Cancer and Metastasis Reviews

, Volume 27, Issue 1, pp 57–66 | Cite as

The tumor microenvironment: regulation by MMP-independent effects of tissue inhibitor of metalloproteinases-2

  • William G. Stetler-Stevenson


Proteolytic remodeling of the extracellular matrix is an important component of disease progression in many chronic disease states and is the initiating event in the formation of the tumor microenvironment in cancer. It is the balance of extracellular matrix degrading enzymes, the matrix metalloproteinases (MMPs) and their endogenous inhibitors that determine the extent of tissue remodeling. Unchecked MMP activity can result in significant tissue damage, facilitate disease progression and is associated with host responses to pathologic injury such as angiogenesis and inflammation. The tissue inhibitors of metalloproteinases (TIMPs) have been shown to regulate MMP activity. However, recent findings demonstrate that the tissue inhibitor of metalloproteinases-2 (TIMP-2) inhibits the mitogenic response of human microvascular endothelial cells to growth factors, such as VEGF-A and FGF-2 in vitro and angiogenesis in vivo. The mechanism of this effect is independent of metalloproteinase inhibition. Our lab is the first to demonstrate a cell-surface signaling receptor for a member of the TIMP family and suggest that TIMP-2 functions to regulate cellular responses to growth factors. These new findings are discussed in terms of a model of TIMP-2 regulation of cellular functions in the tumor microenvironment.


Tissue inhibitor of metalloproteinase TIMP-2 Anti-angiogenic Anti-tumorigenic Cellular differentiation Cancer therapy 


  1. 1.
    Hanahan, D., & Folkman, J. (1996). Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell, 86, 353–364.PubMedCrossRefGoogle Scholar
  2. 2.
    Folkman, J., & Hanahan, D. (1991). Switch to the angiogenic phenotype during tumorigenesis. Princess Takamatsu Symposia, 22, 339–347.PubMedGoogle Scholar
  3. 3.
    Heissig, B., Hattori, K., Friedrich, M., Rafii, S., & Werb, Z. (2003). Angiogenesis: vascular remodeling of the extracellular matrix involves metalloproteinases. Current Opinion in Hematology, 10, 136–141.PubMedCrossRefGoogle Scholar
  4. 4.
    Coussens, L. M., Fingleton, B., & Matrisian, L. M. (2002). Matrix metalloproteinase inhibitors and cancer: Trials and tribulations. Science, 295, 2387–2392.PubMedCrossRefGoogle Scholar
  5. 5.
    Coussens, L. M., & Werb, Z. (2001). Inflammation and cancer. Nature, 420, 860–867.CrossRefGoogle Scholar
  6. 6.
    Sternlicht, M. D., & Werb, Z. (2001). How matrix metalloproteinases regulate cell behavior. Annual Review of Cell & Developmental Biology, 17, 463–516.CrossRefGoogle Scholar
  7. 7.
    Egeblad, M., & Werb, Z. (2002). New functions for the matrix metalloproteinases in cancer progression. Nature Reviews Cancer, 2, 161–174.PubMedCrossRefGoogle Scholar
  8. 8.
    Lambert, E., Dasse, E., Haye, B., & Petitfrere, E. (2004). TIMPs as multifacial proteins. Critical Reviews in Oncology Hematology, 49, 187–198.CrossRefGoogle Scholar
  9. 9.
    Crocker, S. J., Pagenstecher, A., & Campbell, I. L. (2004). The TIMPs tango with MMPs and more in the central nervous system. Journal of Neuroscience Research, 75, 1–11.PubMedCrossRefGoogle Scholar
  10. 10.
    Brew, K., Dinakarpandian, D., & Nagase, H. (2000). Tissue inhibitors of metalloproteinases: Evolution, structure and function. Biochimica et Biophysica Acta, 1477, 267–283.PubMedGoogle Scholar
  11. 11.
    Zhang, J. S., Bai, S., Tanase, C., Nagase, H., & Sarras, M. P. (2003). The expression of tissue inhibitor of metalloproteinase 2 (TIMP-2) is required for normal development of zebrafish embryos. Development Genes and Evolution, 213, 382–389.PubMedCrossRefGoogle Scholar
  12. 12.
