of tissue inhibitor of metalloproteinases (TIMP)-3 and its inhibitory activities define the distinct TIMP gene family. J Biol Chem, 270:14313–14318.

    Article  Google Scholar 

  384. Will, H., and Hinzmann, B., 1995, cDNA sequence and mRNA tissue distribution of a novel human matrix metalloproteinase with a potential transmembrane segment. Eur J Biochem, 231:602–8.

    Article  PubMed  Google Scholar 

  385. Bigg, H. F., Morrison, C. J., Butler, G. S., Bogoyevitch, M. A., Wang, Z., Soloway, P. D., and Overall, C. M., 2001, Tissue inhibitor of metalloproteinases-4 inhibits but does not support the activation of gelatinase A via efficient inhibition of membrane type 1-matrix metalloproteinase. Cancer Res, 61:3610–3608.

    PubMed  Google Scholar 

  386. Liu, Y. E., Wang, M., Greene, J., Su, J., Ullrich, S., Li, H., Sheng, S., Alexander, P., Sang, Q. A., and Shi, Y. E., 1997, Preparation and characterization of recombinant tissue inhibitor of metalloproteinase 4 (TIMP-4). J Biol Chem, 272:20479–20483.

    Article  PubMed  Google Scholar 

  387. Nomura, H., Fujimoto, N., Seiki, M., Mai, M., and Okada, Y., 1996, Enhanced production of matrix metalloproteinases and activation of matrix metalloproteinase 2 (gelatinase A) in human gastric carcinomas. Int J Cancer, 69:9–16.

    Article  PubMed  Google Scholar 

  388. Ko, B. K., Cho, H. R., Choi, D. W., Nam, C. W., Park, C. J., Kim, G. Y., Kim, S. S., Woo, Y. J., Huh, J., and Kim, M. Y., 1998, Reduced expression of tissue inhibitor of metalloproteinase in nodal metastasis of stomach cancer. J Korean Med Sci, 13:286–90.

    PubMed  Google Scholar 

  389. Joo, Y. E., Seo, K. S., Kim, H. S., Rew, J. S., Park, C. S., and Kim, S. J., 2000, Expression of tissue inhibitors of metalloproteinases (TIMPs) in gastric cancer. Dig Dis Sci, 45:114–121.

    Article  PubMed  Google Scholar 

  390. Hong, S. I., Park, I. C., Hong, W. S., Son, Y. S., Lee, S. H., Lee, J. I., Choi, D. W., Moon, N. M., Choe, T. B., and Jang, J. J., 1996, Overexpression of tissue inhibitors of metalloproteinase-1 and-2 in the stroma of gastric cancer. J Korean Med Sci, 11:474–479.

    PubMed  Google Scholar 

  391. Thomas, P., Khokha, R., Shepherd, F. A., Feld, R., and Tsao, M. S., 2000, Differential expression of matrix metalloproteinases and their inhibitors in non-small cell lung cancer. J Pathol, 190:150–156.

    Article  PubMed  Google Scholar 

  392. Bolon, I., Gouyer, V., Devouassoux, M., Vandenbunder, B., Wernert, N., Moro, D., Brambilla, C., and Brambilla, E., 1995, Expression of c-ets-1, collagenase 1, and urokinase-type plasminogen activator genes in lung carcinomas. Am J Pathol, 147:1298–1310.

    PubMed  Google Scholar 

  393. Nawrocki, B., Polette, M., Marchand, V., Monteau, M., Gillery, P., Tournier, J. M., and Birembaut, P., 1997, Expression of matrix metalloproteinases and their inhibitors in human bronchopulmonary carcinomas: quantificative and morphological analyses. Int J Cancer, 72:556–64.

    Article  PubMed  Google Scholar 

  394. Soini, Y., Paakko, P., and Autio-Harmainen, H., 1993, Genes of laminin B1 chain, alpha 1 (IV) chain of type IV collagen, and 72-kd type IV collagenase are mainly expressed by the stromal cells of lung carcinomas. Am J Pathol, 142:1622–1630.

    PubMed  Google Scholar 

  395. Suzuki, M., Iizasa, T., Fujisawa, T., Baba, M., Yamaguchi, Y., Kimura, H., and Suzuki, H., 1998, Expression of matrix metalloproteinases and tissue inhibitor of matrix metalloproteinases in non-small-cell lung cancer. Invasion Metastasis, 18:134–141.

