Conclusions and Perspectives

uPAR is a multifunctional molecule, present in intact and cleaved forms and involved in extracellular proteolysis, cell adhesion, mobility, and cell signaling events [5-8, 155-157]. It is located mainly on stromal cells at the invasive front in breast and colorectal cancer and present in elevated levels in tumor tissue and blood from cancer patients as well as patients with infectious diseases. High levels of uPAR correlate with short survival in breast, colorectal, and lung cancer as well as in patients with HIV. Cleavage of uPAR could be an indication of an active plasminogen activation system. With the design of immunoassays that can quantify the individual uPAR variants, domain I was found to be a stronger prognostic marker than the total uPAR amount in tumor extracts of NSCLC patients [35]. It is possible that domain I or one of the other uPAR forms would have a stronger prognostic potential than the combined uPAR forms both in tumor tissue and blood from cancer patients. The use of either the total amount or the individual forms of uPAR for monitoring therapy response should be investigated. In AML, it has already been shown that the levels of suPAR(II-III) in plasma decrease following chemotherapy and this correlates with a decrease in the number of circulating tumor cells [18].

In a mouse cancer model for breast cancer, the volume of the lung metastases was demonstrated to be significantly reduced in mice deficient in uPA [158]. The therapeutic potential of blocking the interaction between uPAR (I-III) and uPA has been proven in several model systems and reviewed [157]. In vivo studies in mice using xenotransplanted human tumors and syngeneic tumors have demonstrated reduction of primary tumor growth, metastasis, and angiogenesis, by blockage of cellular binding of uPA by various antagonists including pAbs [25, 29, 159, 160]. mAbs raised against uPAR, blocking uPA binding, might thus be potential therapeutic agents [1,26]. The presently available mAbs against uPAR, which prevent uPA binding, are directed against the human form of uPAR (Section 4). Due to species specificity, these will have no effect in mouse on the muPA-muPAR interaction. For therapy experiments in genetically induced mouse cancer models, murine mAbs specific for mouse uPAR are required. Mice deficient in uPAR have no defects in their humoral immune response [161]. Anti-muPAR mouse mAbs that inhibit the muPA-muPAR interaction have recently been obtained by immunizing uPAR mice [162]. These mAbs have in vivo efficacy and will be important tools in therapeutic studies in murine cancer models. The results of such experiments could serve as proof of principle for further development of anti-uPAR mAbs for clinical use.

Acknowledgments

We thank Professor Keld Dan0 and Dr. Ross W. Stephens for critical reading of the chapter and Dr. Kirsty Green for correcting the language. The excellent technical assistance from Annegrethe Poulsen, Ruth Pettersson, and Anne Moller is gratefully acknowledged as is the excellent graphic assistance provided by John Post. This work was supported by EU contracts QLK3-CT-2002-02136 and LSHC-CT-2003-503297 as well as the Danish Cancer Society.