    Gill, S. E., Pape, M. C., Khokha, R., Watson, A. J., & Leco, K. J. (2003). A null mutation for tissue inhibitor of metalloproteinases-3 (Timp-3) impairs murine bronchiole branching morphogenesis. Developmental Biology, 261, 313–323.PubMedCrossRefGoogle Scholar
  13. 13.
    Fata, J. E., Leco, K. J., Voura, E. B., Yu, H. Y., Waterhouse, P., Murphy, G., et al. (2001). Accelerated apoptosis in the Timp-3-deficient mammary gland. Journal of Clinical Investigation, 108, 831–841.PubMedCrossRefGoogle Scholar
  14. 14.
    Godenschwege, T. A., Pohar, N., Buchner, S., & Buchner, E. (2000). Inflated wings, tissue autolysis and early death in tissue inhibitor of metalloproteinases mutants of Drosophila. European Journal of Cell Biology, 79, 495–501.PubMedCrossRefGoogle Scholar
  15. 15.
    Stetler-Stevenson, W. G. (1999). Matrix metalloproteinases in angiogenesis: a moving target for therapeutic intervention. Journal of Clinical Investigation, 103, 1237–1241.PubMedGoogle Scholar
  16. 16.
    Derry, J. M., & Barnard, P. J. (1992). Physical linkage of the A-raf-1, properdin, synapsin I, and TIMP genes on the human and mouse X chromosomes. Genomics, 12, 632–638.PubMedCrossRefGoogle Scholar
  17. 17.
    Dunham, I., Shimizu, N., Roe, B. A., Chissoe, S., Hunt, A. R., Collins, J. E., et al. (1999). The DNA sequence of human chromosome 22.[see comment][erratum appears in Nature 2000 Apr 20;404(6780):904]. Nature, 402, 489–495.PubMedCrossRefGoogle Scholar
  18. 18.
    Pohar, N., Godenschwege, T. A., & Buchner, E. (1999). Invertebrate tissue inhibitor of metalloproteinase: Structure and nested gene organization within the synapsin locus is conserved from Drosophila to human. Genomics, 57, 293–296.PubMedCrossRefGoogle Scholar
  19. 19.
    Caterina, J. J., Yamada, S., Caterina, N. C. M., Longenecker, G., Holmback, K., Shi, J., et al. (2000). Inactivating mutation of the mouse tissue inhibitor of metalloproteinases-2(Timp-2) gene alters proMMP-2 activation. Journal of Biological Chemistry, 275, 26416–26422.PubMedCrossRefGoogle Scholar
  20. 20.
    Jaworski, D. M., Beem-Miller, M., Lluri, G., & Barrantes-Reynolds, R. (2007). Potential regulatory relationship between the nested gene DDC8 and its host gene tissue inhibitor of metalloproteinase-2. Physiological Genomics, 28, 168–178.PubMedCrossRefGoogle Scholar
  21. 21.
    Wang, Z., Juttermann, R., & Soloway, P. D. (2000). TIMP-2 is required for efficient activation of proMMP-2 in vivo. Journal of Biological Chemistry, 275, 26411–26415.PubMedCrossRefGoogle Scholar
  22. 22.
    Docherty, A. J., Lyons, A., Smith, B. J., Wright, E. M., Stephens, P. E., Harris, T. J., et al. (1985). Sequence of human tissue inhibitor of metalloproteinases and its identity to erythroid-potentiating activity. Nature, 318, 66–69.PubMedCrossRefGoogle Scholar
  23. 23.
    Gasson, J. C., Bersch, N., & Golde, D. W. (1985). Characterization of purified human erythroid-potentiating activity. Progress in Clinical & Biological Research, 184, 95–104.Google Scholar
  24. 24.
    Stetler-Stevenson, W. G., Bersch, N., & Golde, D. W. (1992). Tissue inhibitor of metalloproteinase-2 (TIMP-2) has erythroid-potentiating activity. FEBS Letters, 296, 231–234.PubMedCrossRefGoogle Scholar
  25. 25.
