Clinical applications of the urokinase receptor (uPAR) for cancer patients

Current Pharmaceutical Design

Volumn 17, Issue 19, 2011, Pages 1890-1910

  Boonstra, Martin C ^a   Verspaget, Hein W ^a   Ganesh, Sjam ^b   Kubben, Frank J G M ^b   Vahrmeijer, Alexander L ^a   van de Velde, Cornelis J H ^a   Kuppen, Peter J K ^a   Quax, Paul H A ^a   Sier, Cornelis F M ^a  

^a LEIDEN UNIVERSITY MEDICAL CENTER   (Netherlands)

^b Maasstad Hospital Rotterdam   (Netherlands)

Author keywords

Diagnosis; Exosomes; Imaging; Prognosis; Targeting; Therapy; uPAR

Indexed keywords

ANTHRAX TOXIN; APROTININ; BEVACIZUMAB; BIOLOGICAL MARKER; CETUXIMAB; GEMTUZUMAB; IBRITUMOMAB TIUXETAN; MATRIX METALLOPROTEINASE INHIBITOR; NANOPARTICLE; PANITUMUMAB; TRASTUZUMAB; UROKINASE; UROKINASE RECEPTOR;

ANTHRAX; BLADDER CARCINOMA; BREAST CARCINOMA; CANCER CELL; CANCER PATIENT; ENZYME LINKED IMMUNOSORBENT ASSAY; GASTROINTESTINAL CARCINOMA; HUMAN; LUNG CARCINOMA; OVARY CARCINOMA; PRIORITY JOURNAL; PROSTATE CARCINOMA; PROTEIN URINE LEVEL; REVIEW; SINGLE NUCLEOTIDE POLYMORPHISM; SURVIVAL;

ANTINEOPLASTIC AGENTS; DIAGNOSTIC IMAGING; GENE EXPRESSION REGULATION, NEOPLASTIC; HUMANS; NEOPLASMS; RECEPTORS, UROKINASE PLASMINOGEN ACTIVATOR; TUMOR MARKERS, BIOLOGICAL;

EID: 80051686747     PISSN: 13816128     EISSN: 18734286     Source Type: Journal    
DOI: 10.2174/138161211796718233     Document Type: Review

References (298)