References

  • 1] Ronne E, Behrendt N, Ellis V, Ploug M, Dano K, Hoyer-Hansen G. Cell-induced potentiation of the plasminogen activation system is abolished by a monoclonal antibody that recognizes the NH2-terminal domain of the urokinase receptor. FEBS Lett 1991; 288(1-2):233-236.
  • 2] Ellis V, Scully MF, Kakkar VV. Plasminogen activation initiated by single-chain urokinase-type plasminogen activator. Potentiation by U937 monocytes. J Biol Chem 1989; 264(4):2185-2188.
  • 3] Liu S, Bugge TH, Leppla SH. Targeting of tumor cells by cell surface urokinase plasminogen activator-dependent anthrax toxin. J Biol Chem 2001; 276(21):17976-17984.
  • 4] Zhou HM, Nichols A, Meda P, Vassalli JD. Urokinase-type plasminogen activator and its receptor synergize to promote pathogenic proteolysis. EMBO J 2000; 19(17): 4817-4826.
  • 5] Andreasen PA, Egelund R, Petersen HH. The plasminogen activation system in tumor growth, invasion, and metastasis. Cell Mol Life Sci 2000; 57(1):25-40.
  • 6] Behrendt N. The urokinase receptor (uPAR) and the uPAR-associated protein (uPARAP/ Endo180): Membrane proteins engaged in matrix turnover during tissue remodeling. Biol Chem 2004; 385(2):103-136.
  • 7] Dano K, Behrendt N, Hoyer-Hansen G, Johnsen M, Lund LR, Ploug M, et al. Plasmino-gen activation and cancer. Thromb Haemost 2005; 93(4):676-681.
  • 8] Ploug M. Structure-function relationships in the interaction between the urokinase-type plasminogen activator and its receptor. Curr Pharm Des 2003; 9(19):1499-1528.
  • 9] Bugge TH, Suh TT, Flick MJ, Daugherty CC, Romer J, Solberg H, et al. The receptor for urokinase-type plasminogen activator is not essential for mouse development or fertility. J Biol Chem 1995; 270(28):16886-16894.
  • 10] Dewerchin M, Nuffelen AV, Wallays G, Bouche A, Moons L, Carmeliet P, et al. Generation and characterization of urokinase receptor-deficient mice. J Clin Invest 1996; 97(3): 870-878.
  • 11] Bugge TH, Flick MJ, Danton MJ, Daugherty CC, Romer J, Dano K, et al. Urokinase-type plasminogen activator is effective in fibrin clearance in the absence of its receptor or tissue-type plasminogen activator. Proc Natl Acad Sci USA 1996; 93(12):5899-5904.
  • 12] Gyetko MR, Sud S, Kendall T, Fuller JA, Newstead MW, Standiford TJ. Urokinase receptor-deficient mice have impaired neutrophil recruitment in response to pulmonary Pseudomonas aeruginosa infection. J Immunol 2000; 165(3):1513-1519.
  • 13] Gyetko MR, Sud S, Sonstein J, Polak T, Sud A, Curtis JL. Antigen-driven lymphocyte recruitment to the lung is diminished in the absence of urokinase-type plasmin-ogen activator (uPA) receptor, but is independent of uPA. J Immunol 2001; 167(10): 5539-5542.
  • 14] May AE, Kanse SM, Lund LR, Gisler RH, Imhof BA, Preissner KT. Urokinase receptor (CD87) regulates leukocyte recruitment via beta 2 integrins in vivo. J Exp Med 1998; 188(6):1029-1037.
  • 15] Rijneveld AW, Levi M, Florquin S, Speelman P, Carmeliet P, van der PT. Urokinase receptor is necessary for adequate host defense against pneumococcal pneumonia. J Immunol 2002; 168(7):3507-3511.
  • 16] Hoyer-Hansen G, Ronne E, Solberg H, Behrendt N, Ploug M, Lund LR, et al. Urokinase plasminogen activator cleaves its cell surface receptor releasing the ligand-binding domain. J Biol Chem 1992; 267(25):18224-18229.
  • 17] Hoyer-Hansen G, Ploug M, Behrendt N, Ronne E, Dano K. Cell-surface acceleration of urokinase-catalyzed receptor cleavage. Eur J Biochem 1997; 243(1-2):21-26.
  • 18] Mustjoki S, Sidenius N, Sier CF, Blasi F, Elonen E, Alitalo R, et al. Soluble urokinase receptor levels correlate with number of circulating tumor cells in acute myeloid leukemia and decrease rapidly during chemotherapy. Cancer Res 2000; 60(24):7126-7132.
  • 19] Selleri C, Montuori N, Ricci P, Visconte V, Carriero MV, Sidenius N, et al. Involvement of the urokinase-type plasminogen activator receptor in hematopoietic stem cell mobilization. Blood 2005; 105(5):2198-2205.
  • 20] Sidenius N, Sier CF, Blasi F. Shedding and cleavage of the urokinase receptor (uPAR): Identification and characterisation of uPAR fragments in vitro and in vivo. FEBS Lett 2000; 475(1):52-56.
  • 21] Wahlberg K, Hoyer-Hansen G, Casslen B. Soluble receptor for urokinase plasminogen activator in both full-length and a cleaved form is present in high concentration in cystic fluid from ovarian cancer. Cancer Res 1998; 58(15):3294-3298.
  • 22] Wilhelm OG, Wilhelm S, Escott GM, Lutz V, Magdolen V, Schmitt M, et al. Cellular glycosylphosphatidylinositol-specific phospholipase D regulates urokinase receptor shedding and cell surface expression. J Cell Physiol 1999; 180(2):225-235.
  • 23] Llinas P, Le Du MH, Gardsvoll H, Dano K, Ploug M, Gilquin B, et al. Crystal structure of the human urokinase plasminogen activator receptor bound to an antagonist peptide. EMBO J 2005; 24(9):1655-1663.
  • 24] Huai Q, Mazar AP, Kuo A, Parry GC, Shaw DE, Callahan J, et al. Structure of human urokinase plasminogen activator in complex with its receptor. Science 2006; 311(5761): 656-659.
  • 25] Crowley CW, Cohen RL, Lucas BK, Liu G, Shuman MA, Levinson AD. Prevention of metastasis by inhibition of the urokinase receptor. Proc Natl Acad Sci USA 1993; 90(11):5021-5025.
  • 26] List K, Hoyer-Hansen G, Ronne E, Dano K, Behrendt N. Different mechanisms are involved in the antibody mediated inhibition of ligand binding to the urokinase receptor: A study based on biosensor technology. J Immunol Methods 1999; 222(1-2):125-133.