    Stricklin, G. P., & Welgus, H. G. (1986). Physiological relevance of erythroid-potentiating activity of TIMP. Nature, 321, 628.PubMedCrossRefGoogle Scholar
  26. 26.
    Hayakawa, T., Yamashita, K., Tanzawa, K., Uchijima, E., & Iwata, K. (1992). Growth-promoting activity of tissue inhibitor of metalloproteinases-1 (TIMP-1) for a wide range of cells. A possible new growth factor in serum. FEBS Letters, 298, 29–32.PubMedCrossRefGoogle Scholar
  27. 27.
    Guedez, L., Mansoor, A., Birkedal-Hansen, B., Lim, M. S., Fukushima, P., Venzon, D., et al. (2001). Tissue inhibitor of metalloproteinases 1 regulation of interleukin-10 in B-cell differentiation and lymphomagenesis. Blood, 97, 1796–1802.PubMedCrossRefGoogle Scholar
  28. 28.
    Guedez, L., Martinez, A., Zhao, S., Vivero, A., Pittaluga, S., Stetler-Stevenson, M., et al. (2005). Tissue inhibitor of metalloproteinase 1 (TIMP-1) promotes plasmablastic differentiation of a Burkitt lymphoma cell line: Implications in the pathogenesis of plasmacytic/plasmablastic tumors. Blood, 105, 1660–1668.PubMedCrossRefGoogle Scholar
  29. 29.
    Guedez, L., McMarlin, A. J., Kingma, D. W., Bennett, T. A., Stetler-Stevenson, M., & Stetler-Stevenson, W. G. (2001). Tissue inhibitor of metalloproteinase-1 alters the tumorigenicity of Burkitt’s lymphoma via divergent effects on tumor growth and angiogenesis. American Journal of Pathology, 158, 1207–1215.PubMedGoogle Scholar
  30. 30.
    Guedez, L., Stetler-Stevenson, W. G., Wolff, L., Wang, J., Fukushima, P., Mansoor, A., et al. (1998). In vitro suppression of programmed cell death of B cells by tissue inhibitor of metalloproteinases-1. Journal of Clinical Investigation, 102, 2002–2010.PubMedGoogle Scholar
  31. 31.
    Jung, K. K., Liu, X. W., Chirco, R., Fridman, R., & Kim, H. R. (2006). Identification of CD63 as a tissue inhibitor of metalloproteinase-1 interacting cell surface protein. EMBO Journal, 25, 3934–3942.PubMedCrossRefGoogle Scholar
  32. 32.
    Liu, X. W., Bernardo, M. M., Fridman, R., & Kim, H. R. (2003). Tissue inhibitor of metalloproteinase-1 protects human breast epithelial cells against intrinsic apoptotic cell death via the focal adhesion kinase/phosphatidylinositol 3-kinase and MAPK signaling pathway. Journal of Biological Chemistry, 278, 40364–40372.PubMedCrossRefGoogle Scholar
  33. 33.
    Liu, X. W., Taube, M. E., Jung, K. K., Dong, Z., Lee, Y. J., Roshy, S., et al. (2005). Tissue inhibitor of metalloproteinase-1 protects human breast epithelial cells from extrinsic cell death: A potential oncogenic activity of tissue inhibitor of metalloproteinase-1. Cancer Research, 65, 898–906.PubMedGoogle Scholar
  34. 34.
    Taube, M. E., Liu, X. W., Fridman, R., & Kim, H. R. (2006). TIMP-1 regulation of cell cycle in human breast epithelial cells via stabilization of p27(KIP1) protein. Oncogene, 25, 3041–3048.PubMedCrossRefGoogle Scholar
  35. 35.
    Mohammed, F. F., Smookler, D. S., Taylor, S. E. M., Fingleton, B., Kassiri, Z., Sanchez, O. H., et al. (2004). Abnormal TNF activity in Timp3(−/−) mice leads to chronic hepatic inflammation and failure of liver regeneration. Nature Genetics, 36, 969–977.PubMedCrossRefGoogle Scholar
  36. 36.