    Article  PubMed  Google Scholar 

  396. Bolon, I., Devouassoux, M., Robert, C., Moro, D., Brambilla, C., and Brambilla, E., 1997, Expression of urokinase-type plasminogen activator, stromelysin 1, stromelysin 3, and matrilysin genes in lung carcinomas. Am J Pathol, 150:1619–1629.

    PubMed  Google Scholar 

  397. Nagashima, Y., Hasegawa, S., Koshikawa, N., Taki, A., Ichikawa, Y., Kitamura, H., Misugi, K., Kihira, Y., Matuo, Y., Yasumitsu, H., and Miyazaki, K., 1997, Expression of matrilysin in vascular endothelial cells adjacent to matrilysin-producing tumors. Int J Cancer, 72:441–5.

    Article  PubMed  Google Scholar 

  398. Michael, M., Babic, B., Khokha, R., Tsao, M., Ho, J., Pintilie, M., Leco, K., Chamberlain, D., and Shepherd, F. A., 1999, Expression and prognostic significance of metalloproteinases and their tissue inhibitors in patients with small-cell lung cancer. J Clin Oncol, 17:1802–8.

    PubMed  Google Scholar 

  399. Kodate, M., Kasai, T., Hashimoto, H., Yasumoto, K., Iwata, Y., and Manabe, H., 1997, Expression of matrix metalloproteinase (gelatinase) in T1 adenocarcinoma of the lung. Pathol Int, 47:461–9.

    PubMed  Google Scholar 

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

    PubMed  Google Scholar 

  401. Cox, G., Jones, J. L., and O'Byrne, K. J., 2000, Matrix metalloproteinase 9 and the epidermal growth factor signal pathway in operable non-small cell lung cancer. Clin Cancer Res, 6:2349–2355.

    PubMed  Google Scholar 

  402. Anderson, I. C., Sugarbaker, D. J., Ganju, R. K., Tsarwhas, D. G., Richards, W. G., Sunday, M., Kobzik, L., and Shipp, M. A., 1995, Stromelysin-3 is overexpressed by stromal elements in primary non-small cell lung cancers and regulated by retinoic acid in pulmonary fibroblasts. Cancer Res, 55:4120–4126.

    PubMed  Google Scholar 

  403. Cho, N. H., Hong, K. P., Hong, S. H., Kang, S., Chung, K. Y., and Cho, S. H., 2004, MMP expression profiling in recurred stage IB lung cancer. Oncogene, 23:845–851.

    Article  PubMed  Google Scholar 

  404. Bodey, B., Bodey, B., Jr., Groger, A. M., Siegel, S. E., and Kaiser, H. E., 2001, Invasion and metastasis: the expression and significance of matrix metalloproteinases in carcinomas of the lung. In Vivo, 15:175–180.

    Google Scholar 

  405. Polette, M., Nawrocki, B., Gilles, C., Sato, H., Seiki, M., Tournier, J. M., and Birembaut, P., 1996, MTMMP expression and localisation in human lung and breast cancers. Virchows Arch, 428:29–35.

    Article  PubMed  Google Scholar 

  406. Marchenko, G. N., Ratnikov, B. I., Rozanov, D. V., Godzik, A., Deryugina, E. I., and Strongin, A. Y., 2001, Characterization of matrix metalloproteinase-26, a novel metalloproteinase widely expressed in cancer cells of epithelial origin. Biochem J, 356:705–718.

    Article  PubMed  Google Scholar 

  407. Polette, M., Gilbert, N., Stas, I., Nawrocki, B., Noel, A., Remacle, A., Stetler-Stevenson, W. G., Birembaut, P., and Foidart, M., 1994, Gelatinase A expression and localization in human breast cancers. An in situ hybridization study and immunohistochemical detection using confocal microscopy. Virchows Arch, 424:641–5.

    Article  PubMed  Google Scholar 

  408. Ioachim, E. E., Athanassiadou, S. E., Kamina, S., Carassavoglou, K., and Agnantis, N. J., 1998, Matrix metalloproteinase expression in human breast cancer: an immunohistochemical study including correlation with cathepsin D, type IV collagen, laminin, fibronectin, EGFR, c-erbB-2 oncoprotein, p53, steroid receptors status and proliferative indices. Anticancer Res, 18:1665–1670.