  • 27] Lu H, Yeh P, Guitton JD, Mabilat C, Desanlis F, Maury I, et al. Blockage ofthe urokinase receptor on the cell surface: Construction and characterization of a hybrid protein consisting of the N-terminal fragment of human urokinase and human albumin. FEBS Lett 1994; 356(1):56-59.
  • 28] Luther T, Magdolen V, Albrecht S, Kasper M, Riemer C, Kessler H, et al. Epitope-mapped monoclonal antibodies as tools for functional and morphological analyses of the human urokinase receptor in tumor tissue. Am J Pathol 1997; 150(4):1231-1244.
  • 29] Min HY, Doyle LV, Vitt CR, Zandonella CL, Stratton-Thomas JR, Shuman MA, et al. Urokinase receptor antagonists inhibit angiogenesis and primary tumor growth in synge-neicmice. Cancer Res 1996; 56(10):2428-2433.
  • 30] Ploug M, Ostergaard S, Gardsvoll H, Kovalski K, Holst-Hansen C, Holm A, et al. Peptide-derived antagonists of the urokinase receptor. Affinity maturation by combinatorial chemistry, identification of functional epitopes, and inhibitory effect on cancer cell intravasation. Biochemistry 2001; 40(40):12157-12168.
  • 31] Schmiedeberg N, Schmitt M, Rolz C, Truffault V, Sukopp M, Burgle M, et al. Synthesis, solution structure, and biological evaluation of urokinase type plasminogen activator (uPA)-derived receptor binding domain mimetics. J Med Chem 2002; 45(23):4984-4994.
  • 32] Tressler RJ, Pitot PA, Stratton JR, Forrest LD, Zhuo S, Drummond RJ, et al. Urokinase receptor antagonists: Discovery and application to in vivo models of tumor growth. APMIS 1999; 107(1):168-173.
  • 33] Pyke C, Graem N, Ralfkiaer E, Ronne E, Hoyer-Hansen G, Brunner N, et al. Receptor for urokinase is present in tumor-associated macrophages in ductal breast carcinoma. Cancer Res 1993; 53(8):1911-1915.
  • 34] Pyke C, Ralfkiaer E, Ronne E, Hoyer-Hansen G, Kirkeby L, Dano K. Immunohistochem-ical detection of the receptor for urokinase plasminogen activator in human colon cancer. Histopathology 1994; 24(2):131-138.
  • 35] Almasi CE, Hoyer-Hansen G, Christensen IJ, Dano K, Pappot H. Prognostic impact of liberated domain I of the urokinase plasminogen activator receptor in squamous cell lung cancer tissue. Lung Cancer 2005; 48(3):349-355.
  • 36] Ganesh S, Sier CF, Heerding MM, Griffioen G, Lamers CB, Verspaget HW. Urokinase receptor and colorectal cancer survival. Lancet 1994; 344(8919):401-402.
  • 37] Grondahl-Hansen J, Peters HA, van Putten WL, Look MP, Pappot H, Ronne E, et al. Prognostic significance of the receptor for urokinase plasminogen activator in breast cancer. Clin Cancer Res 1995; 1(10):1079-10787.
  • 38] Kotzsch M, Luther T, Harbeck N, Ockert D, Lutz V, Noack F, et al. New ELISA for quantitation of human urokinase receptor (CD87) in cancer. Int J Oncol 2000; 17(4): 827-834.
  • 39] Pedersen H, Brunner N, Francis D, Osterlind K, Ronne E, Hansen HH, et al. Prognostic impact of urokinase, urokinase receptor, and type 1 plasminogen activator inhibitor in squamous and large cell lung cancer tissue. Cancer Res 1994; 54(17):4671-4675.
  • 40] Riisbro R, Christensen IJ, Piironen T, Greenall M, Larsen B, Stephens RW, et al. Prognostic significance of soluble urokinase plasminogen activator receptor in serum and cytosol of tumor tissue from patients with primary breast cancer. Clin Cancer Res 2002; 8(5):1132-1141.
  • 41] Stephens RW, Nielsen HJ, Christensen IJ, Thorlacius-Ussing O, Sorensen S, Dano K, et al. Plasma urokinase receptor levels in patients with colorectal cancer: Relationship to prognosis. J Natl Cancer Inst 1999; 91(10):869-874.
  • 42] Ostrowski SR, Piironen T, Hoyer-Hansen G, Gerstoft J, Pedersen BK, Ullum H. High plasma levels of intact and cleaved soluble urokinase receptor reflect immune activation and are independent predictors of mortality in HIV-1-infected patients. J Acquir Immune Defic Syndr 2005; 39(1):23-31.
  • 43] Ostrowski SR, Ullum H, Goka BQ, Hoyer-Hansen G, Obeng-Adjei G, Pedersen BK, et al. Plasma concentrations of soluble urokinase-type plasminogen activator receptor are increased in patients with malaria and are associated with a poor clinical or a fatal outcome. J Infect Dis 2005; 191(8):1331-1341.
  • 44] Sidenius N, Sier CF, Ullum H, Pedersen BK, Lepri AC, Blasi F, et al. Serum level of soluble urokinase-type plasminogen activator receptor is a strong and independent predictor of survival in human immunodeficiency virus infection. Blood 2000; 96(13): 4091-4095.
  • 45] Perch M, Kofoed P, Fischer TK, Co F, Rombo L, Aaby P, et al. Serum levels of soluble urokinase plasminogen activator receptor is associated with parasitemia in children with acute Plasmodium falciparum malaria infection. Parasite Immunol 2004; 26(5):207-211.
  • 46] Vassalli JD, Baccino D, Belin D. A cellular binding site for the Mr 55,000 form of the human plasminogen activator, urokinase. J Cell Biol 1985; 100(1):86-92.
  • 47] Plesner T, Ralfkiaer E, Wittrup M, Johnsen H, Pyke C, Pedersen TL, et al. Expression of the receptor for urokinase-type plasminogen activator in normal and neoplastic blood cells and hematopoietic tissue. Am J Clin Pathol 1994; 102(6):835-841.
  • 48] Plesner T, Behrendt N, Ploug M. Structure, function and expression on blood and bone marrow cells of the urokinase-type plasminogen activator receptor, uPAR. Stem Cells 1997; 15(6):398-408.
  • 49] Nykjaer A, Petersen CM, Moller B, Andreasen PA, Gliemann J. Identification and characterization of urokinase receptors in natural killer cells and T-cell-derived lympho-kine activated killer cells. FEBS Lett 1992; 300(1):13-17.