    Qi, J. H., Ebrahem, Q., Moore, N., Murphy, G., Claesson-Welsh, L., Bond, M., et al. (2003). A novel function for tissue inhibitor of metalloproteinases-3 (TIMP3): Inhibition of angiogenesis by blockage of VEGF binding to VEGF receptor-2. Nature Medicine, 9, 407–415.PubMedCrossRefGoogle Scholar
  37. 37.
    Jiang, Y., Wang, M., Celiker, M. Y., Liu, Y. E., Sang, Q. X., Goldberg, I. D., et al. (2001). Stimulation of mammary tumorigenesis by systemic tissue inhibitor of matrix metalloproteinase 4 gene delivery. Cancer Research, 61, 2365–2370.PubMedGoogle Scholar
  38. 38.
    Celiker, M. Y., Wang, M., Atsidaftos, E., Liu, X., Liu, Y. E., Jiang, Y., et al. (2001). Inhibition of Wilms’ tumor growth by intramuscular administration of tissue inhibitor of metalloproteinases-4 plasmid DNA. Oncogene, 20, 4337–4343.PubMedCrossRefGoogle Scholar
  39. 39.
    Fernandez, C. A., & Moses, M. A. (2006). Modulation of angiogenesis by tissue inhibitor of metalloproteinase-4. Biochemical and Biophysical Research Communications, 345, 523–529.PubMedCrossRefGoogle Scholar
  40. 40.
    Yu, W. H., Yu, S., Meng, Q., Brew, K., & Woessner Jr., J. F. (2000). TIMP-3 binds to sulfated glycosaminoglycans of the extracellular matrix. Journal of Biological Chemistry, 275, 31226–31232.PubMedCrossRefGoogle Scholar
  41. 41.
    Johnson, M. D., Kim, H. R., Chesler, L., Tsao-Wu, G., Bouck, N., & Polverini, P. J. (1994). Inhibition of angiogenesis by tissue inhibitor of metalloproteinase. Journal of Cellular Physiology, 160, 194–202.PubMedCrossRefGoogle Scholar
  42. 42.
    Anand-Apte, B., Pepper, M. S., Voest, E., Montesano, R., Olsen, B., Murphy, G., et al. (1997). Inhibition of angiogenesis by tissue inhibitor of metalloproteinase-3. Investigative Ophthalmology & Visual Science, 38, 817–823.Google Scholar
  43. 43.
    Baker, A. H., Zaltsman, A. B., George, S. J., & Newby, A. C. (1998). Divergent effects of tissue inhibitor of metalloproteinase-1, -2, or -3 overexpression on rat vascular smooth muscle cell invasion, proliferation, and death in vitro. TIMP-3 promotes apoptosis. Journal of Clinical Investigation, 101, 1478–1487.PubMedGoogle Scholar
  44. 44.
    Brown, P. D. (1998). Matrix metalloproteinase inhibitors. Angiogenesis, 1, 142–154.PubMedCrossRefGoogle Scholar
  45. 45.
    Moses, M. A., Sudhalter, J., & Langer, R. (1990). Identification of an inhibitor of neovascularization from cartilage. Science, 248, 1408–1410.PubMedCrossRefGoogle Scholar
  46. 46.
    Takigawa, M., Nishida, Y., Suzuki, F., Kishi, J., Yamashita, K., & Hayakawa, T. (1990). Induction of angiogenesis in chick yolk-sac membrane by polyamines and its inhibition by tissue inhibitors of metalloproteinases (TIMP and TIMP-2). Biochemical & Biophysical Research Communications, 171, 1264–1271.CrossRefGoogle Scholar
  47. 47.
    Murphy, A. N., Unsworth, E. J., & Stetler-Stevenson, W. G. (1993). Tissue inhibitor of metalloproteinases-2 inhibits bFGF-induced human microvascular endothelial cell proliferation. Journal of Cellular Physiology, 157, 351–358.PubMedCrossRefGoogle Scholar
  48. 48.