    PubMed  Google Scholar 

  409. Bodey, B., Bodey, B., Jr., Siegel, S. E., and Kaiser, H. E., 2001, Matrix metalloproteinases in neoplasm-induced extracellular matrix remodeling in breast carcinomas, Anticancer Res 21:2021–2028.

    PubMed  Google Scholar 

  410. Basset, P., Wolf, C., Rouyer, N., Bellocq, J. P., Rio, M. C., and Chambon, P., 1994, Stromelysin-3 in stromal tissue as a control factor in breast cancer behavior. Cancer, 74:1045–1049.

    PubMed  Google Scholar 

  411. Ueno, H., Nakamura, H., Inoue, M., Imai, K., Noguchi, M., Sato, H., Seiki, M., and Okada, Y., 1997, Expression and tissue localization of membrane-types 1, 2, and 3 matrix metalloproteinases in human invasive breast carcinomas. Cancer Res, 57:2055–2060.

    PubMed  Google Scholar 

  412. Bisson, C., Blacher, S., Polette, M., Blanc, J. F., Kebers, F., Desreux, J., Tetu, B., Rosenbaum, J., Foidart, J. M., Birembaut, P., and Noel, A., 2003, Restricted expression of membrane type 1-matrix metalloproteinase by myofibroblasts adjacent to human breast cancer cells. Int J Cancer, 105:7–13.

    Article  Google Scholar 

  413. Djonov, V., Hogger, K., Sedlacek, R., Laissue, J., and Draeger, A., 2001, MMP-19: cellular localization of a novel metalloproteinase within normal breast tissue and mammary gland tumours. J Pathol, 195:147–155.

    Article  PubMed  Google Scholar 

  414. Boag, A. H., and Young, I. D., 1994, Increased expression of the 72-kd type IV collagenase in prostatic adenocarcinoma. Demonstration by immunohistochemistry and in situ hybridization. Am J Pathol, 144:585–591.

    PubMed  Google Scholar 

  415. Stearns, M. E., and Wang, M., 1993, Type IV collagenase (M(r) 72,000) expression in human prostate: benign and malignant tissue. Cancer Res, 53:878–883.

    PubMed  Google Scholar 

  416. Upadhyay, J., Shekarriz, B., Nemeth, J. A., Dong, Z., Cummings, G. D., Fridman, R., Sakr, W., Grignon, D. J., and Cher, M. L., 1999, Membrane type 1-matrix metalloproteinase (MT1-MMP) and MMP-2 immunolocalization in human prostate: change in cellular localization associated with high-grade prostatic intraepithelial neoplasia. Clin Cancer Res, 5:4105–4110.

    PubMed  Google Scholar 

  417. Knox, J. D., Wolf, C., McDaniel, K., Clark, V., Loriot, M., Bowden, G. T., and Nagle, R. B., 1996, Matrilysin expression in human prostate carcinoma. Mol Carcinog, 15:57–63.

    Article  PubMed  Google Scholar 

  418. Kuniyasu, H., Ellis, L. M., Evans, D. B., Abbruzzese, J. L., Fenoglio, C. J., Bucana, C. D., Cleary, K. R., Tahara, E., and Fidler, I. J., 1999, Relative expression of E-cadherin and type IV collagenase genes predicts disease outcome in patients with resectable pancreatic carcinoma. Clin Cancer Res, 5:25–33.

    PubMed  Google Scholar 

  419. Zhao, Y. G., Xiao, A. Z., Newcomer, R. G., Park, H. I., Kang, T., Chung, L. W., Swanson, M. G., Zhau, H. E., Kurhanewicz, J., and Sang, Q. X., 2003, Activation of pro-gelatinase B by endometase/matrilysin-2 promotes invasion of human prostate cancer cells. J Biol Chem, 278:15056–15064.

    Article  PubMed  Google Scholar 

  420. Shiozawa, J., Ito, M., Nakayama, T., Nakashima, M., Kohno, S., and Sekine, I., 2000, Expression of matrix metalloproteinase-1 in human colorectal carcinoma. Mod Pathol, 13:925–933.

    Article  PubMed  Google Scholar 

  421. Otani, Y., Okazaki, I., Arai, M., Kameyama, K., Wada, N., Maruyama, K., Yoshino, K., Kitajima, M., Hosoda, Y., and Tsuchiya, M., 1994, Gene expression of interstitial collagenase (matrix metalloproteinase 1) in gastrointestinal tract cancers. J Gastroenterol, 29:391–7.