1. Blasi F, Sidenius N. The urokinase receptor: focused cell surface proteolysis, cell adhesion and signaling. FEBS Lett 2010; 584: 1923-1930.
2. Riggenbach N, von Kaulla KN. Urokinase excretion in patients with carcinoma. Cancer 1961; 14: 889-896.
3. Duffy MJ, O'Grady P, Devaney D, O'Siorain L, Fennelly JJ, Lijnen HJ. Urokinase-plasminogen activator, a marker for aggressive breast carcinomas. Preliminary report. Cancer 1988; 62: 531-533.
4. Sumiyoshi K, Serizawa K, Urano T, Takada Y, Takada A, Baba S. Plasminogen activator system in human breast cancer. Int J Cancer 1992; 50: 345-348.
5. Harris L, Fritsche H, Mennel R, et al. American Society of Clinical Oncology 2007 update of recommendations for the use of tumor markers in breast cancer. J Clin Oncol 2007; 25: 5287-5312.
6. Mengele K, Napieralski R, Magdolen V, et al. Characteristics of the level-of-evidence-1 disease forecast cancer biomarkers uPA and its inhibitor PAI-1. Expert Rev Mol Diagn 2010; 7: 947-962.
7. 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: 86-92.
8. Schlechte W, Murano G, Boyd D. Examination of the role of the urokinase receptor in human colon cancer mediated laminin degradation. Cancer Res 1989; 49: 6064-6069.
9. Ossowski L, Clunie G, Masucci MT, Blasi F. In vivo paracrine interaction between urokinase and its receptor: effect on tumor cell invasion. J Cell Biol 1991; 115: 1107-1112.
10. Casslén B, Gustavsson B, Åstedt B. Cell membrane receptors for urokinase plasminogen activator are increased in malignant ovarian tumours. Eur J Cancer 1991; 27: 1445-1448.
11. Pyke C, Graem N, Ralfkiaer E, et al. Receptor for urokinase is present in tumor-associated macrophages in ductal breast carcinoma. Cancer Res 1993; 53: 1911-1915.
12. Jankun J, Merrick HW, Goldblatt PJ. Expression and localization of elements of the plasminogen activation system in benign breast disease and breast cancers. J Cell Biochem 1993; 53: 135-144.
13. Sier CF, Quax PH, Vloedgraven HJ, et al. Increased urokinase receptor levels in human gastrointestinal neoplasia and related liver metastases. Invasion Metastasis 1993;13: 277-288.
14. Ploug M, Eriksen J, Plesner T, Hansen NE, Danø K. A soluble form of the glycolipid-anchored receptor for urokinase-type plasminogen activator is secreted from peripheral blood leukocytes from patients with paroxysmal nocturnal hemoglobinuria. Eur J Biochem 1992; 208: 397-404.
15. Sier CF, Sidenius N, Mariani A, et al. Presence of urokinase-type plasminogen activator receptor in urine of cancer patients and its possible clinical relevance. Lab Invest 1999; 79: 717-722.
16. Mustjoki S, Sidenius N, Sier CF, 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: 7126-7132.
17. Sidenius N, Sier CF, Ullum H, 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: 4091-4095.
18. Rabna P, Andersen A, Wejse C, et al. Urine suPAR levels compared with plasma suPAR levels as predictors of postconsultation mortality risk among individuals assumed to be TBnegative: a prospective cohort study. Inflammation 2010; 33: 374-380.
19. Slot O, Brünner 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: 488-492.
20. Pyke C, Ralfkiaer E, Rønne E, Høyer-Hansen G, Kirkeby L, Danø K. Immunohistochemical detection of the receptor for urokinase plasminogen activator in human colon cancer. Histopathology 1994; 24: 131-138.
21. Hildenbrand R, Leitz M, Magdolen V, et al. Validation of immunolocalization of the urokinase receptor expression in ductal carcinoma in situ of the breast: comparison with detection by nonisotopic in-situ hybridization. Histopathology 2000; 36: 499-504.
22. Hayes DF, Bast RC, Desch CE, et al. Tumor marker utility grading system: a framework to evaluate clinical utility of tumor markers. J Natl Cancer Inst 1996; 88: 1456-1466.
23. Schmitt M, Mengele K, Napieralski R, et al. Clinical utility of level-of-evidence-1 disease forecast cancer biomarkers uPA and its inhibitor PAI-1. Expert Rev Mol Diagn 2010; 10: 1051-1067.
24. Foekens JA, Peters HA, Look MP, et al. The urokinase system of plasminogen activation and prognosis in 2780 breast cancer patients. Cancer Res 2000; 60: 636-643.
25. Borstnar S, Vrhovec I, Svetic B, Cufer T. Prognostic value of the urokinase-type plasminogen activator, and its inhibitors and receptor in breast cancer patients. Clin Breast Cancer 2002; 3: 138-146.
