Skip to main content
SpringerLink
Log in

Role of the Extracellular Matrix: Enzyme Activities and Metastasis

  • Chapter
  • First Online:
Cancer Targeted Drug Delivery

  • 2874 Accesses

Abstract

The local milieu of malignant tumor cells has key roles in cancer progression. A major component of the niche is the extracellular matrix (ECM), a complex interdigitating meshwork of macromolecules with multiple biophysical and biochemical characteristics. Although tightly controlled during normal tissue development and homeostasis, the ECM is mostly deregulated and becomes disorganized in cancer. Abnormal ECM has an impact on cancer progression by promoting tumor malignancy and metastatic dissemination. Importantly, the altered ECM in tumor is associated with deregulated ECM-regulating enzymes (matrix metalloproteinases, lysyl oxidase, urokinase plasminogen activator, and cysteine cathepsin). Excess expression of ECM-regulating enzymes alters behavior of cancer cells in the tumor niche, and its sustained upregulation results in the progressive breakdown of normal ECM which is replaced by tumor-derived ECM, thereby allowing tumor malignancy and cancer cell dissemination. Thus, ECM-regulating enzymes act as essential mediators of deregulating and disorganizing ECM. In this chapter, we will review and discuss how ECM-regulating enzymes generate disruption of ECM homeostasis and contribute to cancer progression, especially cancer metastasis.

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

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 189.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 249.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 249.99
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

References

  1. Kim ES, Glisson BS (2003) Treatment of metastatic head and neck cancer: chemotherapy and novel agents. Cancer Treat Res 114:295–314

    PubMed  Google Scholar 

  2. Chang J, Clark GM, Allred DC, Mohsin S, Chamness G, Elledge RM (2003) Survival of patients with metastatic breast carcinoma: importance of prognostic markers of the primary tumor. Cancer 97(3):545–553

    PubMed  Google Scholar 

  3. Hanahan D, Weinberg RA (2000) The hallmarks of cancer. Cell 100(1):57–70

    CAS  PubMed  Google Scholar 

  4. Bhowmick NA, Neilson EG, Moses HL (2004) Stromal fibroblasts in cancer initiation and progression. Nature 432(7015):332–337

    CAS  PubMed Central  PubMed  Google Scholar 

  5. Sternlicht MD, Lochter A, Sympson CJ, Huey B, Rougier JP, Gray JW, Pinkel D, Bissell MJ, Werb Z (1999) The stromal proteinase mmp3/stromelysin-1 promotes mammary carcinogenesis. Cell 98(2):137–146

    CAS  PubMed Central  PubMed  Google Scholar 

  6. Paszek MJ, Zahir N, Johnson KR, Lakins JN, Rozenberg GI, Gefen A, Reinhart-King CA, Margulies SS, Dembo M, Boettiger D, Hammer DA, Weaver VM (2005) Tensional homeostasis and the malignant phenotype. Cancer Cell 8(3):241–254

    CAS  PubMed  Google Scholar 

  7. Erler JT, Bennewith KL, Nicolau M, Dornhofer N, Kong C, Le QT, Chi JT, Jeffrey SS, Giaccia AJ (2006) Lysyl oxidase is essential for hypoxia-induced metastasis. Nature 440(7088):1222–1226

    CAS  PubMed  Google Scholar 

  8. Levental KR, Yu H, Kass L, Lakins JN, Egeblad M, Erler JT, Fong SF, Csiszar K, Giaccia A, Weninger W, Yamauchi M, Gasser DL, Weaver VM (2009) Matrix crosslinking forces tumor progression by enhancing integrin signaling. Cell 139(5):891–906

    CAS  PubMed Central  PubMed  Google Scholar 

  9. Hynes RO (2009) The extracellular matrix: not just pretty fibrils. Science 326(5957):1216–1219

    CAS  PubMed Central  PubMed  Google Scholar 

  10. Page-McCaw A, Ewald AJ, Werb Z (2007) Matrix metalloproteinases and the regulation of tissue remodelling. Nat Rev Mol Cell Biol 8(3):221–233

    CAS  PubMed Central  PubMed  Google Scholar 

  11. Cox TR, Erler JT (2011) Remodeling and homeostasis of the extracellular matrix: implications for fibrotic diseases and cancer. Dis Model Mech 4(2):165–178

    CAS  PubMed Central  PubMed  Google Scholar 

  12. Lu P, Weaver VM, Werb Z (2012) The extracellular matrix: a dynamic niche in cancer progression. J Cell Biol 196(4):395–406

    CAS  PubMed  Google Scholar 

  13. Gjorevski N, Nelson CM (2009) Bidirectional extracellular matrix signaling during tissue morphogenesis. Cytokine Growth Factor Rev 20(5–6):459–465

