Advertisement

Effect of Antisense Inhibition of Urokinase Receptor on Malignancy

  • L. Ossowski
Part of the Current Topics in Microbiology and Immunology book series (CT MICROBIOLOGY, volume 213/3)

Abstract

Plasminogen activator of the urokinase type (uPA) has been shown to be overexpressed in most experimental malignant tumors and human cancers (Dano et al. 1985; DeBruin et al. 1987; Sappino et al. 1987; Markus 1988; Sim et al. 1988; Duffy et al. 1990; Janicke et al. 1990; Testa and Quigley 1990; Sappino et al. 1991; Mignatti and Rifkin 1993). The overproduction of uPA by tumor cells was detected in primary cultures, organ cultures, and cancer cell lines. However, examination by in situ analyses (both immunocytochemistry and in situ hybridization) of sections of human tumors consisting of multiple cell types identified in some instances cells other than cancer cells as the uPA producers. Depending on the type of cancer, and in some instances the laboratory and the reagents used to perform the analysis, tumor, stromal, and sometimes infiltrating macrophages were found to be the main source of uPA and/or its receptor (Grondahl-Hansen et al. 1991; Pyke et al. 1991, 1993; Bianchi et al. 1994; Carriero et al. 1994). Regardless of its source, however, it has been firmly established in several human cancers that high levels of uPA are predictive of more aggressive disease with shorter relapse-free survival (Duffy et al. 1990; Janicke et al. 1990, 1991; Grondahl-Hansen et al. 1993; Kobayashi et al. 1994).