    PubMed  Google Scholar 

  422. Grigioni, W. F., D'Errico, A., Fiorentino, M., Baccarini, P., Onisto, M., Caenazzo, C., Stetler-Stevenson, W. G., Garbisa, S., and Mancini, A. M., 1994, Gelatinase A (MMP-2) and its mRNA detected in both neoplastic and stromal cells of tumors with different invasive and metastatic properties. Diagn Mol Pathol, 3:163–169.

    PubMed  Google Scholar 

  423. Kikuchi, R., Noguchi, T., Takeno, S., Kubo, N., and Uchida, Y., 2000, Immunohistochemical detection of membrane-type-1-matrix metalloproteinase in colorectal carcinoma. Br J Cancer, 83:215–8.

    Article  PubMed  Google Scholar 

  424. Poulsom, R., Pignatelli, M., Stetler-Stevenson, W. G., Liotta, L. A., Wright, P. A., Jeffery, R. E., Longcroft, J. M., Rogers, L., and Stamp, G. W., 1992, Stromal expression of 72 kda type IV collagenase (MMP-2) and TIMP-2 mRNAs in colorectal neoplasia. Am J Pathol, 141:389–96.

    PubMed  Google Scholar 

  425. Bodey, B., Bodey, B., Jr., Siegel, S. E., and Kaiser, H. E., 2000, Prognostic significance of matrix metalloproteinase expression in colorectal carcinomas. In Vivo, 14:659–666.

    Google Scholar 

  426. McDonnell, S., Navre, M., Coffey, R. J., Jr., and Matrisian, L. M., 1991, Expression and localization of the matrix metalloproteinase pump-1 (MMP-7) in human gastric and colon carcinomas. Mol Carcinog, 4:527–33.

    PubMed  Google Scholar 

  427. Adachi, Y., Yamamoto, H., Itoh, F., Arimura, Y., Nishi, M., Endo, T., and Imai, K., 2001, Clinicopathologic and prognostic significance of matrilysin expression at the invasive front in human colorectal cancers. Int J Cancer, 95:290–294.

    Article  PubMed  Google Scholar 

  428. Ring, P., Johansson, K., Hoyhtya, M., Rubin, K., and Lindmark, G., 1997, Expression of tissue inhibitor of metalloproteinases TIMP-2 in human colorectal cancer—a predictor of tumour stage. Br J Cancer, 76:805–811.

    PubMed  Google Scholar 

  429. Porte, H., Chastre, E., Prevot, S., Nordlinger, B., Empereur, S., Basset, P., Chambon, P., and Gespach, C., 1995, Neoplastic progression of human colorectal cancer is associated with overexpression of the stromelysin-3 and BM-40/SPARC genes. Int J Cancer, 64:70–5.

    PubMed  Google Scholar 

  430. Yang, W., Arii, S., Gorrin-Rivas, M. J., Mori, A., Onodera, H., and Imamura, M., 2001, Human macrophage metalloelastase gene expression in colorectal carcinoma and its clinicopathologic significance. Cancer, 91:1277–1283.

    Article  PubMed  Google Scholar 

  431. Ohtani, H., Motohashi, H., Sato, H., Seiki, M., and Nagura, H., 1996, Dual over-expression pattern of membrane-type metalloproteinase-1 in cancer and stromal cells in human gastrointestinal carcinoma revealed by in situ hybridization and immunoelectron microscopy. Int J Cancer, 68:565–70.

    Article  PubMed  Google Scholar 

  432. Ahokas, K., Lohi, J., Lohi, H., Elomaa, O., Karjalainen-Lindsberg, M. L., Kere, J., and Saarialho-Kere, U., 2002, Matrix metalloproteinase-21, the human orthologue for XMMP, is expressed during fetal development and in cancer. Gene, 301:31–41.

    Article  PubMed  Google Scholar 

  433. Davidson, B., Reich, R., Berner, A., Givant-Horwitz, V., Goldberg, I., Risberg, B., Kristensen, G. B., Trope, C. G., Bryne, M., Kopolovic, J., and Nesland, J. M., 2001, Ovarian carcinoma cells in serous effusions show altered MMP-2 and TIMP-2 mRNA levels. Eur J Cancer, 37:2040–2049.