    CAS  PubMed Central  PubMed  Google Scholar 

  14. Erler JT, Weaver VM (2009) Three-dimensional context regulation of metastasis. Clin Exp Metastasis 26(1):35–49

    PubMed Central  PubMed  Google Scholar 

  15. Frantz C, Stewart KM, Weaver VM (2010) The extracellular matrix at a glance. J Cell Sci 123(Pt 24):4195–4200

    CAS  PubMed  Google Scholar 

  16. Harburger DS, Calderwood DA (2009) Integrin signalling at a glance. J Cell Sci 122(Pt 2):159–163

    CAS  PubMed  Google Scholar 

  17. Humphries JD, Byron A, Humphries MJ (2006) Integrin ligands at a glance. J Cell Sci 119(Pt 19):3901–3903

    CAS  PubMed Central  PubMed  Google Scholar 

  18. Leitinger B, Hohenester E (2007) Mammalian collagen receptors. Matrix Biol 26(3):146–155

    CAS  PubMed  Google Scholar 

  19. Xian X, Gopal S, Couchman JR (2010) Syndecans as receptors and organizers of the extracellular matrix. Cell Tissue Res 339(1):31–46

    CAS  PubMed  Google Scholar 

  20. Schmidt S, Friedl P (2010) Interstitial cell migration: integrin-dependent and alternative adhesion mechanisms. Cell Tissue Res 339(1):83–92

    CAS  PubMed Central  PubMed  Google Scholar 

  21. Ozbek S, Balasubramanian PG, Chiquet-Ehrismann R, Tucker RP, Adams JC (2010) The evolution of extracellular matrix. Mol Biol Cell 21(24):4300–4305

    PubMed Central  PubMed  Google Scholar 

  22. Whittaker CA, Bergeron KF, Whittle J, Brandhorst BP, Burke RD, Hynes RO (2006) The echinoderm adhesome. Dev Biol 300(1):252–266

    CAS  PubMed Central  PubMed  Google Scholar 

  23. Rozario T, DeSimone DW (2010) The extracellular matrix in development and morphogenesis: a dynamic view. Dev Biol 341(1):126–140

    CAS  PubMed Central  PubMed  Google Scholar 

  24. Li DY, Brooke B, Davis EC, Mecham RP, Sorensen LK, Boak BB, Eichwald E, Keating MT (1998) Elastin is an essential determinant of arterial morphogenesis. Nature 393(6682):276–280

    CAS  PubMed  Google Scholar 

  25. Debelle L, Tamburro AM (1999) Elastin: molecular description and function. Int J Biochem Cell Biol 31(2):261–272

    CAS  PubMed  Google Scholar 

  26. Pankov R, Yamada KM (2002) Fibronectin at a glance. J Cell Sci 115(Pt 20):3861–3863

    CAS  PubMed  Google Scholar 

  27. Tsang KY, Cheung MC, Chan D, Cheah KS (2010) The developmental roles of the extracellular matrix: beyond structure to regulation. Cell Tissue Res 339(1):93–110

    CAS  PubMed  Google Scholar 

  28. Levick JR (1987) Flow through interstitium and other fibrous matrices. Q J Exp Physiol 72(4):409–437

    CAS  PubMed  Google Scholar 

  29. Iozzo RV, Murdoch AD (1996) Proteoglycans of the extracellular environment: clues from the gene and protein side offer novel perspectives in molecular diversity and function. FASEB J 10(5):598–614

    CAS  PubMed  Google Scholar 

  30. Hayen W, Goebeler M, Kumar S, Riessen R, Nehls V (1999) Hyaluronan stimulates tumor cell migration by modulating the fibrin fiber architecture. J Cell Sci 112(Pt 13):2241–2251

    CAS  PubMed  Google Scholar 

  31. Toole BP (2001) Hyaluronan in morphogenesis. Semin Cell Dev Biol 12(2):79–87

    CAS  PubMed  Google Scholar 

  32. Vuorio E, de Crombrugghe B (1990) The family of collagen genes. Annu Rev Biochem 59:837–872

    CAS  PubMed  Google Scholar 

  33. Barocas VH, Tranquillo RT (1997) An anisotropic biphasic theory of tissue-equivalent mechanics: the interplay among cell traction, fibrillar network deformation, fibril alignment, and cell contact guidance. J Biomech Eng 119(2):137–145

    CAS  PubMed  Google Scholar 

  34. Bosman FT, Stamenkovic I (2003) Functional structure and composition of the extracellular matrix. J Pathol 200(4):423–428

    CAS  PubMed  Google Scholar 

  35. Xu R, Boudreau A, Bissell MJ (2009) Tissue architecture and function: dynamic reciprocity via extra- and intra-cellular matrices. Cancer Metastasis Rev 28(1–2):167–176

    PubMed Central  PubMed  Google Scholar 

  36. Hagios C, Lochter A, Bissell MJ (1998) Tissue architecture: the ultimate regulator of epithelial function? Philos Trans R Soc Lond B Biol Sci 353(1370):857–870

    CAS  PubMed  Google Scholar 

  37. Bissell MJ, Kenny PA, Radisky DC (2005) Microenvironmental regulators of tissue structure and function also regulate tumor induction and progression: the role of extracellular matrix and its degrading enzymes. Cold Spring Harb Symp Quant Biol 70:343–356

    CAS  PubMed Central  PubMed  Google Scholar 

  38. Liotta LA, Tryggvason K, Garbisa S, Hart I, Foltz CM, Shafie S (1980) Metastatic potential correlates with enzymatic degradation of basement membrane collagen. Nature 284(5751):67–68