26. de Witte JH, Foekens JA, Brünner N, 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: 85-92.
27. de Witte JH, Sweep CG, Klijn JG, et al. Prognostic impact of urokinase-type plasminogen activator (uPA) and its inhibitor (PAI-1) in cytosols and pellet extracts derived from 892 breast cancer patients. Br J Cancer 1999; 79: 1190-1198.
28. Bedard PL, Cardoso F. Can some patients avoid adjuvant chemotherapy for early-stage breast cancer? Nat Rev Clin Oncol 2011; 8: 272-279.
29. Ganesh S, Sier CF, Heerding MM, Griffioen G, Lamers CB, Verspaget HW. Urokinase receptor and colorectal cancer survival. Lancet 1994; 344: 401-402.
30. Heiss MM, Babic R, Allgayer H, et al. Tumor-associated proteolysis and prognosis: new functional risk factors in gastric cancer defined by the urokinase-type plasminogen activator system. J Clin Oncol 1995; 13: 2084-2093.
31. Suzuki S, Hayashi Y, Wang Y, et al. Urokinase type plasminogen activator receptor expression in colorectal neoplasms. Gut 1998; 43: 798-805.
32. Illemann M, Bird N, Majeed A, et al. Two distinct expression patterns of urokinase, urokinase receptor and plasminogen activator inhibitor-1 in colon cancer liver metastases. Int J Cancer 2009; 124: 1860-1870.
33. Zlobec I, Holler S, Tornillo L, Terracciano L, Lugli A. Combined histomorphologic and immunohistochemical phenotype to predict the presence of vascular invasion in colon cancer. Dis Colon Rectum 2009; 52: 1114-1121.
34. Minoo P, Baker K, Baumhoer D, Terracciano L, Lugli A, Zlobec I. Urokinase-type plasminogen activator is a marker of aggressive phenotype and an independent prognostic factor in mismatch repair-proficient colorectal cancer. Hum Pathol 2010: 41: 70-78.
35. Bacchiocchi R, Rubini C, Pierpaoli E, et al. Prognostic value analysis of urokinase-type plasminogen activator receptor in oral squamous cell carcinoma: an immunohistochemical study. BMC Cancer 2008; 8: 220.
36. Hildenbrand R, Niedergethmann M, Marx A, et al. Amplification of the urokinase-type plasminogen activator receptor (uPAR) gene in ductal pancreatic carcinomas identifies a clinically high-risk group. Am J Pathol 2009; 174: 2246-2253.
37. Shin VY, Jin HC, Ng EK, Sung JJ, Chu KM, Cho CH. Activation of 5-lipoxygenase is required for nicotine mediated epithelialmesenchymal transition and tumor cell growth. Cancer Lett 2010; 292: 237-245.
38. Werle B, Kotzsch M, Lah TT, et al. Cathepsin B, plasminogenactivator-inhibitor (PAI-1) and plasminogenactivatorreceptor (uPAR) are prognostic factors for patients with non-small cell lung cancer. Anticancer Res 2004; 24: 4147-4161.
39. Pappot H, Skov BG, Pyke C, Grøndahl-Hansen J. Levels of plasminogen activator inhibitor type 1 and urokinase plasminogen activator receptor in non-small cell lung cancer as measured by quantitative ELISA and semiquantitative immunohistochemistry. Lung Cancer 1997; 17: 197-209.
40. Salden M, Splinter TA, Peters HA, et al. The urokinase-type plasminogen activator system in resected non-small-cell lung cancer. Rotterdam Oncology Thoracic Study Group. Ann Oncol 2000; 11: 327-332.
41. Tecimer C, Doering DL, Goldsmith LJ, Meyer JS, Abdulhay G, Wittliff JL. Clinical relevance of urokinase-type plasminogen activator, its receptor and inhibitor type 1 in ovarian cancer. Int J Gynecol Cancer 2000; 10: 372-381.
42. Kenny HA, Leonhardt P, Ladanyi A, et al. Targeting the urokinase plasminogen activator receptor inhibits ovarian cancer metastasis. Clin Cancer Res 2011; 17: 459-471.
43. Borgfeldt C, Bendahl PO, Gustavsson B, 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: 658-665.
44. Wang L, Madigan MC, Chen H, et al. Expression of urokinase plasminogen activator and its receptor in advanced epithelial ovarian cancer patients. Gynecol Oncol 2009; 114: 265-272.
45. Casella R, Shariat SF, Monoski MA, Lerner SP. Urinary levels of urokinase-type plasminogen activator and its receptor in the detection of bladder carcinoma. Cancer 2002; 95: 2494-2499.
46. Sier CF, Nicoletti I, Lisa SM, et al. Metabolism of tumour-derived urokinase receptor and receptor fragments in cancer patients and xenografted mice. Thromb Haemost 2004; 91: 403-411.