Keywords

Chick Embryo Urokinase Receptor Antisense Inhibition uPAR Expression uPAR mRNA 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Anchini E, Fibbi G, Pucci M, Caldini R, Chevanne M, Del Rosso M (1994) Production of second messengers following chemotactic and mitogenic urokinase-receptor interaction in human fibroblasts transfected with human urokinase receptor. Exp Cell Res 213: 438–448CrossRefGoogle Scholar
  2. Axelrod JH, Reich R, Miskin R (1989) Expression of human recombinant plasminogen activators enhances invasion and experimental metastasis of H-ras-transformed NIH 3T3 cells. Mol Cell Biol 9: 2133–2141PubMedGoogle Scholar
  3. Behrfendt N, Ploug M, Patthy L, Houen G, Blasi F, Dano K (1991) The ligand binding domain of the cell surface receptor for urokinase-type plasminogen activator. J Biol Chem 266: 7842–7847Google Scholar
  4. Bianchi E, Cohn RL, Thor AT, Todd RF 3rd, Mizukami IF, Lawrence DA, Ljung BM, Shuman MA, Smith HS (1994) The urokinase receptor is expressed in invasive breast cancer but not in normal breast tissue. Cancer Res 54: 861–866PubMedGoogle Scholar
  5. Busso N, Masur SK, Lazega D, Waxman S, Ossowski L (1994) Induction of cell migration by pro-urokinase binding to its receptor: possible mechanism for signal transduction. J Cell Biol 126: 259–270PubMedCrossRefGoogle Scholar
  6. Carmeliet P, Schoonjans L, Kieckens L, Ream B, Degen J, Bronson R, Devos R, van den Ord J, Collen D, Mulligan R (1994) Physiological consequences of the loss of plasminogen activator gene formation in mice. Nature 368: 419–424PubMedCrossRefGoogle Scholar
  7. Carriero MV, Franco P, Del-Vecchio S, Massa O, Botti G, D’Aiuto G, Stoppelli MP, Salvatore M (1994) Tissue distribution of soluble and receptor bound urokinase in human breast cancer using a panel of monoclonal antibodies. Cancer Res 54: 5445–5454PubMedGoogle Scholar
  8. Crowley CW, Cohen R, Lucas BK, Liu G, Shuman MA, Levinson AD (1993) Prevention of metastasis by inhibition of the urokinase receptor. Proc Natl Acad Sci USA 90: 5021–5025PubMedCrossRefGoogle Scholar
  9. Cubellis MV, Andreasen P, Ragno P, Mayer M, Dano K, Blasi F (1989) Accessibility of receptor-bound urokinase to type-1 palsminogen activator inhibitor. Proc Natl Acad Sci USA 86: 4828–4834PubMedCrossRefGoogle Scholar
  10. Dano K, Andreasen PA, Grondahl-Hansen J, Kristensen P, Nielsen L, Skriver L (1985) Plasminogen activators, tissue degradation and cancer. Adv Cancer Res 44: 139–266PubMedCrossRefGoogle Scholar
  11. DeBruin PA, Griffioen G, Verspaget HV, Verheijen JH (1987) Plasminogen activators and tumor development in the human colon. Activity levels in normal mucosa, adenomateous tissue, polyps and adenocarcinomas. Cancer Res 47: 4654–4657Google Scholar
  12. Del Rosso M, Anichini E, Pedersen N, Blasi F, Fibbi G, Pucci M, Ruggiero M (1993) Urokinase-urokinase receptor interaction: non-mitogenic signal transduction in human epidermal cells. Biochem Biophys Res Commun 190: 347–352PubMedCrossRefGoogle Scholar
  13. Duffy MJ, Reilly D, O’Sullivan C, O’Higgins N, Fennely JJ (1990) Urokinase plasminogen activator and prognosis in breast cancer. Lancet 13: 108–111CrossRefGoogle Scholar
  14. Dumler I, Petri T, Schleuning W-D (1993) Interaction of urokinase-type plasminogen activator (uPA) with its cellular receptor (uPAR) induces phosphorylation on tyrosine of a 38 kDa protein. FEBS Lett 322:37–40PubMedCrossRefGoogle Scholar
  15. Dumler I, Petri T, Schleuning W-D (1994) Induction of c-fos gene expression by urokinase-type plasminogen activator in human ovarian cancer cells. FEBS Lett 343: 103–106PubMedCrossRefGoogle Scholar
  16. Fibbi G, Ziche M, Morbidelli L, Magnelli L, Del Rosso M (1988) Interaction of Urokinase with specific receptors stimulates mobilization of bovine adrenal capillary endothelial cells. Exp Cell Res 179: 385–395PubMedCrossRefGoogle Scholar