    CAS  PubMed  Google Scholar 

  39. Egeblad M, Nakasone ES, Werb Z (2010) Tumors as organs: complex tissues that interface with the entire organism. Dev Cell 18(6):884–901

    CAS  PubMed Central  PubMed  Google Scholar 

  40. Lopez JI, Kang I, You WK, McDonald DM, Weaver VM (2011) In situ force mapping of mammary gland transformation. Integr Biol (Camb) 3(9):910–921

    CAS  Google Scholar 

  41. Stetler-Stevenson WG, Aznavoorian S, Liotta LA (1993) Tumor cell interactions with the extracellular matrix during invasion and metastasis. Annu Rev Cell Biol 9:541–573

    CAS  PubMed  Google Scholar 

  42. Coussens LM, Werb Z (1996) Matrix metalloproteinases and the development of cancer. Chem Biol 3(11):895–904

    CAS  PubMed  Google Scholar 

  43. Roy R, Yang J, Moses MA (2009) Matrix metalloproteinases as novel biomarkers and potential therapeutic targets in human cancer. J Clin Oncol 27(31):5287–5297

    CAS  PubMed  Google Scholar 

  44. Castellano G, Malaponte G, Mazzarino MC, Figini M, Marchese F, Gangemi P, Travali S, Stivala F, Canevari S, Libra M (2008) Activation of the osteopontin/matrix metalloproteinase-9 pathway correlates with prostate cancer progression. Clin Cancer Res 14(22):7470–7480

    CAS  PubMed  Google Scholar 

  45. Kessenbrock K, Plaks V, Werb Z (2010) Matrix metalloproteinases: regulators of the tumor microenvironment. Cell 141(1):52–67

    CAS  PubMed Central  PubMed  Google Scholar 

  46. Minn AJ, Gupta GP, Siegel PM, Bos PD, Shu W, Giri DD, Viale A, Olshen AB, Gerald WL, Massague J (2005) Genes that mediate breast cancer metastasis to lung. Nature 436(7050):518–524

    CAS  PubMed Central  PubMed  Google Scholar 

  47. Minn AJ, Kang Y, Serganova I, Gupta GP, Giri DD, Doubrovin M, Ponomarev V, Gerald WL, Blasberg R, Massague J (2005) Distinct organ-specific metastatic potential of individual breast cancer cells and primary tumors. J Clin Invest 115(1):44–55

    CAS  PubMed Central  PubMed  Google Scholar 

  48. Radisky DC, Levy DD, Littlepage LE, Liu H, Nelson CM, Fata JE, Leake D, Godden EL, Albertson DG, Nieto MA, Werb Z, Bissell MJ (2005) Rac1b and reactive oxygen species mediate mmp-3-induced emt and genomic instability. Nature 436(7047):123–127

    CAS  PubMed Central  PubMed  Google Scholar 

  49. Weigelt B, Peterse JL, van’t Veer LJ (2005) Breast cancer metastasis: markers and models. Nat Rev Cancer 5(8):591–602

    CAS  PubMed  Google Scholar 

  50. Giannelli G, Falk-Marzillier J, Schiraldi O, Stetler-Stevenson WG, Quaranta V (1997) Induction of cell migration by matrix metalloprotease-2 cleavage of laminin-5. Science 277(5323):225–228

    CAS  PubMed  Google Scholar 

  51. Koshikawa N, Giannelli G, Cirulli V, Miyazaki K, Quaranta V (2000) Role of cell surface metalloprotease mt1-mmp in epithelial cell migration over laminin-5. J Cell Biol 148(3):615–624

    CAS  PubMed  Google Scholar 

  52. Kajita M, Itoh Y, Chiba T, Mori H, Okada A, Kinoh H, Seiki M (2001) Membrane-type 1 matrix metalloproteinase cleaves cd44 and promotes cell migration. J Cell Biol 153(5):893–904

    CAS  PubMed  Google Scholar 

  53. Nakahara H, Howard L, Thompson EW, Sato H, Seiki M, Yeh Y, Chen WT (1997) Transmembrane/cytoplasmic domain-mediated membrane type 1-matrix metalloprotease docking to invadopodia is required for cell invasion. Proc Natl Acad Sci USA 94(15):7959–7964

    CAS  PubMed  Google Scholar 

  54. Brooks PC, Stromblad S, Sanders LC, von Schalscha TL, Aimes RT, Stetler-Stevenson WG, Quigley JP, Cheresh DA (1996) Localization of matrix metalloproteinase mmp-2 to the surface of invasive cells by interaction with integrin alpha v beta 3. Cell 85(5):683–693

    CAS  PubMed  Google Scholar 

  55. Yu Q, Stamenkovic I (1999) Localization of matrix metalloproteinase 9 to the cell surface provides a mechanism for cd44-mediated tumor invasion. Genes Dev 13(1):35–48

    CAS  PubMed  Google Scholar 

  56. Boire A, Covic L, Agarwal A, Jacques S, Sherifi S, Kuliopulos A (2005) Par1 is a matrix metalloprotease-1 receptor that promotes invasion and tumorigenesis of breast cancer cells. Cell 120(3):303–313