  • 50] Nykjaer A, Moller B, Todd RF, III, Christensen T, Andreasen PA, Gliemann J, et al. Urokinase receptor. An activation antigen in human T lymphocytes. J Immunol 1994; 152(2):505-516.
  • 51] Pierleoni C, Samuelsen GB, Graem N, Ronne E, Nielsen BS, Kaufmann P, et al. Immu-nohistochemical identification of the receptor for urokinase plasminogen activator associated with fibrin deposition in normal and ectopic human placenta. Placenta 1998; 19(7): 501-508.
  • 52] Vagnarelli P, Raimondi E, Mazzieri R, De CL, Mignatti P. Assignment of the human urokinase receptor gene (PLAUR) to 19q13. Cytogenet Cell Genet 1992; 60(3-4): 197-199.
  • 53] Behrendt N, Ronne E, Ploug M, Petri T, Lober D, Nielsen LS, et al. The human receptor for urokinase plasminogen activator. NH2-terminal amino acid sequence and glycosyla-tion variants. J Biol Chem 1990; 265(11):6453-6460.
  • 54] Nielsen LS, Kellerman GM, Behrendt N, Picone R, Dano K, Blasi F. A 55,000-60,000 Mr receptor protein for urokinase-type plasminogen activator. Identification in human tumor cell lines and partial purification. J Biol Chem 1988; 263(5):2358-2363.
  • 55] Moller LB, Ploug M, Blasi F. Structural requirements for glycosyl-phosphatidylinositol-anchor attachment in the cellular receptor for urokinase plasminogen activator. Eur J Biochem 1992; 208(2):493-500.
  • 56] Ploug M, Ronne E, Behrendt N, Jensen AL, Blasi F, Dano K. Cellular receptor for urokinase plasminogen activator. Carboxyl-terminal processing and membrane anchoring by glycosyl-phosphatidylinositol. J Biol Chem 1991; 266(3):1926-1933.
  • 57] Behrendt N, Ploug M, Patthy L, Houen G, Blasi F, Dano K. The ligand-binding domain of the cell surface receptor for urokinase-type plasminogen activator. J Biol Chem 1991; 266(12):7842-7847.
  • 58] Ploug M, Ellis V. Structure-function relationships in the receptor for urokinase-type plasminogen activator. Comparison to other members of the Ly-6 family and snake venom alpha-neurotoxins. FEBS Lett 1994; 349(2):163-168.
  • 59] Ploug M, Kjalke M, Ronne E, Weidle U, Hoyer-Hansen G, Dano K. Localization of the disulfide bonds in the NH2-terminal domain of the cellular receptor for human urokinase-type plasminogen activator. A domain structure belonging to a novel superfamily of glycolipid-anchored membrane proteins. J Biol Chem 1993; 268(23):17539-17546.
  • 60] Roldan AL, Cubellis MV, Masucci MT, Behrendt N, Lund LR, Dano K, et al. Cloning and expression of the receptor for human urokinase plasminogen activator, a central molecule in cell surface, plasmin dependent proteolysis. EMBO J 1990; 9(2):467-474.
  • 61] Ploug M, Rahbek-Nielsen H, Nielsen PF, Roepstorff P, Dano K. Glycosylation profile of a recombinant urokinase-type plasminogen activator receptor expressed in Chinese hamster ovary cells. J Biol Chem 1998; 273(22):13933-13943.
  • 62] Moller LB, Pollanen J, Ronne E, PedersenN, Blasi F. N-linked glycosylation of the ligand-binding domain of the human urokinase receptor contributes to the affinity for its ligand. J Biol Chem 1993; 268(15):11152-11159.
  • 63] Solberg H, Lober D, Eriksen J, Ploug M, Ronne E, Behrendt N, et al. Identification and characterization of the murine cell surface receptor for the urokinase-type plasminogen activator. Eur J Biochem 1992; 205(2):451-458.
  • 64] Ellis V, Behrendt N, Dano K. Plasminogen activation by receptor-bound urokinase. A kinetic study with both cell-associated and isolated receptor. J Biol Chem 1991; 266 (19):12752-12758.
  • 65] Gardsvoll H, Dano K, Ploug M. Mapping part of the functional epitope for ligand binding on the receptor for urokinase-type plasminogen activator by site-directed mutagenesis. J Biol Chem 1999; 274(53):37995-38003.
  • 66] Behrendt N, Ronne E, Dano K. Domain interplay in the urokinase receptor. Requirement for the third domain in high affinity ligand binding and demonstration of ligand contact sites in distinct receptor domains. J Biol Chem 1996; 271(37):22885-22894.
  • 67] Ploug M, Ellis V, Dano K. Ligand interaction between urokinase-type plasminogen activator and its receptor probed with 8-anilino-1-naphthalenesulfonate. Evidence for a hydrophobic binding site exposed only on the intact receptor. Biochemistry 1994; 33(30): 8991-8997.
  • 68] Bolon I, Zhou HM, Charron Y, Wohlwend A, Vassalli JD. Plasminogen mediates the pathological effects of urokinase-type plasminogen activator overexpression. Am J Pathol 2004; 164(6):2299-2304.
  • 69] Wei Y, Waltz DA, Rao N, Drummond RJ, Rosenberg S, Chapman HA. Identification of the urokinase receptor as an adhesion receptor for vitronectin. J Biol Chem 1994; 269(51):32380-32388.
  • 70] Hoyer-Hansen G, Behrendt N, Ploug M, Dano K, Preissner KT. The intact urokinase receptor is required for efficient vitronectin binding: Receptor cleavage prevents ligand interaction. FEBS Lett 1997; 420(1):79-85.
  • 71] Kanse SM, Kost C, Wilhelm OG, Andreasen PA, Preissner KT. The urokinase receptor is a major vitronectin-binding protein on endothelial cells. Exp Cell Res 1996; 224(2): 344-353.
  • 72] Sidenius N, Blasi F. Domain 1 of the urokinase receptor (uPAR) is required for uPAR-mediated cell binding to vitronectin. FEBS Lett 2000; 470(1):40-46.
  • 73] Deng G, Royle G, Wang S, Crain K, Loskutoff J. Structural and functional analysis of the plasminogen activator inhibitor-1 binding motif in the somatomedin B domain of vitronectin. J Biol Chem 1996; 271(22):12716-12723.