  17. Goodson RJ, Doyle MV, Kaufman SE, Rosenberg S (1994) High affinity urokinase receptor antagonists identified with bacteriophage peptide display. Proc Natl Acad Sci USA 91: 7129–7133PubMedCrossRefGoogle Scholar
  18. Grondahl-Hansen J, Ralfkiaer E, Kirkeby L, Kristensen P, Lund LR, Dano K (1991) Localization of urokinase-type plasminogen activator in stromal cells in adenocarcinomas of the colon in humans. Am J Pathol 138: 111–117PubMedGoogle Scholar
  19. Grondahl-Hansen J, Christensen IJ, Rosenquist C, Brunner N, Mouridsen HT, Dano K, Blichert-Toft M (1993) High levels of urokinase-type palsminogen activator and its inhibitor PAI-1 in cytosolic extracts of breast carcinomas are associated with poor prognosis. Cancer Res 53: 2513–2521PubMedGoogle Scholar
  20. Gudewicz PW, Gilboa N (1987) Human urokinase-type plasminogen activator stimulates chemotaxis of human neutrophils. Biochem Biophys Res Commun 147: 1176–1181PubMedCrossRefGoogle Scholar
  21. Hearing VJ, Law LW, Corti A, Appella E, Blasi F (1988) Modulation of metastatic potential by cell surface urokinase of murine melanoma cells. Cancer Res 48: 1270–1278PubMedGoogle Scholar
  22. Hollas W, Blasi F, Boyd D (1991) Role of urokinase receptor in facilitating extracellular matrix invasion by cultured colon cancer. Cancer Res 51: 3690–3695PubMedGoogle Scholar
  23. Janicke F, Schmidt M, Hollrieder A, Babic R, Ulm K, Gossner W, Graeff H (1990) Urokinase-type plasminogen activator (uPA) is a predictor of early relapse in breast cancer. Fibrinolysis 4: 69–78CrossRefGoogle Scholar
  24. Janicke F, Graeff H, Schmitt M (1991) Clinical relevance of urokinase-type and tissue-type plasminogen activators and their type I inhibitor in breast cancer. Semin Thromb Hemost 17: 303–312PubMedCrossRefGoogle Scholar
  25. Kariko K, Megyeri K, Xiao Q, Barrnathan ES (1994) Lipofectin aided cell delivery of ribozyme targeted to human urokinase receptor mRNA. FEBS Lett 352: 41–44PubMedCrossRefGoogle Scholar
  26. Kirchheimer JC, Remold HG (1989) Functional characteristic of receptor-bound urokinase on human monocytes: catalytic efficiency and susceptibility to inactivation by plasminogen activator inhibitors. Blood 74: 1396–1402PubMedGoogle Scholar
  27. Kobayashi H, Fujishiro S, Terao T (1994) Impact of urokinase-type plasminogen activator and its inhibitor type I on prognosis in cervical cancer. Cancer Res 54: 6539–6548PubMedGoogle Scholar
  28. Kobayashi H, Gotoh J, Fujie M, Shinohara H, Moniwa N, Terao T (1994) Inhibition of metastasis of Lewis lung carcinoma by a synthetic peptide within growth factor domain of urokinase in the experimental and spontaneous metastasis model. Int J Cancer 57: 727–733PubMedCrossRefGoogle Scholar
  29. Kook Y-H, Adamsk J, Zelent A, Ossowski L (1994) The effect of antisense inhibition of urokinase receptor in human squamous cell carcinoma on malignancy. EMBO J 13: 3983–3991PubMedGoogle Scholar
  30. Liu G, Shuman MA, Cohen RL (1995) Co-expression of urokinase, urokinase receptor and PAI-1 is necessary for optimum invasiveness of cultured lung cells. Int J Cancer 60: 501–506PubMedCrossRefGoogle Scholar
  31. Lu H, Yeh P, Guitton JD, Mabilat C, Desanlis F, Maury I, Legrand Y, Soria J, Soria C (1994) Blockage of the urokinase receptor on the cell surface: construction and characterization of hybrid protein consisting of the N-terminal fragment of human urokinase and human albumin. FEBS Lett 356: 56–59PubMedCrossRefGoogle Scholar
  32. Markus G (1988) The relevance of plasminogen activators to neopalstic growth. Enzyme 40: 158–172PubMedGoogle Scholar