    Wingfield, P. T., Sax, J. K., Stahl, S. J., Kaufman, J., Palmer, I., Chung, V., et al. (1999). Biophysical and functional characterization of full-length, recombinant human tissue inhibitor of metalloproteinases-2 (TIMP-2) produced in Escherichia coli. Comparison of wild type and amino-terminal alanine appended variant with implications for the mechanism of TIMP functions. Journal of Biological Chemistry, 274, 21362–21368.PubMedCrossRefGoogle Scholar
  49. 49.
    Hoegy, S. E., Oh, H. R., Corcoran, M. L., & Stetler-Stevenson, W. G. (2001). Tissue inhibitor of metalloproteinases-2 (TIMP-2) suppresses TKR-growth factor signaling independent of metalloproteinase inhibition. Journal of Biological Chemistry, 276, 3203–3214.PubMedCrossRefGoogle Scholar
  50. 50.
    Itoh, Y., Ito, A., Iwata, K., Tanzawa, K., Mori, Y., & Nagase, H. (1998). Plasma membrane-bound tissue inhibitor of metalloproteinases (TIMP)-2 specifically inhibits matrix metalloproteinase 2 (gelatinase A) activated on the cell surface. Journal of Biological Chemistry, 273, 24360–24367.PubMedCrossRefGoogle Scholar
  51. 51.
    Bernardo, M. M., & Fridman, R. (2003). TIMP-2 (tissue inhibitor of metalloproteinase-2) regulates MMP-2 (matrix metalloproteinase-2) activity in the extracellular environment after pro-MMP-2 activation by MT1 (membrane type 1)-MMP. Biochemical Journal, 374, 739–745.PubMedCrossRefGoogle Scholar
  52. 52.
    Fernandez, C. A., Butterfield, C., Jackson, G., & Moses, M. A. (2003). Structural and functional uncoupling of the enzymatic and angiogenic inhibitory activities of tissue inhibitor of metalloproteinase-2 (TIMP-2): Loop 6 is a novel angiogenesis inhibitor. Journal of Biological Chemistry, 278, 40989–40995.PubMedCrossRefGoogle Scholar
  53. 53.
    Seo, D. W., Li, H., Guedez, L., Wingfield, P. T., Diaz, T., Salloum, R., et al. (2003). TIMP-2 mediated inhibition of angiogenesis: an MMP-independent mechanism. Cell, 114, 171–180.PubMedCrossRefGoogle Scholar
  54. 54.
    Seo, D. W., Li, H., Qu, C. K., Kim, Y. S., Diaz, T., Wei, B., et al. (2006). Shp-1 mediates the antiproliferative activity of tissue inhibitor of metalloproteinase-2 in human microvascular endothelial cells. Journal of Biological Chemistry, 281, 3711–3721.PubMedCrossRefGoogle Scholar
  55. 55.
    Oh, J., Seo, D. W., Diaz, T., Wei, B., Ward, Y., Ray, J. M., et al. (2004). Tissue inhibitors of metalloproteinase 2 inhibits endothelial cell migration through increased expression of RECK. Cancer Research, 64, 9062–9069.PubMedCrossRefGoogle Scholar
  56. 56.
    Oh, J., Diaz, T., Wei, B., Chang, H., Noda, M., & Stetler-Stevenson, W. G. (2006). TIMP-2 upregulates RECK expression via dephosphorylation of paxillin tyrosine residues 31 and 118. Oncogene, 25, 4230–4234.PubMedCrossRefGoogle Scholar
  57. 57.
    Nuttall, R. K., Sampieri, C. L., Pennington, C. J., Gill, S. E., Schultz, G. A., & Edwards, D. R. (2004). Expression analysis of the entire MMP and TIMP gene families during mouse tissue development. FEBS Letters, 563, 129–134.PubMedCrossRefGoogle Scholar
  58. 58.
    Blavier, L., & DeClerck, Y. A. (1997). Tissue inhibitor of metalloproteinases-2 is expressed in the interstitial matrix in adult mouse organs and during embryonic development. Molecular Biology of the Cell, 8, 1513–1527.PubMedGoogle Scholar
  59. 59.