  • 74] Okumura Y, Kamikubo Y, Curriden SA, Wang J, Kiwada T, Futaki S, et al. Kinetic analysis of the interaction between vitronectin and the urokinase receptor. J Biol Chem 2002; 277(11):9395-9404.
  • 75] Montuori N, Carriero MV, Salzano S, Rossi G, Ragno P. The cleavage of the urokinase receptor regulates its multiple functions. J Biol Chem 2002; 277(49):46932-46939.
  • 76] Wei Y, Eble JA, Wang Z, Kreidberg JA, Chapman HA. Urokinase receptors promote beta1 integrin function through interactions with integrin alpha3beta1. Mol Biol Cell 2001; 12(10):2975-2986.
  • 77] Aguirre Ghiso JA, Kovalski K, Ossowski L. Tumor dormancy induced by downregulation of urokinase receptor in human carcinoma involves integrin and MAPK signaling. J Cell Biol 1999; 147(1):89-104.
  • 78] Bohuslav J, Horejsi V, Hansmann C, Stockl J, Weidle UH, Majdic O, et al. Urokinase plasminogen activator receptor, beta 2-integrins, and Src-kinases within a single receptor complex of human monocytes. J Exp Med 1995; 181(4):1381-1390.
  • 79] Simon DI, Rao NK, Xu H, Wei Y, Majdic O, Ronne E, et al. Mac-1 (CD11b/CD18) and the urokinase receptor (CD87) form a functional unit on monocytic cells. Blood 1996; 88(8):3185-3194.
  • 80] Tarui T, Andronicos N, Czekay RP, Mazar AP, Bdeir K, Parry GC, et al. Critical role of integrin alpha 5 beta 1 in urokinase (uPA)/urokinase receptor (uPAR, CD87) signaling. J Biol Chem 2003; 278(32):29863-29872.
  • 81] Ragno P, Montuori N, Covelli B, Hoyer-Hansen G, Rossi G. Differential expression of a truncated form of the urokinase-type plasminogen-activator receptor in normal and tumor thyroid cells. Cancer Res 1998; 58(6):1315-1319.
  • 82] Sier CF, Nicoletti I, Santovito ML, Frandsen T, Aletti G, Ferrari A, et al. Metabolism of tumour-derived urokinase receptor and receptor fragments in cancer patients and xeno-grafted mice. Thromb Haemost 2004; 91(2):403-411.
  • 83] Solberg H, Romer J, Brunner N, Holm A, Sidenius N, Dano K, et al. A cleaved form of the receptor for urokinase-type plasminogen activator in invasive transplanted human and murine tumors. Int J Cancer 1994; 58(6):877-881.
  • 84] Hoyer-Hansen G, Solberg H, Ronne E, Behrendt N, Dano K. Variants of the receptor for urokinase-type plasminogen activator. In: Preissner KT, Rosenblatt S, Kost C, Wegerhoff J, Mosher DF, editors. Biology of Vitronectins and Their Receptors. Elsevier Science Publishers B.V. Amsterdam, 1993: 289-294.
  • 85] Mazzieri R, Hoyer-Hansen G, Ronne E, Vagnarelli P, Raimondi E, De Carli L, et al. Urokinase and urokinase receptor expression in somatic cell hybrids. Fibrinolysis 1994; 8:344-352.
  • 86] Hoyer-Hansen G, Pessara U, Holm A, Pass J, Weidle U, Dano K, et al. Urokinase-catalysed cleavage of the urokinase receptor requires an intact glycolipid anchor. Biochem J 2001; 358(Pt 3):673-679.
  • 87] Ronne E, Hoyer-Hansen G, Brunner N, Pedersen H, Rank F, Osborne CK, et al. Urokinase receptor in breast cancer tissue extracts. Enzyme-linked immunosorbent assay with a combination of mono- and polyclonal antibodies. Breast Cancer Res Treat 1995; 33(3): 199-207.
  • 88] Beaufort N, Leduc D, Rousselle JC, Namane A, Chignard M, Pidard D. Plasmin cleaves the juxtamembrane domain and releases truncated species of the urokinase receptor (CD87) from human bronchial epithelial cells. FEBS Lett 2004; 574(1-3):89-94.
  • 89] Beaufort N, Leduc D, Rousselle JC, Magdolen V, Luther T, Namane A, et al. Proteolytic regulation of the urokinase receptor/CD87 on monocytic cells by neutrophil elastase and cathepsin G. J Immunol 2004; 172(1):540-549.
  • 90] Koolwijk P, Sidenius N, Peters E, Sier CF, Hanemaaijer R, Blasi F, et al. Proteolysis of the urokinase-type plasminogen activator receptor by metalloproteinase-12: Implication for angiogenesis in fibrin matrices. Blood 2001; 97(10):3123-3131.
  • 91] Montuori N, Rossi G, Ragno P. Cleavage of urokinase receptor regulates its interaction with integrins in thyroid cells. FEBS Lett 1999; 460(1):32-36.
  • 92] Olson D, Pollanen J, Hoyer-Hansen G, Ronne E, Sakaguchi K, Wun TC, et al. Internali-zation of the urokinase-plasminogen activator inhibitor type-1 complex is mediated by the urokinase receptor. J Biol Chem 1992; 267(13):9129-9133.
  • 93] Nykjaer A, Conese M, Christensen EI, Olson D, Cremona O, Gliemann J, et al. Recycling of the urokinase receptor upon internalization of the uPA:serpin complexes. EMBO J 1997; 16(10):2610-2620.
  • 94] Czekay RP, Kuemmel TA, Orlando RA, Farquhar MG. Direct binding of occupied urokinase receptor (uPAR) to LDL receptor-related protein is required for endocytosis of uPAR and regulation of cell surface urokinase activity. Mol Biol Cell 2001; 12(5): 1467-1479.
  • 95] Nykjaer A, Kjoller L, Cohen RL, Lawrence DA, Garni-Wagner BA, Todd RF, III, et al. Regions involved in binding of urokinase-type-1 inhibitor complex and pro-urokinase to the endocytic alpha 2-macroglobulin receptor/low density lipoprotein receptor-related protein. Evidence that the urokinase receptor protects pro-urokinase against binding to the endocytic receptor. J Biol Chem 1994; 269(41):25668-25676.
  • 96] Ploug M, Plesner T, Ronne E, Ellis V, Hoyer-Hansen G, Hansen NE, et al. The receptor for urokinase-type plasminogen activator is deficient on peripheral blood leukocytes in patients with paroxysmal nocturnal hemoglobinuria. Blood 1992; 79(6):1447-1455.
  • 97] Mizukami IF, Faulkner NE, Gyetko MR, Sitrin RG, Todd RF, III. Enzyme-linked immunoabsorbent assay detection of a soluble form of urokinase plasminogen activator receptor in vivo. Blood 1995; 86(1):203-211.