    CAS  PubMed  Google Scholar 

  57. Dufour A, Sampson NS, Zucker S, Cao J (2008) Role of the hemopexin domain of matrix metalloproteinases in cell migration. J Cell Physiol 217(3):643–651

    CAS  PubMed Central  PubMed  Google Scholar 

  58. Polyak K, Weinberg RA (2009) Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits. Nat Rev Cancer 9(4):265–273

    CAS  PubMed  Google Scholar 

  59. Birchmeier C, Birchmeier W, Brand-Saberi B (1996) Epithelial-mesenchymal transitions in cancer progression. Acta Anat (Basel) 156(3):217–226

    CAS  Google Scholar 

  60. Lochter A, Galosy S, Muschler J, Freedman N, Werb Z, Bissell MJ (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(7):1861–1872

    CAS  PubMed  Google Scholar 

  61. Noe V, Fingleton B, Jacobs K, Crawford HC, Vermeulen S, Steelant W, Bruyneel E, Matrisian LM, Mareel M (2001) Release of an invasion promoter e-cadherin fragment by matrilysin and stromelysin-1. J Cell Sci 114(Pt 1):111–118

    CAS  PubMed  Google Scholar 

  62. Bergers G, Coussens LM (2000) Extrinsic regulators of epithelial tumor progression: metalloproteinases. Curr Opin Genet Dev 10(1):120–127

    CAS  PubMed  Google Scholar 

  63. Lee KH, Choi EY, Hyun MS, Jang BI, Kim TN, Kim SW, Song SK, Kim JH, Kim JR (2007) Association of extracellular cleavage of e-cadherin mediated by mmp-7 with hgf-induced in vitro invasion in human stomach cancer cells. Eur Surg Res 39(4):208–215

    CAS  PubMed  Google Scholar 

  64. Zavadil J, Bottinger EP (2005) Tgf-beta and epithelial-to-mesenchymal transitions. Oncogene 24(37):5764–5774

    CAS  PubMed  Google Scholar 

  65. Giannelli G, Bergamini C, Fransvea E, Sgarra C, Antonaci S (2005) Laminin-5 with transforming growth factor-beta1 induces epithelial to mesenchymal transition in hepatocellular carcinoma. Gastroenterology 129(5):1375–1383

    CAS  PubMed  Google Scholar 

  66. Peinado H, Quintanilla M, Cano A (2003) Transforming growth factor beta-1 induces snail transcription factor in epithelial cell lines: mechanisms for epithelial mesenchymal transitions. J Biol Chem 278(23):21113–21123

    CAS  PubMed  Google Scholar 

  67. van Zijl F, Mair M, Csiszar A, Schneller D, Zulehner G, Huber H, Eferl R, Beug H, Dolznig H, Mikulits W (2009) Hepatic tumor-stroma crosstalk guides epithelial to mesenchymal transition at the tumor edge. Oncogene 28(45):4022–4033

    PubMed Central  PubMed  Google Scholar 

  68. Illman SA, Lehti K, Keski-Oja J, Lohi J (2006) Epilysin (mmp-28) induces tgf-beta mediated epithelial to mesenchymal transition in lung carcinoma cells. J Cell Sci 119(Pt 18):3856–3865

    CAS  PubMed  Google Scholar 

  69. Kim J, Yu W, Kovalski K, Ossowski L (1998) Requirement for specific proteases in cancer cell intravasation as revealed by a novel semiquantitative pcr-based assay. Cell 94(3):353–362

    CAS  PubMed  Google Scholar 

  70. Tsunezuka Y, Kinoh H, Takino T, Watanabe Y, Okada Y, Shinagawa A, Sato H, Seiki M (1996) Expression of membrane-type matrix metalloproteinase 1 (mt1-mmp) in tumor cells enhances pulmonary metastasis in an experimental metastasis assay. Cancer Res 56(24):5678–5683

    CAS  PubMed  Google Scholar 

  71. Tien YW, Lee PH, Hu RH, Hsu SM, Chang KJ (2003) The role of gelatinase in hepatic metastasis of colorectal cancer. Clin Cancer Res 9(13):4891–4896

    CAS  PubMed  Google Scholar 

  72. Vande Broek I, Asosingh K, Allegaert V, Leleu X, Facon T, Vanderkerken K, Van Camp B, Van Riet I (2004) Bone marrow endothelial cells increase the invasiveness of human multiple myeloma cells through upregulation of mmp-9: evidence for a role of hepatocyte growth factor. Leukemia 18(5):976–982

    CAS  PubMed  Google Scholar 

  73. Sheu BC, Hsu SM, Ho HN, Lien HC, Huang SC, Lin RH (2001) A novel role of metalloproteinase in cancer-mediated immunosuppression. Cancer Res 61(1):237–242

    CAS  PubMed  Google Scholar 

  74. Yu Q, Stamenkovic I (2000) Cell surface-localized matrix metalloproteinase-9 proteolytically activates tgf-beta and promotes tumor invasion and angiogenesis. Genes Dev 14(2):163–176