    Article  PubMed  Google Scholar 

  434. Paju, A., Sorsa, T., Tervahartiala, T., Koivunen, E., Haglund, C., Leminen, A., Wahlstrom, T., Salo, T., and Stenman, U. H., 2001, The levels of trypsinogen isoenzymes in ovarian tumour cyst fluids are associated with promatrix metalloproteinase-9 but not promatrix metalloproteinase-2 activation. Br J Cancer, 84:1363–1371.

    Article  PubMed  Google Scholar 

  435. Westerlund, A., Apaja-Sarkkinen, M., Hoyhtya, M., Puistola, U., and Turpeenniemi-Hujanen, T., 1999, Gelatinase A-immunoreactive protein in ovarian lesions-prognostic value in epithelial ovarian cancer. Gynecol Oncol, 75:91–98.

    Article  PubMed  Google Scholar 

  436. Davidson, B., Goldberg, I., Gotlieb, W. H., Kopolovic, J., Ben-Baruch, G., Nesland, J. M., Berner, A., Bryne, M., and Reich, R., 1999, High levels of MMP-2, MMP-9, MT1-MMP and TIMP-2 mRNA correlate with poor survival in ovarian carcinoma. Clin Exp Metastasis, 17:799–808.

    Article  PubMed  Google Scholar 

  437. Naylor, M. S., Stamp, G. W., Davies, B. D., and Balkwill, F. R., 1994, Expression and activity of MMPS and their regulators in ovarian cancer. Int J Cancer, 58:50–56.

    PubMed  Google Scholar 

  438. Tanimoto, H., Underwood, L. J., Shigemasa, K., Parmley, T. H., Wang, Y., Yan, Y., Clarke, J., and O'Brien, T. J., 1999, The matrix metalloprotease pump-1 (MMP-7, Matrilysin): A candidate marker/target for ovarian cancer detection and treatment. Tumour Biol, 20:88–98.

    Article  Google Scholar 

  439. Huang, L. W., Garrett, A. P., Bell, D. A., Welch, W. R., Berkowitz, R. S., and Mok, S. C., 2000, Differential expression of matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 protein and mRNA in epithelial ovarian tumors. Gynecol Oncol, 77:369–376.

    Article  PubMed  Google Scholar 

  440. Davidson, B., Goldberg, I., Berner, A., Nesland, J. M., Givant-Horwitz, V., Bryne, M., Risberg, B., Kristensen, G. B., Trope, C. G., Kopolovic, J., and Reich, R., 2001, Expression of membrane-type 1, 2, and 3 matrix metalloproteinases messenger RNA in ovarian carcinoma cells in serous effusions. Am J Clin Pathol, 115:517–524.

    Article  PubMed  Google Scholar 

  441. Mueller, J., Brebeck, B., Schmalfeldt, B., Kuhn, W., Graeff, H., and Hofler, H., 2000, Stromelysin-3 expression in invasive ovarian carcinomas and tumours of low malignant potential. Virchows Arch, 437:618–24.

    Article  PubMed  Google Scholar 

  442. Tsukifuji, R., Tagawa, K., Hatamochi, A., and Shinkai, H., 1999, Expression of matrix metalloproteinase-1,-2 and-3 in squamous cell carcinoma and actinic keratosis. Br J Cancer, 80:1087–91.

    Article  PubMed  Google Scholar 

  443. Shimada, T., Nakamura, H., Yamashita, K., Kawata, R., Murakami, Y., Fujimoto, N., Sato, H., Seiki, M., and Okada, Y., 2000, Enhanced production and activation of progelatinase A mediated by membrane-type 1 matrix metalloproteinase in human oral squamous cell carcinomas: implications for lymph node metastasis. Clin Exp Metastasis, 18:179–188.

    Article  PubMed  Google Scholar 

  444. Pyke, C., Ralfkiaer, E., Huhtala, P., Hurskainen, T., Dano, K., and Tryggvason, K., 1992, Localization of messenger RNA for Mr 72,000 and 92,000 type IV collagenases in human skin cancers by in situ hybridization. Cancer Res, 52:1336–41.

    PubMed  Google Scholar 

  445. Airola, K., Johansson, N., Kariniemi, A. L., Kahari, V. M., and Saarialho-Kere, U. K., 1997, Human collagenase-3 is expressed in malignant squamous epithelium of the skin. J Invest Dermatol, 109:225–231.