101 102

110 111

Ronne E, Pappot H, Grondahl-Hansen J, Hoyer-Hansen G, Plesner T, Hansen NE, et al. The receptor for urokinase plasminogen activator is present in plasma from healthy donors and elevated in patients with paroxysmal nocturnal haemoglobinuria. Br J Haematol 1995; 89(3):576-581.

Pedersen N, Schmitt M, Ronne E, Nicoletti MI, Hoyer-Hansen G, Conese M, et al. A ligand-free, soluble urokinase receptor is present in the ascitic fluid from patients with ovarian cancer. J Clin Invest 1993; 92(5):2160-2167.

Andolfo A, English WR, Resnati M, Murphy G, Blasi F, Sidenius N. Metalloproteases cleave the urokinase-type plasminogen activator receptor in the D1-D2 linker region and expose epitopes not present in the intact soluble receptor. Thromb Haemost 2002; 88(2): 298-306. Kukulansky T, Abramovitch S, Hollander N. Cleavage of the glycosylphosphatidylinositol anchor affects the reactivity of thy-1 with antibodies. J Immunol 1999; 162(10):5993-5997. English A, Kosoy R, Pawlinski R, Bamezai A. A monoclonal antibody against the 66-kDa protein expressed in mouse spleen and thymus inhibits Ly-6A.2-dependent cell-cell adhesion. J Immunol 2000; 165(7):3763-3771.

Durbin H, Young S, Stewart LM, Wrba F, Rowan AJ, Snary D, et al. An epitope on carcinoembryonic antigen defined by the clinically relevant antibody PR1A3. Proc Natl Acad Sci USA 1994; 91(10):4313-4317.

Butikofer P, Malherbe T, Boschung M, Roditi I. GPI-anchored proteins: Now you see 'em, now you don't. FASEB J 2001; 15(2):545-548.

Resnati M, Guttinger M, Valcamonica S, Sidenius N, Blasi F, Fazioli F. Proteolytic cleavage of the urokinase receptor substitutes for the agonist-induced chemotactic effect. EMBO J 1996; 15(7):1572-1582.

Fazioli F, Resnati M, Sidenius N, Higashimoto Y, Appella E, Blasi F. A urokinase-sensitive region of the human urokinase receptor is responsible for its chemotactic activity. EMBO J 1997; 16(24):7279-7286.

Resnati M, Pallavicini I, Wang JM, Oppenheim J, Serhan CN, Romano M, et al. The fibrinolytic receptor for urokinase activates the G protein-coupled chemotactic receptor FPRL1/LXA4R. Proc Natl Acad Sci USA 2002; 99(3):1359-1364.

Piironen T, Laursen B, Pass J, List K, Gardsvoll H, Ploug M, et al. Specific immunoassays for detection of intact and cleaved forms of the urokinase receptor. Clin Chem 2004; 50(11):2059-2068.

Mizukami IF, Vinjamuri SD, Trochelman RD, Todd RF, III. A structural characterization of the Mo3 activation antigen expressed on the plasma membrane of human mono-nuclear phagocytes. J Immunol 1990; 144(5):1841-1848.

Todd RF, III, Schlossman SF. Analysis of antigenic determinants on human monocytes and macrophages. Blood 1982; 59(4):775-786.

Todd RF, III, Alvarez PA, Brott DA, Liu DY. Bacterial lipopolysaccharide, phorbol myristate acetate, and muramyl dipeptide stimulate the expression of a human monocyte surface antigen, Mo3e. J Immunol 1985; 135(6):3869-3877.

Min HY, Semnani R, Mizukami IF, Watt K, Todd RF, III, Liu DY. cDNA for Mo3, a monocyte activation antigen, encodes the human receptor for urokinase plasminogen activator. J Immunol 1992; 148(11):3636-3642.

Knapp W, Majdic O, Stockinger H, Bettelheim P, Liszka K, Koller U, et al. Monoclonal antibodies to human myelomonocyte differentiation antigens in the diagnosis of acute myeloid leukemia. Med Oncol Tumor Pharmacother 1984; 1(4):257-262. Gadd SJ, Majdic O, Kasinrerk W, Stockinger H, Maurer D, Eher R, et al. M5, a phosphoinositol-linked human myelomonocytic activation-associated antigen. Clin Exp Immunol 1990; 80(2):252-256.

120 121

Sillaber C, Baghestanian M, Hofbauer R, Virgolini I, Bankl HC, Fureder W, et al. Molecular and functional characterization of the urokinase receptor on human mast cells. J Biol Chem 1997; 272(12):7824-7832.

Ronne E, Behrendt N, Ploug M, Nielsen HJ, Wollisch E, Weidle U, et al. Quantitation of the receptor for urokinase plasminogen activator by enzyme-linked immunosorbent assay. J Immunol Methods 1994; 167(1-2):91-101.

Duffy MJ. The urokinase plasminogen activator system: Role in malignancy. Curr Pharm Des 2004; 10(1):39-49.

Look M, van PW, Duffy M, Harbeck N, Christensen IJ, Thomssen C, et al. Pooled analysis of prognostic impact of uPA and PAI-1 in breast cancer patients. Thromb Hae-most 2003; 90(3):538-548.

Grondahl-Hansen J, Christensen IJ, Rosenquist C, Brunner N, Mouridsen HT, Dano K, et al. High levels of urokinase-type plasminogen activator and its inhibitor PAI-1 in cytosolic extracts of breast carcinomas are associated with poor prognosis. Cancer Res 1993; 53(11):2513-2521.

Stephens RW, Pedersen AN, Nielsen HJ, Hamers MJ, Hoyer-Hansen G, Ronne E, et al. ELISA determination of soluble urokinase receptor in blood from healthy donors and cancer patients. Clin Chem 1997; 43(10):1868-1876.