    PubMed  Google Scholar 

  75. Gorelik L, Flavell RA (2001) Immune-mediated eradication of tumors through the blockade of transforming growth factor-beta signaling in t cells. Nat Med 7(10):1118–1122

    CAS  PubMed  Google Scholar 

  76. Kataoka H, Uchino H, Iwamura T, Seiki M, Nabeshima K, Koono M (1999) Enhanced tumor growth and invasiveness in vivo by a carboxyl-terminal fragment of alpha1-proteinase inhibitor generated by matrix metalloproteinases: a possible modulatory role in natural killer cytotoxicity. Am J Pathol 154(2):457–468

    CAS  PubMed  Google Scholar 

  77. Folgueras AR, Pendas AM, Sanchez LM, Lopez-Otin C (2004) Matrix metalloproteinases in cancer: from new functions to improved inhibition strategies. Int J Dev Biol 48(5–6):411–424

    CAS  PubMed  Google Scholar 

  78. Suzuki M, Raab G, Moses MA, Fernandez CA, 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(50):31730–31737

    CAS  PubMed  Google Scholar 

  79. Yu WH, Woessner JF Jr, McNeish JD, 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(3):307–323

    CAS  PubMed  Google Scholar 

  80. Thrailkill KM, Quarles LD, Nagase H, Suzuki K, Serra DM, Fowlkes JL (1995) Characterization of insulin-like growth factor-binding protein 5-degrading proteases produced throughout murine osteoblast differentiation. Endocrinology 136(8):3527–3533

    CAS  PubMed  Google Scholar 

  81. Fowlkes JL, Enghild JJ, Suzuki K, Nagase H (1994) Matrix metalloproteinases degrade insulin-like growth factor-binding protein-3 in dermal fibroblast cultures. J Biol Chem 269(41):25742–25746

    CAS  PubMed  Google Scholar 

  82. Manes S, Mira E, Barbacid MM, Cipres A, Fernandez-Resa P, Buesa JM, Merida I, Aracil M, Marquez G, Martinez AC (1997) Identification of insulin-like growth factor-binding protein-1 as a potential physiological substrate for human stromelysin-3. J Biol Chem 272(41):25706–25712

    CAS  PubMed  Google Scholar 

  83. Manes S, Llorente M, Lacalle RA, Gomez-Mouton C, Kremer L, Mira E, Martinez AC (1999) The matrix metalloproteinase-9 regulates the insulin-like growth factor-triggered autocrine response in du-145 carcinoma cells. J Biol Chem 274(11):6935–6945

    CAS  PubMed  Google Scholar 

  84. Egeblad M, Werb Z (2002) New functions for the matrix metalloproteinases in cancer progression. Nat Rev Cancer 2(3):161–174

    CAS  PubMed  Google Scholar 

  85. Hashizume H, Baluk P, Morikawa S, McLean JW, Thurston G, Roberge S, Jain RK, McDonald DM (2000) Openings between defective endothelial cells explain tumor vessel leakiness. Am J Pathol 156(4):1363–1380

    CAS  PubMed  Google Scholar 

  86. Bikfalvi A (2012) Angiogenesis and invasion in cancer. Handb Clin Neurol 104:35–43

    PubMed  Google Scholar 

  87. Genis L, Gonzalo P, Tutor AS, Galvez BG, Martinez-Ruiz A, Zaragoza C, Lamas S, Tryggvason K, Apte SS, Arroyo AG (2007) Functional interplay between endothelial nitric oxide synthase and membrane type 1 matrix metalloproteinase in migrating endothelial cells. Blood 110(8):2916–2923

    CAS  PubMed  Google Scholar 

  88. van Hinsbergh VW, Koolwijk P (2008) Endothelial sprouting and angiogenesis: matrix metalloproteinases in the lead. Cardiovasc Res 78(2):203–212

    PubMed  Google Scholar 

  89. Houck KA, Leung DW, Rowland AM, Winer J, Ferrara N (1992) Dual regulation of vascular endothelial growth factor bioavailability by genetic and proteolytic mechanisms. J Biol Chem 267(36):26031–26037

    CAS  PubMed  Google Scholar 

  90. Bergers G, Brekken R, McMahon G, Vu TH, Itoh T, Tamaki K, Tanzawa K, Thorpe P, Itohara S, Werb Z, Hanahan D (2000) Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis. Nat Cell Biol 2(10):737–744

    CAS  PubMed Central  PubMed  Google Scholar 

  91. Whitelock JM, Murdoch AD, Iozzo RV, Underwood PA (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(17):10079–10086

    CAS  PubMed  Google Scholar 

  92. Le QT, Kong C, Lavori PW, O'Byrne K, Erler JT, Huang X, Chen Y, Cao H, Tibshirani R, Denko N, Giaccia AJ, Koong AC (2007) Expression and prognostic significance of a panel of tissue hypoxia markers in head-and-neck squamous cell carcinomas. Int J Radiat Oncol Biol Phys 69(1):167–175