    Article  PubMed  Google Scholar 

  446. Karelina, T. V., Goldberg, G. I., and Eisen, A. Z., 1994, Matrilysin (PUMP) correlates with dermal invasion during appendageal development and cutaneous neoplasia. J Invest Dermatol, 103:482–7.

    Article  PubMed  Google Scholar 

  447. Stahle-Backdahl, M., and Parks, W. C., 1993, 92-kd gelatinase is actively expressed by eosinophils and stored by neutrophils in squamous cell carcinoma. Am J Pathol, 142:995–1000.

    PubMed  Google Scholar 

  448. Kerkela, E., Ala-aho, R., Lohi, J., Grenman, R., V, M. K., and Saarialho-Kere, U., 2001, Differential patterns of stromelysin-2 (MMP-10) and MT1-MMP (MMP-14) expression in epithelial skin cancers. Br J Cancer, 84:659–69.

    Article  PubMed  Google Scholar 

  449. Thewes, M., Worret, W. I., Engst, R., and Ring, J., 1999, Stromelysin-3 (ST-3): immunohistochemical characterization of the matrix metalloproteinase (MMP)-11 in benign and malignant skin tumours and other skin disorders. Clin Exp Dermatol, 24:122–126.

    Article  PubMed  Google Scholar 

  450. Kerkela, E., Ala-Aho, R., Jeskanen, L., Rechardt, O., Grenman, R., Shapiro, S. D., Kahari, V. M., and Saarialho-Kere, U., 2000, Expression of human macrophage metalloelastase (MMP-12) by tumor cells in skin cancer. J Invest Dermatol, 114:1113–9.

    Article  PubMed  Google Scholar 

  451. Impola, U., Toriseva, M., Suomela, S., Jeskanen, L., Hieta, N., Jahkola, T., Grenman, R., Kahari, V. M., and Saarialho-Kere, U., 2003, Matrix metalloproteinase-19 is expressed by proliferating epithelium but disappears with neoplastic dedifferentiation. Int J Cancer, 103:709–716.

    Article  PubMed  Google Scholar 

  452. Nakamura, H., Fujii, Y., Inoki, I., Sugimoto, K., Tanzawa, K., Matsuki, H., Miura, R., Yamaguchi, Y., and Okada, Y., 2000, Brevican is degraded by matrix metalloproteinases and aggrecanase-1 (ADAMTS4) at different sites. J Biol Chem, 275:38885–90.

    Article  PubMed  Google Scholar 

  453. Fernandez-Patron, C., Radomski, M. W., and Davidge, S. T., 1999, Vascular matrix metalloproteinase-2 cleaves big endothelin-1 yielding a novel vasoconstrictor. Circ Res, 85:906–911.

    PubMed  Google Scholar 

  454. Rodriguez-Manzaneque, J. C., Milchanowski, A. B., Dufour, E. K., Leduc, R., and Iruela-Arispe, M. L., 2000, Characterization of METH-1/ADAMTS1 processing reveals two distinct active forms. J Biol Chem, 275:33471–9.

    Article  Google Scholar 

  455. Agostini, C., Trentin, L., Facco, M., Sancetta, R., Cerutti, A., Tassinari, C., Cimarosto, L., Adami, F., Cipriani, A., Zambello, R., and Semenzato, G., 1996, Role of IL-15, IL-2, and their receptors in the development of T cell alveolitis in pulmonary sarcoidosis. J Immunol, 157:910–918.

    PubMed  Google Scholar 

  456. Ogata, Y., Enghild, J. J., and Nagase, H., 1992, Matrix metalloproteinase 3 (stromelysin) activates the precursor for the human matrix metalloproteinase 9. J Biol Chem, 267:3581–3584.

    PubMed  Google Scholar 

  457. Lijnen, H. R., and Collen, D., 1990, Serine proteases and their serpin inhibitors in the nervous system. Plenum Press, New York.

    Google Scholar 

  458. Ugwu, F., Van Hoef, B., Bini, A., Collen, D., and Lijnen, H. R., 1998, Proteolytic cleavage of urokinase-type plasminogen activator by stromelysin-1 (MMP-3). Biochemistry, 37:7231–7236.