Hoyer-Hansen G, Hamers MJ, Pedersen AN, Nielsen HJ, Brunner N, Dano K, et al. Loss of ELISA specificity due to biotinylation of monoclonal antibodies. J Immunol Methods 2000; 235(1-2):91-99.

Riisbro R, Piironen T, Brunner N, Larsen B, Nielsen HJ, Stephens RW, et al. Measurement of soluble urokinase plasminogen activator receptor in serum. J Clin Ligand Assay 2002; 25(1):53-56.

Bianchi E, Cohen RL, Thor AT, Todd RF, III, Mizukami IF, Lawrence DA, et al. The urokinase receptor is expressed in invasive breast cancer but not in normal breast tissue. Cancer Res 1994; 54(4):861-866.

Camiolo SM, Siuta MR, Madeja JM. Improved medium for extraction of plasminogen activator from tissue. Prep Biochem 1982; 12(4):297-305.

Thorpe SM. Immunological quantitation of nuclear receptors in human breast cancer: Relation to cytosolic estrogen and progesterone receptors. Cancer Res 1987; 47(7): 1830-1835.

de Witte JH, Foekens JA, Brunner N, Heuvel JJ, van TT, Look MP, et al. Prognostic impact of urokinase-type plasminogen activator receptor (uPAR) in cytosols and pellet extracts derived from primary breast tumours. Br J Cancer 2001; 85(1):85-92. Ohtani H, Pyke C, Dano K, Nagura H. Expression of urokinase receptor in various stromal-cell populations in human colon cancer: Immunoelectron microscopical analysis. Int J Cancer 1995; 62(6):691-696.

Dubuisson L, Monvoisin A, Nielsen BS, Le BB, Bioulac-Sage P, Rosenbaum J. Expression and cellular localization of the urokinase-type plasminogen activator and its receptor in human hepatocellular carcinoma. J Pathol 2000; 190(2):190-195.

Ganesh S, Sier CF, Griffioen G, Vloedgraven HJ, de BA, Welvaart K, et al. Prognostic relevance of plasminogen activators and their inhibitors in colorectal cancer. Cancer Res 1994; 54(15):4065-4071.

Konno H, Abe J, Kaneko T, Baba M, Shoji A, Sunayama K, et al. Urokinase receptor and vascular endothelial growth factor are synergistically associated with the liver metastasis of colorectal cancer. Jpn J Cancer Res 2001; 92(5):516-523.

Benedet JL, Bender H, Jones H, III, Ngan HY, Pecorelli S. FIGO staging classifications and clinical practice guidelines in the management of gynecologic cancers. FIGO Committee on Gynecologic Oncology. Int J Gynaecol Obstet 2000; 70(2):209-262.

132] Turnbull RB, Jr, Kyle K, Watson FR, Spratt J. Cancer of the colon: The influence of the no-touch isolation technic on survival rates. Ann Surg 1967; 166(3):420-427.

133] Plebani M, Herszenyi L, Carraro P, De PM, Roveroni G, Cardin R, et al. Urokinase-type plasminogen activator receptor in gastric cancer: Tissue expression and prognostic role. Clin Exp Metastasis 1997; 15(4):418-425.

134] Heiss MM, Allgayer H, Gruetzner KU, Funke I, Babic R, Jauch KW, et al. Individual development and uPA-receptor expression of disseminated tumour cells in bone marrow: A reference to early systemic disease in solid cancer. Nat Med 1995; 1(10):1035-1039.

135] Heiss MM, Simon EH, Beyer BC, Gruetzner KU, Tarabichi A, Babic R, et al. Minimal residual disease in gastric cancer: Evidence of an independent prognostic relevance of urokinase receptor expression by disseminated tumor cells in the bone marrow. J Clin Oncol 2002; 20(8):2005-2016.

136] Pappot H. The plasminogen activation system in lung cancer—with special reference to the prognostic role in "non-small cell lung cancer.'' APMIS Suppl 1999; 92:1-29.

137] Werle B, Kotzsch M, Lah TT, Kos J, Gabrijelcic-Geiger D, Spiess E, et al. Cathepsin B, plasminogenactivator-inhibitor (PAI-1) and plasminogenactivator-receptor (uPAR) are prognostic factors for patients with non-small cell lung cancer. Anticancer Res 2004; 24(6):4147-4161.

138] Pappot H, Hoyer-Hansen G, Ronne E, Hansen HH, Brunner N, Dano K, et al. Elevated plasma levels of urokinase plasminogen activator receptor in non-small cell lung cancer patients. Eur J Cancer 1997; 33(6):867-872.

139] Cobos E, Jumper C, Lox C. Pretreatment determination of the serum urokinase plasmin-ogen activator and its soluble receptor in advanced small-cell lung cancer or non-small-cell lung cancer. Clin Appl Thromb Hemost 2003; 9(3):241-246.

140] Usher PA, Thomsen OF, Iversen P, Johnsen M, Brunner N, Hoyer-Hansen G, et al. Expression of urokinase plasminogen activator, its receptor and type-1 inhibitor in malignant and benign prostate tissue. Int J Cancer 2005; 113(6):870-880.

141] Miyake H, Hara I, Yamanaka K, Gohji K, Arakawa S, Kamidono S. Elevation of serum levels of urokinase-type plasminogen activator and its receptor is associated with disease progression and prognosis in patients with prostate cancer. Prostate 1999; 39(2): 123-129.

142] Piironen T, Haese A, Huland H, Steuber T, Christensen IJ, Brünner N, et al. Enhanced discrimination of benign from malignant prostatic disease by selective measurements of cleaved forms of urokinase receptor in serum. Clin Chem 2006; 52(5):838-844.