    Perez-Martinez, L., & Jaworski, D. M. (2005). Tissue inhibitor of metalloproteinase-2 promotes neuronal differentiation by acting as an anti-mitogenic signal. Journal of Neuroscience, 25, 4917–4929.PubMedCrossRefGoogle Scholar
  60. 60.
    Jaworski, D. M., & Perez-Martinez, L. (2006). Tissue inhibitor of metalloproteinase-2 (TIMP-2) expression is regulated by multiple neural differentiation signals. Journal of Neurochemistry, 98, 234–247.PubMedCrossRefGoogle Scholar
  61. 61.
    Jaworski, D. M., Soloway, P., Caterina, J., & Falls, W. A. (2006). Tissue inhibitor of metalloproteinase-2(TIMP-2)-deficient mice display motor deficits. Journal of Neurobiology, 66, 82–94.PubMedCrossRefGoogle Scholar
  62. 62.
    Lamoreaux, W. J., Fitzgerald, M. E., Reiner, A., Hasty, K. A., & Charles, S. T. (1998). Vascular endothelial growth factor increases release of gelatinase A and decreases release of tissue inhibitor of metalloproteinases by microvascular endothelial cells in vitro. Microvascular Research, 55, 29–42.PubMedCrossRefGoogle Scholar
  63. 63.
    Carmeliet, P. (2000). Mechanisms of angiogenesis and arteriogenesis. Nature Medicine, 6, 389–395.PubMedCrossRefGoogle Scholar
  64. 64.
    Caterina, J. J., Yamada, S., Caterina, N. C., Longenecker, G., Holmback, K., Shi, J., et al. (2000). Inactivating mutation of the mouse tissue inhibitor of metalloproteinases-2(Timp-2) gene alters proMMP-2 activation. Journal of Biological Chemistry, 275, 26416–26422.PubMedCrossRefGoogle Scholar
  65. 65.
    Blavier, L., Lazaryev, A., Dorey, F., Shackleford, G. M., & DeClerck, Y. (2006). Matrix metalloproteinases play an active role in Wnt1-induced mammary tumorigenesis. Cancer Research, 66, 2691–2699.PubMedCrossRefGoogle Scholar
  66. 66.
    Rhee, J. S., Diaz, R., Korets, L., Hodgson, J. G., & Coussens, L. M. (2004). TIMP-1 alters susceptibility to carcinogenesis. Cancer Research, 64, 952–991.PubMedCrossRefGoogle Scholar
  67. 67.
    Akahane, T., Akahane, M., Shah, A., Connor, C. M., & Thorgeirsson, U. P. (2004). TIMP-1 inhibits microvascular endothelial cell migration by MMP-dependent and MMP-independent mechanisms. Experimental Cell Research, 301, 158–167.PubMedCrossRefGoogle Scholar
  68. 68.
    Akahane, T., Akahane, M., Shah, A., & Thorgeirsson, U. P. (2004). TIMP-1 stimulates proliferation of human aortic smooth muscle cells and Ras effector pathways. Biochemical & Biophysical Research Communications, 324, 440–445.CrossRefGoogle Scholar
  69. 69.
    Thorgeirsson, U. P., Yoshiji, H., Sinha, C. C., & 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.PubMedGoogle Scholar
  70. 70.
    Yamazaki, M., Akahane, T., Buck, T., Yoshiji, H., Gomez, D. E., Schoeffner, D. J., et al. (2004). Long-term exposure to elevated levels of circulating TIMP-1 but not mammary TIMP-1 suppresses growth of mammary carcinomas in transgenic mice. Carcinogenesis, 25, 1735–1746.PubMedCrossRefGoogle Scholar
  71. 71.
    Yoshiji, H., Kuriyama, S., Miyamoto, Y., Thorgeirsson, U. P., Gomez, D. E., Kawata, M., et al. (2000). Tissue inhibitor of metalloproteinases-1 promotes liver fibrosis development in a transgenic mouse model. Hepatology, 32, 1248–1254.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  1. 1.Cell & Cancer Biology BranchVascular Biology FacultyBethesdaUSA

Personalised recommendations