    Article  PubMed  Google Scholar 

  459. Preece, G., Murphy, G., and Ager, A., 1996, Metalloproteinase-mediated regulation of L-selectin levels on leucocytes. J Biol Chem, 271:11634–40.

    Article  PubMed  Google Scholar 

  460. Imai, K., Yokohama, Y., Nakanishi, I., Ohuchi, E., Fujii, Y., Nakai, N., and Okada, Y., 1995, Matrix metalloproteinase 7 (matrilysin) from human rectal carcinoma cells. Activation of the precursor, interaction with other matrix metalloproteinases and enzymic properties. J Biol Chem, 270:6691–6697.

    Article  PubMed  Google Scholar 

  461. Agnihotri, R., Crawford, H. C., Haro, H., Matrisian, L. M., Havrda, M. C., and Liaw, L., 2001, Osteopontin, a novel substrate for matrix metalloproteinase-3 (stromelysin-1) and matrix metalloproteinase-7 (matrilysin). J Biol Chem, 276:28261–28267.

    Article  PubMed  Google Scholar 

  462. Fernandez-Patron, C., Zouki, C., Whittal, R., Chan, J. S., Davidge, S. T., and Filep, J. G., 2001, Matrix metalloproteinases regulate neutrophil-endothelial cell adhesion through generation of endothelin-1. Faseb J, 15:2230–2240.

    Article  PubMed  Google Scholar 

  463. Ochieng, J., Fridman, R., Nangia-Makker, P., Kleiner, D. E., Liotta, L. A., Stetler-Stevenson, W. G., and Raz, A., 1994, Galectin-3 is a novel substrate for human matrix metalloproteinases-2 and-9. Biochemistry, 33:14109–14114.

    Article  PubMed  Google Scholar 

  464. Nicholson, R., Murphy, G., and Breathnach, R., 1989, Human and rat malignant-tumor-associated mRNAs encode stromelysin-like metalloproteinases. Biochemistry, 28:5195–203.

    Article  PubMed  Google Scholar 

  465. Nakamura, H., Fujii, Y., Ohuchi, E., Yamamoto, E., and Okada, Y., 1998, Activation of the precursor of human stromelysin 2 and its interactions with other matrix metalloproteinases. Eur J Biochem, 253:67–75.

    Article  Google Scholar 

  466. Knauper, V., Smith, B., Lopez-Otin, C., and Murphy, G., 1997, Activation of progelatinase B (proMMP-9) by active collagenase-3 (MMP-13). Eur J Biochem, 248:369–73.

    Article  PubMed  Google Scholar 

  467. Banda, M. J., Clark, E. J., and Werb, Z., 1983, Selective proteolysis of immunoglobulins by mouse macrophage elastase. J Exp Med, 157:1184–1196.

    Article  PubMed  Google Scholar 

  468. Knauper, V., Cowell, S., Smith, B., Lopez-Otin, C., O'shea, M., Morris, H., Zardi, L., and Murphy, G., 1997, The role of the C-terminal domain of human collagenase-3 (MMP-13) in the activation of procollagenase-3, substrate specificity, and tissue inhibitor of metalloproteinase interaction. J Biol Chem, 272:7608–16.

    Article  PubMed  Google Scholar 

  469. d'Ortho, M. P., Clerici, C., Yao, P. M., Delacourt, C., Delclaux, C., Franco-Montoya, M. L., Harf, A., and Lafuma, C., 1997, Alveolar epithelial cells in vitro produce gelatinases and tissue inhibitor of matrix metalloproteinase-2. Am J Physiol, 273:663–675.

    Google Scholar 

  470. Deryugina, E. I., Ratnikov, B. I., Postnova, T. I., Rozanov, D. V., and Strongin, A. Y., 2002, Processing of integrin alpha(v) subunit by membrane type 1 matrix metalloproteinase stimulates migration of breast carcinoma cells on vitronectin and enhances tyrosine phosphorylation of focal adhesion kinase. J Biol Chem, 277:9749–56.

    Article  PubMed  Google Scholar 

  471. d'Ortho, M. P., Will, H., Atkinson, S., Butler, G., Messent, A., Gavrilovic, J., Smith, B., Timpl, R., Zardi, L., and Murphy, G., 1997, Membrane-type matrix metalloproteinases 1 and 2 exhibit broad-spectrum proteolytic capacities comparable to many matrix metalloproteinases. Eur J Biochem, 250:751–757.