143] Borgfeldt C, Bendahl PO, Gustavsson B, Langstrom E, Ferno M, Willen R, et al. High tumor tissue concentration of urokinase plasminogen activator receptor is associated with good prognosis in patients with ovarian cancer. Int J Cancer 2003; 107(4):658-665.

144] Sier CF, Stephens R, Bizik J, Mariani A, Bassan M, Pedersen N, et al. The level of urokinase-type plasminogen activator receptor is increased in serum of ovarian cancer patients. Cancer Res 1998; 58(9):1843-1849.

145] Riisbro R, Stephens RW, Brunner N, Christensen IJ, Nielsen HJ, Heilmann L, et al. Soluble urokinase plasminogen activator receptor in preoperatively obtained plasma from patients with gynecological cancer or benign gynecological diseases. Gynecol Oncol 2001; 82(3):523-531.

146] Begum FD, Hogdall CK, Kjaer SK, Christensen L, Blaakaer J, Bock JE, et al. The prognostic value of plasma soluble urokinase plasminogen activator receptor (suPAR) levels in stage III ovarian cancer patients. Anticancer Res 2004; 24(3b):1981-1985.

147] Jardi M, Ingles-Esteve J, Burgal M, Azqueta C, Velasco F, Lopez-Pedrera C, et al. Distinct patterns of urokinase receptor (uPAR) expression by leukemic cells and peripheral blood cells. Thromb Haemost 1996; 76(6):1009-1019.

148] Lanza F, Castoldi GL, Castagnari B, Todd RF, III, Moretti S, Spisani S, et al. Expression and functional role of urokinase-type plasminogen activator receptor in normal and acute leukaemic cells. Br J Haematol 1998; 103(1):110-123.

149] Bacher U, Kern W, Schnittger S, Hiddemann W, Schoch C, Haferlach T. Further correlations of morphology according to FAB and WHO classification to cytogenetics in de novo acute myeloid leukemia: A study on 2,235 patients. Ann Hematol 2005; 84(12):785-791.

150] Speth C, Pichler I, Stockl G, Mair M, Dierich MP. Urokinase plasminogen activator receptor (uPAR; CD87) expression on monocytic cells and T cells is modulated by HIV-1 infection. Immunobiology 1998; 199(1):152-162.

151] Ostrowski SR, Katzenstein TL, Piironen T, Gerstoft J, Pedersen BK, Ullum H. Soluble urokinase receptor levels in plasma during 5 years of highly active antiretroviral therapy in HIV-1-infected patients. J Acquir Immune Defic Syndr 2004; 35(4):337-342.

152] Eugen-Olsen J, Gustafson P, Sidenius N, Fischer TK, Parner J, Aaby P, et al. The serum level of soluble urokinase receptor is elevated in tuberculosis patients and predicts mortality during treatment: A community study from Guinea-Bissau. Int J Tuberc Lung Dis 2002; 6(8):686-692.

153] Ostrowski SR, Plomgaard P, Fischer CP, Steensberg AS, Moller K, Hoyer-Hansen G, et al. Interleukin-6 infusion during human endotoxaemia inhibits in vitro release of the urokinase receptor from peripheral blood mononuclear cells. Scand J Immunol 2005; 61(2):197-206.

154] Slot O, Brunner N, Locht H, Oxholm P, Stephens RW. Soluble urokinase plasminogen activator receptor in plasma of patients with inflammatory rheumatic disorders: Increased concentrations in rheumatoid arthritis. Ann Rheum Dis 1999; 58(8):488-492.

155] Blasi F, Carmeliet P. uPAR: A versatile signalling orchestrator. Nat Rev Mol Cell Biol 2002; 3(12):932-943.

156] Montuori N, Visconte V, Rossi G, Ragno P. Soluble and cleaved forms of the urokinase-receptor: Degradation products or active molecules? Thromb Haemost 2005; 93(2): 192-198.

157] Romer J, Nielsen BS, Ploug M. The urokinase receptor as a potential target in cancer therapy. Curr Pharm Des 2004; 10(19):2359-2376.

158] Almholt K, Lund LR, Rygaard J, Nielsen BS, Dano K, Romer J, et al. Reduced metastasis of transgenic mammary cancer in urokinase-deficient mice. Int J Cancer 2005; 113(4):525-532.

159] Kruger A, Soeltl R, Lutz V, Wilhelm OG, Magdolen V, Rojo EE, et al. Reduction of breast carcinoma tumor growth and lung colonization by overexpression of the soluble urokinase-type plasminogen activator receptor (CD87). Cancer Gene Ther 2000; 7(2):292-299.

160] Rabbani SA, Gladu J. Urokinase receptor antibody can reduce tumor volume and detect the presence of occult tumor metastases in vivo. Cancer Res 2002; 62(8):2390-2397.

161] Pass J, Gardsvoll H, Lund LR, Dano K, Hoyer-Hansen G. Generation of antibodies to the urokinase receptor (uPAR) by DNA immunization of uPAR knockout mice: Membrane-bound uPAR is not required for an antibody response. Scand J Immunol 2003; 58(3): 298-305.

[162] Pass J, Joggi A, Lund IK, Rono B, Rasch MG, Gardsvoll H, et al. Murine monoclonal antibodies against murine uPA receptor produced in gene-deficient mice: Inhibitory effects on receptor-mediated uPA activity in vitro and in vivo. Thromb Haemost 2007; 97(5): [in press].

ADVANCES IN CLINICAL CHEMISTRY, VOL. 44

10 Ways To Fight Off Cancer

10 Ways To Fight Off Cancer

Learning About 10 Ways Fight Off Cancer Can Have Amazing Benefits For Your Life The Best Tips On How To Keep This Killer At Bay Discovering that you or a loved one has cancer can be utterly terrifying. All the same, once you comprehend the causes of cancer and learn how to reverse those causes, you or your loved one may have more than a fighting chance of beating out cancer.

Get My Free Ebook


Post a comment