    CAS  PubMed  Google Scholar 

  93. Le QT, Harris J, Magliocco AM, Kong CS, Diaz R, Shin B, Cao H, Trotti A, Erler JT, Chung CH, Dicker A, Pajak TF, Giaccia AJ, Ang KK (2009) Validation of lysyl oxidase as a prognostic marker for metastasis and survival in head and neck squamous cell carcinoma: radiation therapy oncology group trial 90-03. J Clin Oncol 27(26):4281–4286

    CAS  PubMed  Google Scholar 

  94. Zhu GG, Risteli L, Makinen M, Risteli J, Kauppila A, Stenback F (1995) Immunohistochemical study of type i collagen and type i pn-collagen in benign and malignant ovarian neoplasms. Cancer 75(4):1010–1017

    CAS  PubMed  Google Scholar 

  95. Kauppila S, Stenback F, Risteli J, Jukkola A, Risteli L (1998) Aberrant type i and type iii collagen gene expression in human breast cancer in vivo. J Pathol 186(3):262–268

    CAS  PubMed  Google Scholar 

  96. Huijbers IJ, Iravani M, Popov S, Robertson D, Al-Sarraj S, Jones C, Isacke CM (2010) A role for fibrillar collagen deposition and the collagen internalization receptor endo180 in glioma invasion. PLoS One 5(3):e9808

    PubMed Central  PubMed  Google Scholar 

  97. Kirschmann DA, Seftor EA, Fong SF, Nieva DR, Sullivan CM, Edwards EM, Sommer P, Csiszar K, Hendrix MJ (2002) A molecular role for lysyl oxidase in breast cancer invasion. Cancer Res 62(15):4478–4483

    CAS  PubMed  Google Scholar 

  98. Payne SL, Fogelgren B, Hess AR, Seftor EA, Wiley EL, Fong SF, Csiszar K, Hendrix MJ, Kirschmann DA (2005) Lysyl oxidase regulates breast cancer cell migration and adhesion through a hydrogen peroxide-mediated mechanism. Cancer Res 65(24):11429–11436

    CAS  PubMed  Google Scholar 

  99. Desgrosellier JS, Cheresh DA (2010) Integrins in cancer: biological implications and therapeutic opportunities. Nat Rev Cancer 10(1):9–22

    CAS  PubMed  Google Scholar 

  100. Laufs S, Schumacher J, Allgayer H (2006) Urokinase-receptor (u-par): an essential player in multiple games of cancer: A review on its role in tumor progression, invasion, metastasis, proliferation/dormancy, clinical outcome and minimal residual disease. Cell Cycle 5(16):1760–1771

    CAS  PubMed  Google Scholar 

  101. Andreasen PA, Kjoller L, Christensen L, Duffy MJ (1997) The urokinase-type plasminogen activator system in cancer metastasis: a review. Int J Cancer 72(1):1–22

    CAS  PubMed  Google Scholar 

  102. Schmitt M, Janicke F, Graeff H (1990) Tumour-associated fibrinolysis: the prognostic relevance of plasminogen activators upa and tpa in human breast cancer. Blood Coagul Fibrinolysis 1(6):695–702

    CAS  PubMed  Google Scholar 

  103. Miyake H, Hara I, Yamanaka K, Arakawa S, Kamidono S (1999) Elevation of urokinase-type plasminogen activator and its receptor densities as new predictors of disease progression and prognosis in men with prostate cancer. Int J Oncol 14(3):535–541

    CAS  PubMed  Google Scholar 

  104. Morita S, Sato A, Hayakawa H, Ihara H, Urano T, Takada Y, Takada A (1998) Cancer cells overexpress mrna of urokinase-type plasminogen activator, its receptor and inhibitors in human non-small-cell lung cancer tissue: analysis by northern blotting and in situ hybridization. Int J Cancer 78(3):286–292

    CAS  PubMed  Google Scholar 

  105. Hudson MA, McReynolds LM (1997) Urokinase and the urokinase receptor: association with in vitro invasiveness of human bladder cancer cell lines. J Natl Cancer Inst 89(10):709–717

    CAS  PubMed  Google Scholar 

  106. Pyke C, Kristensen P, Ralfkiaer E, Grondahl-Hansen J, Eriksen J, Blasi F, Dano K (1991) Urokinase-type plasminogen activator is expressed in stromal cells and its receptor in cancer cells at invasive foci in human colon adenocarcinomas. Am J Pathol 138(5):1059–1067

    CAS  PubMed  Google Scholar 

  107. De Petro G, Tavian D, Copeta A, Portolani N, Giulini SM, Barlati S (1998) Expression of urokinase-type plasminogen activator (u-pa), u-pa receptor, and tissue-type pa messenger rnas in human hepatocellular carcinoma. Cancer Res 58(10):2234–2239

    PubMed  Google Scholar 

  108. Lakka SS, Bhattacharya A, Mohanam S, Boyd D, Rao JS (2001) Regulation of the upa gene in various grades of human glioma cells. Int J Oncol 18(1):71–79

    CAS  PubMed  Google Scholar 

  109. Zhang X, Bu XY, Zhen HN, Fei Z, Zhang JN, Fu LA (2000) Expression and localisation of urokinase-type plasminogen activator gene in gliomas. J Clin Neurosci 7(2):116–119