  33. Mignatti P, Rifkin DB (1993) Biology and biochemistry of proteinases in tumor invasion. Physiol Rev 73: 161–195PubMedGoogle Scholar
  34. Mignatti P, Robbins E, Rifkin DB (1986) Tumor invasion through the human amniotic membrane: requirement of proteinase cascade. Cell 47: 487–498PubMedCrossRefGoogle Scholar
  35. Moroni MC, Willingham MC, Beguinot L (1992) EGF-R antisense blocks expression of the epidermal growth factor receptor and suppresses the transformed phenotype of a human carcinoma cell line. J Biol Chem 267: 2714–2722PubMedGoogle Scholar
  36. Odekon LE, Sato Y, Rifkin DB (1992) Urokinase-type palsminogen activator mediates basic fibroblast growth factor-induced bovine endothelial cell migration independent of its proteolytic activity. J Cell Physiol 150: 258–263PubMedCrossRefGoogle Scholar
  37. Ossowski L (1988a) Plasminogen activator dependent pathways in the dissemination of human tumor cells in the chick embryo. Cell 52: 321–328PubMedCrossRefGoogle Scholar
  38. Ossowski L (1988b) In vivo invasion of modified membrane by tumor cells: the role of cell surface-bound urokinase. J Cell Biol 107: 2437–2445PubMedCrossRefGoogle Scholar
  39. Ossowski L (1992) Invasion of connective tissue by human carcinoma cell lines: requirement for urokinase, urokinase receptor, and interstitial collagenase. Cancer Res 52: 6754–6760PubMedGoogle Scholar
  40. Ossowski L, Reich E (1980) Experimental model for quantitative study of metastasis. Cancer Res 40: 2300–2309PubMedGoogle Scholar
  41. Ossowski L, Reich E (1983) Antibodies to plasminogen activator inhibit human tumor metastasis. Cell 35: 611–619PubMedCrossRefGoogle Scholar
  42. Ossowski L, Russo-Payne H, Gartner M, Wilson EL (1987) Inhibition of urokinase-type plasminogen activator by antibodies: the effect of dissemination of human tumor in the nude mouse. Cancer Res 51: 274–281Google Scholar
  43. Osswski L, Clunie G, Masucci T, Blasi F (1991) In vivo paracrine interaction between urokinase and its receptor: effect on tumor cell invasion. J Cell Biol 115: 1107–1112CrossRefGoogle Scholar
  44. Pyke C, Graem N, Ralfkiaer E, Hoyer-Hansen G, Brunner N, Dano K (1993) Receptor for urokinase is present in tumor-associated macrophages in ductal breast carcinoma. Cancer Res 53: 1911–1915PubMedGoogle Scholar
  45. Pyke C, Kristensen P, Ralkfiaer E, Ronne 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 in invasive foci in human colon adenocarcinomas. Am J Pathol 138: 1059–1067PubMedGoogle Scholar
  46. Quattrone A, Fibbi G, Anichini E, Pucci M, Zamperini A, Capaccioli S, Del Rosso M (1995) Reversion of the invasive phenotype of transformed human fibroblasts by anti-messenger oligonucleotide inhibition of urokinase receptor gene expression. Cancer Res 55: 90–95PubMedGoogle Scholar
  47. Quax PHA, Padersen N, Masucci MT, Weeningverhoeff EJD, Dano K, Verheijnen JH, Blasi F (1991) Complementation between urokinase-producing and receptor-producing cells in extracellular matrix degradation. Cell Regul 2: 793–803PubMedGoogle Scholar
  48. Raschella G, Negroni A, Skorski T, Pucci S, Nieborowska-Skorska M, Romeo A, Calabretta B (1992) Inhibition of proliferation by c-myb antisense RNA and Oligonucleotides in transformed neuroectodermal cell lines. Cancer Res 52: 4221–4226PubMedGoogle Scholar
  49. Reich R, Thompson EW, Iwamoto Y, Martin GR, Deason JR, Fuller GC, Miskin R (1988) Effect of inhibitors of plasminogen activator, serine proteinases and collagenase IV on the invasion of basement membranes by metastatic cells. Cancer Res 48: 3307–3312PubMedGoogle Scholar
  50. Roldan AL, Cubellis MV, Masucci MT, Behrendt N, Lund LR, Dano K, Appela E, Blasi F (1990) Cloning and expression of the receptor for human urokinase plasminogen activator, a central molecule in cell surface plasmin-dependent proteolysis. EMBO J 9: 467–474PubMedGoogle Scholar