    Article  PubMed  Google Scholar 

  472. Morrison, C. J., Butler, G. S., Bigg, H. F., Roberts, C. R., Soloway, P. D., and Overall, C. M., 2001, Cellular activation of MMP-2 (gelatinase A) by MT2-MMP occurs via a TIMP-2-independent pathway. J Biol Chem, 276:47402–47410.

    Article  PubMed  Google Scholar 

  473. Shofuda, K., Yasumitsu, H., Nishihashi, A., Miki, K., and Miyazaki, K., 1997, Expression of three membrane-type matrix metalloproteinases (MTMMPs) in rat vascular smooth muscle cells and characterization of MT3-MMPs with and without transmembrane domain. J Biol Chem, 272:9749–9754.

    Article  PubMed  Google Scholar 

  474. Wang, Y., Johnson, A. R., Ye, Q. Z., and Dyer, R. D., 1999, Catalytic activities and substrate specificity of the human membrane type 4 matrix metalloproteinase catalytic domain. J Biol Chem, 274:33043–33049.

    Article  PubMed  Google Scholar 

  475. Stracke, J. O., Fosang, A. J., Last, K., Mercuri, F. A., Pendas, A. M., Llano, E., Perris, R., Di Cesare, P. E., Murphy, G., and Knauper, V., 2000, Matrix metalloproteinases 19 and 20 cleave aggrecan and cartilage oligomeric matrix protein (COMP). FEBS Lett, 478:52–56.

    Article  PubMed  Google Scholar 

  476. Yang, M., and Kurkinen, M., 1998, Cloning and characterization of a novel matrix metalloproteinase (MMP), CMMP, from chicken embryo fibroblasts. CMMP, Xenopus XMMP, and human MMP19 have a conserved unique cysteine in the catalytic domain. J Biol Chem, 273:17893–17900.

    Article  PubMed  Google Scholar 

  477. Velasco, G., Cal, S., Merlos-Suarez, A., Ferrando, A. A., Alvarez, S., Nakano, A., Arribas, J., and Lopez-Otin, C., 2000, Human MT6-matrix metalloproteinase: identification, progelatinase A activation, and expression in brain tumors. Cancer Res, 60:877–882.

    PubMed  Google Scholar 

  478. de Coignac, A. B., Elson, G., Delneste, Y., Magistrelli, G., Jeannin, P., Aubry, J. P., Berthier, O., Schmitt, D., Bonnefoy, J. Y., and Gauchat, J. F., 2000, Cloning of MMP-26. A novel matrilysin-like proteinase. Eur J Biochem, 267:3323–3329.

    Article  PubMed  Google Scholar 

  479. Lohi, J., Wilson, C. L., Roby, J. D., and Parks, W. C., 2001, Epilysin, a novel human matrix metalloproteinase (MMP-28) expressed in testis and keratinocytes and in response to injury. J Biol Chem, 276:10134–44.

    Article  PubMed  Google Scholar 

  480. Balbin, M., Fueyo, A., Knauper, V., Lopez, J. M., Alvarez, J., Sanchez, L. M., Quesada, V., Bordallo, J., Murphy, G., and Lopez-Otin, C., 2001, Identification and enzymatic characterization of two diverging murine counterparts of human interstitial collagenase (MMP-1) expressed at sites of embryo implantation. J Biol Chem, 276:10253–10262.

    Article  PubMed  Google Scholar 

  481. Hahn-Dantona, E. A., Aimes, R. T., and Quigley, J. P., 2000, The isolation, characterization, and molecular cloning of a 75-kDa gelatinase B-like enzyme, a member of the matrix metalloproteinase (MMP) family. An avian enzyme that is MMP-9-like in its cell expression pattern but diverges from mammalian gelatinase B in sequence and biochemical properties. J Biol Chem, 275:40827–40838.

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2005 Springer

About this chapter

Cite this chapter

Diaz, R.J., Eichten, A., de Visser, K.E., Coussens, L.M. (2005). Matrix Metalloproteinases: Mediators of Tumour-Host Cell Interactions. In: Meadows, G.G. (eds) Integration/Interaction of Oncologic Growth. Cancer Growth and Progression, vol 15. Springer, Dordrecht. https://doi.org/10.1007/1-4020-3414-8_6

Download citation

Publish with us

Policies and ethics