    CAS  PubMed  Google Scholar 

  110. Kirchheimer JC, Pfluger H, Ritschl P, Hienert G, Binder BR (1985) Plasminogen activator activity in bone metastases of prostatic carcinomas as compared to primary tumors. Invasion Metastasis 5(6):344–355

    CAS  PubMed  Google Scholar 

  111. Andreasen PA, Egelund R, Petersen HH (2000) The plasminogen activation system in tumor growth, invasion, and metastasis. Cell Mol Life Sci 57(1):25–40

    CAS  PubMed  Google Scholar 

  112. Naldini L, Tamagnone L, Vigna E, Sachs M, Hartmann G, Birchmeier W, Daikuhara Y, Tsubouchi H, Blasi F, Comoglio PM (1992) Extracellular proteolytic cleavage by urokinase is required for activation of hepatocyte growth factor/scatter factor. EMBO J 11(13):4825–4833

    CAS  PubMed  Google Scholar 

  113. Gold LI, Schwimmer R, Quigley JP (1989) Human plasma fibronectin as a substrate for human urokinase. Biochem J 262(2):529–534

    CAS  PubMed  Google Scholar 

  114. Duffy MJ (1992) The role of proteolytic enzymes in cancer invasion and metastasis. Clin Exp Metastasis 10(3):145–155

    CAS  PubMed  Google Scholar 

  115. Gunzler WA, Steffens GJ, Otting F, Kim SM, Frankus E, Flohe L (1982) The primary structure of high molecular mass urokinase from human urine. The complete amino acid sequence of the a chain. Hoppe Seylers Z Physiol Chem 363(10):1155–1165

    CAS  PubMed  Google Scholar 

  116. He CS, Wilhelm SM, Pentland AP, Marmer BL, Grant GA, Eisen AZ, Goldberg GI (1989) Tissue cooperation in a proteolytic cascade activating human interstitial collagenase. Proc Natl Acad Sci U S A 86(8):2632–2636

    CAS  PubMed Central  PubMed  Google Scholar 

  117. Matrisian LM, Bowden GT (1990) Stromelysin/transin and tumor progression. Semin Cancer Biol 1(2):107–115

    CAS  PubMed  Google Scholar 

  118. Baramova EN, Bajou K, Remacle A, L'Hoir C, Krell HW, Weidle UH, Noel A, Foidart JM (1997) Involvement of pa/plasmin system in the processing of pro-mmp-9 and in the second step of pro-mmp-2 activation. FEBS Lett 405(2):157–162

    CAS  PubMed  Google Scholar 

  119. Festuccia C, Guerra F, D'Ascenzo S, Giunciuglio D, Albini A, Bologna M (1998) In vitro regulation of pericellular proteolysis in prostatic tumor cells treated with bombesin. Int J Cancer 75(3):418–431

    CAS  PubMed  Google Scholar 

  120. Carmeliet P, Moons L, Lijnen R, Baes M, Lemaitre V, Tipping P, Drew A, Eeckhout Y, Shapiro S, Lupu F, Collen D (1997) Urokinase-generated plasmin activates matrix metalloproteinases during aneurysm formation. Nat Genet 17(4):439–444

    CAS  PubMed  Google Scholar 

  121. Turk V, Turk B, Turk D (2001) Lysosomal cysteine proteases: facts and opportunities. EMBO J 20(17):4629–4633

    CAS  PubMed  Google Scholar 

  122. Turk D, Guncar G (2003) Lysosomal cysteine proteases (cathepsins): promising drug targets. Acta Crystallogr D Biol Crystallogr 59(Pt 2):203–213

    PubMed  Google Scholar 

  123. Turk V, Turk B, Guncar G, Turk D, Kos J (2002) Lysosomal cathepsins: structure, role in antigen processing and presentation, and cancer. Adv Enzyme Regul 42:285–303

    CAS  PubMed  Google Scholar 

  124. Honey K, Rudensky AY (2003) Lysosomal cysteine proteases regulate antigen presentation. Nat Rev Immunol 3(6):472–482

    CAS  PubMed  Google Scholar 

  125. Stoch SA, Wagner JA (2008) Cathepsin k inhibitors: a novel target for osteoporosis therapy. Clin Pharmacol Ther 83(1):172–176

    CAS  PubMed  Google Scholar 

  126. Deal C (2009) Potential new drug targets for osteoporosis. Nat Clin Pract Rheumatol 5(1):20–27

    CAS  PubMed  Google Scholar 

  127. Friedrichs B, Tepel C, Reinheckel T, Deussing J, von Figura K, Herzog V, Peters C, Saftig P, Brix K (2003) Thyroid functions of mouse cathepsins b, k, and l. J Clin Invest 111(11):1733–1745

    CAS  PubMed Central  PubMed  Google Scholar 

  128. Funkelstein L, Toneff T, Mosier C, Hwang SR, Beuschlein F, Lichtenauer UD, Reinheckel T, Peters C, Hook V (2008) Major role of cathepsin l for producing the peptide hormones acth, beta-endorphin, and alpha-msh, illustrated by protease gene knockout and expression. J Biol Chem 283(51):35652–35659