  51. Ronne E, Behrendt N, Ellis V, Ploug M, Dano K, Hoyer-Hansen G (1991) Cell-induce potentiation of the plasminogen activation system is abolished by a monoclonal antibody that recognizes the NH2 amino terminal domain of urokinase receptor. FEBS Lett 288: 233–236PubMedCrossRefGoogle Scholar
  52. Sappino AP, Busso N, Belin D, Vassalli J-D (1987) Increase of urokinase-type plasminogen activator gene expression in human lung and breast carcinomas. Cancer Res 47: 4043–4046.PubMedGoogle Scholar
  53. Sappino A-P, Belin D, Huarte J, Hirschel-Scholtz S, Saurat J-H, Vassalli J-D (1991) Differential protease expression by cutaneous squamous and basal cell carcinomas. J Clin Invest 88: 1073–1079PubMedCrossRefGoogle Scholar
  54. Schlechte W, Murano G, Boyd D (1989) Examination of the role of urokinase receptors in human colon cancer mediated laminin degradation. Cancer Res 49: 6064–6069PubMedGoogle Scholar
  55. Sim P-S, Stephens RW, Fayle DRH, Doe WF (1988) Urokinase-type plasminogen activator in colorectal carcinomas and adenomatous polyps: quantitative expression of active and proenzyme. Int J Cancer 42: 483–488PubMedCrossRefGoogle Scholar
  56. Solberg H, Romer J, Brunner N, Sidenius N, Dano K, Hoyer-Hansen G (1994) A cleaved form of the receptor for urokinase-type plasminogen activator in invasive translated human and murine tumors. Int J Cancer 58: 877–881PubMedCrossRefGoogle Scholar
  57. Stahl A, Mueller BM (1994) Binding of urokinase to its receptor promotes migration and invasion of human melanoma cells in vitro. Cancer Res 54: 3066–3071PubMedGoogle Scholar
  58. Stoppelli MP, Corti A, Sofientini A, Cassani G, Blasi F, Assoian RK (1985) Differentiation-enhanced binding of the amino terminal fragment of human urokinase plasminogen activator to a specific receptor on U937 monocytes. Proc Natl Acad Sci USA 82: 4939–4943PubMedCrossRefGoogle Scholar
  59. Testa JE, Quigley JP (1990) The role of plasminogen activator in aggressive tumor behavior. Cancer Metastasis Rev 9: 353–367PubMedCrossRefGoogle Scholar
  60. Toolan HW (1954) Transplantable human neoplasms maintained in cortisone-treated laboratory animals: HS#1, H.E.p#1, H.Ep.#2, H.Ep.#3 and H.Emb.#1. Cancer Res 14: 660–666PubMedGoogle Scholar
  61. Vassalli J-D, Baccino D, Belin (1985) A cellular binding site for the Mr 55,000 form of the human plasminogen activator, urokinase. J Cell Biol 100: 86–92PubMedCrossRefGoogle Scholar
  62. Wei Y, Waltz DA, Drummond RJ, Rosenberg S, Chapman HA (1994) Identification of the urokinase receptor as an adhesion receptor for vitronectin. J Biol Chem 269: 32380–32388PubMedGoogle Scholar
  63. Wilhelm O, Weidle U, Hohl S, Rottenberger P, Schmitt M, Graeff H (1994) Recombinant soluble urokinase receptor as a scavenger for urokinase-type plasminogen activator. Inhibition of proliferation and invasion of human ovarian cancer cells. FEBS Lett 337: 131–134PubMedCrossRefGoogle Scholar
  64. Wolf BB, Gibson CA, Kapur V, Hussaini IM, Musser JM, Gonias SL (1994) Proteolytically active streptococcal pyrogenic exotoxin B cleaves monocytic cell urokinase receptor and releases an active fragment of the receptor from the cell surface. J Biol Chem 269: 30682–30687PubMedGoogle Scholar
  65. Yu H, Schultz RM (1990) Relationship between secreted urokinase plasminogen activator activity and metastatic potential in murine B 16 cells transfected with human urokinase sense and antisense genes. Cancer Res 50: 7623–7633PubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1996

Authors and Affiliations

  • L. Ossowski
    • 1
  1. 1.Department of Medicine, Division of Neoplastic DiseasesMount Sinai School of MedicineNew YorkUSA

Personalised recommendations