    CAS  PubMed  Google Scholar 

  129. Mohamed MM, Sloane BF (2006) Cysteine cathepsins: multifunctional enzymes in cancer. Nat Rev Cancer 6(10):764–775

    CAS  PubMed  Google Scholar 

  130. Gocheva V, Joyce JA (2007) Cysteine cathepsins and the cutting edge of cancer invasion. Cell Cycle 6(1):60–64

    CAS  PubMed  Google Scholar 

  131. Jedeszko C, Sloane BF (2004) Cysteine cathepsins in human cancer. Biol Chem 385(11):1017–1027

    CAS  PubMed  Google Scholar 

  132. Mort JS, Recklies AD, Poole AR (1985) Release of cathepsin b precursors from human and murine tumours. Prog Clin Biol Res 180:243–245

    CAS  PubMed  Google Scholar 

  133. Mai J, Finley RL Jr, Waisman DM, Sloane BF (2000) Human procathepsin b interacts with the annexin ii tetramer on the surface of tumor cells. J Biol Chem 275(17):12806–12812

    CAS  PubMed  Google Scholar 

  134. Lah TT, Buck MR, Honn KV, Crissman JD, Rao NC, Liotta LA, Sloane BF (1989) Degradation of laminin by human tumor cathepsin b. Clin Exp Metastasis 7(4):461–468

    CAS  PubMed  Google Scholar 

  135. Buck MR, Karustis DG, Day NA, Honn KV, Sloane BF (1992) Degradation of extracellular-matrix proteins by human cathepsin b from normal and tumour tissues. Biochem J 282(Pt 1):273–278

    CAS  PubMed  Google Scholar 

  136. Ishidoh K, Kominami E (1995) Procathepsin l degrades extracellular matrix proteins in the presence of glycosaminoglycans in vitro. Biochem Biophys Res Commun 217(2):624–631

    CAS  PubMed  Google Scholar 

  137. Mai J, Sameni M, Mikkelsen T, Sloane BF (2002) Degradation of extracellular matrix protein tenascin-c by cathepsin b: an interaction involved in the progression of gliomas. Biol Chem 383(9):1407–1413

    CAS  PubMed  Google Scholar 

  138. Guinec N, Dalet-Fumeron V, Pagano M (1993) “In vitro” study of basement membrane degradation by the cysteine proteinases, cathepsins b, b-like and l. Digestion of collagen iv, laminin, fibronectin, and release of gelatinase activities from basement membrane fibronectin. Biol Chem Hoppe Seyler 374(12):1135–1146

    CAS  PubMed  Google Scholar 

  139. Gocheva V, Zeng W, Ke D, Klimstra D, Reinheckel T, Peters C, Hanahan D, Joyce JA (2006) Distinct roles for cysteine cathepsin genes in multistage tumorigenesis. Genes Dev 20(5):543–556

    CAS  PubMed  Google Scholar 

  140. Eeckhout Y, Vaes G (1977) Further studies on the activation of procollagenase, the latent precursor of bone collagenase. Effects of lysosomal cathepsin b, plasmin and kallikrein, and spontaneous activation. Biochem J 166(1):21–31

    CAS  PubMed  Google Scholar 

  141. Kobayashi H, Moniwa N, Sugimura M, Shinohara H, Ohi H, Terao T (1993) Effects of membrane-associated cathepsin b on the activation of receptor-bound prourokinase and subsequent invasion of reconstituted basement membranes. Biochim Biophys Acta 1178(1):55–62

    CAS  PubMed  Google Scholar 

  142. Guo M, Mathieu PA, Linebaugh B, Sloane BF, Reiners JJ Jr (2002) Phorbol ester activation of a proteolytic cascade capable of activating latent transforming growth factor-betal a process initiated by the exocytosis of cathepsin b. J Biol Chem 277(17):14829–14837

    CAS  PubMed  Google Scholar 

  143. Rao JS (2003) Molecular mechanisms of glioma invasiveness: the role of proteases. Nat Rev Cancer 3(7):489–501

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Bioengineering, College of Engineering, Hanyang University, Seoul, South Korea

    Il-Kyu Choi & Chae-Ok Yun Ph.D

Authors
  1. Il-Kyu Choi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Chae-Ok Yun Ph.D
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Chae-Ok Yun Ph.D .

Editor information

Editors and Affiliations

  1. Pharmacutics & Pharmacutical Chemistry, University of Utah, Salt Lake City, Utah, USA

    You Han Bae

  2. Department of Pharmacy & Pharmacology, University of Bath, Claverton Down, Bath, United Kingdom

    Randall J. Mrsny

  3. Department of Biomedical Engineering, Purdue University, West Lafayette, Indiana, USA

    Kinam Park

Rights and permissions

Reprints and permissions

Copyright information

© 2013 Springer Science+Business Media New York

About this chapter

Cite this chapter

Choi, IK., Yun, CO. (2013). Role of the Extracellular Matrix: Enzyme Activities and Metastasis. In: Bae, Y., Mrsny, R., Park, K. (eds) Cancer Targeted Drug Delivery. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-7876-8_11

Download citation

Publish with us

Policies and ethics

Search

Navigation