47. Sier CF, Blasi F, Sidenius N. Urinary levels of urokinase-type plasminogen activator and its receptor in the detection of bladder carcinoma. Cancer 2003; 98: 1995-1996.
48. Ecke TH, Schlechte HH, Schulze G, Lenk SV, Loening SA. Four tumour markers for urinary bladder cancer--tissue polypeptide antigen (TPA), HER-2/neu (ERB B2), urokinase-type plasminogen activator receptor (uPAR) and TP53 mutation. Anticancer Res 2005; 25: 635-641.
49. Milanese G, Dellabella M, Fazioli F, et al. Increased urokinasetype plasminogen activator receptor and epidermal growth factor receptor in serum of patients with prostate cancer. J Urol 2009; 181: 1393-1400.
50. Shariat SF, Casella R, Monoski MA, Sulser T, Gasser TC, Lerner SP. The addition of urinary urokinase-type plasminogen activator to urinary nuclear matrix protein 22 and cytology improves the detection of bladder cancer. J Urol 2003; 170: 2244-2247.
51. Sier CF, Casetta G, Verheijen JH, et al. Enhanced urinary gelatinase activities (matrix metalloproteinases 2 and 9) are associated with early-stage bladder carcinoma: a comparison with clinically used tumor markers. Clin Cancer Res 2000; 6: 2333-2340.
52. Moon PG, You S, Lee JE, Hwang D, Baek MC. Urinary exosomes and proteomics. Mass Spectrom Rev 2011 May 4; Epub ahead of print.
53. Mathivanan S, Lim JW, Tauro BJ, Ji H, Moritz RL, Simpson RJ. Proteomics analysis of A33 immunoaffinity-purified exosomes released from the human colon tumor cell line LIM1215 reveals a tissue-specific protein signature. Mol Cell Proteomics 2010; 9: 197-208.
54. Muralidharan-Chari V, Clancy JW, Sedgwick A, D'Souza-Schorey C. Microvesicles: mediators of extracellular communication during cancer progression. J Cell Sci 2010; 123: 1603-1611.
55. Hood JL, San RS, Wickline SA. Exosomes released by melanoma cells prepare sentinel lymph nodes for tumor metastasis. Cancer Res 2011 Apr 8; Epub ahead of print.
56. 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: 52-56.
57. Pedersen N, Schmitt M, Rønne E, et al. A ligand-free, soluble urokinase receptor is present in the ascitic fluid from patients with ovarian cancer. J Clin Invest 1993; 92: 2160-2167.
58. Stephens RW, Pedersen AN, Nielsen HJ, et al. ELISA determination of soluble urokinase receptor in blood from healthy donors and cancer patients. Clin Chem 1997; 43: 1868-1876.
59. Sier CF, Stephens R, Bizik J, et al. The level of urokinase-type plasminogen activator receptor is increased in serum of ovarian cancer patients. Cancer Res 1998; 58: 1843-1849.
60. Rha SY, Yang WI, Gong SJ, et al. Correlation of tissue and blood plasminogen activation system in breast cancer. Cancer Lett 2000; 150: 137-145.
61. Koolwijk P, Sidenius N, Peters E, et al. Proteolysis of the urokinase-type plasminogen activator receptor by metalloproteinase-12: implication for angiogenesis in fibrin matrices. Blood 2001; 97: 3123-3131.
62. Rasch MG, Lund IK, Almasi CE, Høyer-Hansen G. Intact and cleaved uPAR forms: diagnostic and prognostic value in cancer. Front Biosci 2008;13: 6752-6762.
63. Henic E, Borgfeldt C, Christensen IJ, Casslen B, Høyer-Hansen G. Cleaved forms of the urokinase plasminogen activator receptor in plasma have diagnostic potential and predict postoperative survival in patients with ovarian cancer. Clin Cancer Res 2008; 14: 5785-5793.
64. Almasi CE, Høyer-Hansen G, Christensen IJ, Pappot H. Prognostic significance of urokinase plasminogen activator receptor and its cleaved forms in blood from patients with non-small cell lung cancer. APMIS 2009; 117: 755-761.
65. Almasi CE, Brasso K, Iversen P, et al. Prognostic and predictive value of intact and cleaved forms of the urokinase plasminogen activator receptor in metastatic prostate cancer. Prostate 2011; 71: 899-907.
66. Thurison T, Lomholt AF, Rasch MG, et al. A new assay for measurement of the liberated domain I of the urokinase receptor in plasma improves the prediction of survival in colorectal cancer. Clin Chem 2010; 56: 1636-1640.
67. Piironen T, Haese A, Huland H, 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: 838-844.
68. Borstnar S, Sadikov A, Mozina B, Cufer T. High levels of uPA and PAI-1 predict a good response to anthracyclines. Breast Cancer Res Treat 2010:121: 615-624.
69. Florquin S, Van den Berg JG, Olszyna DP, et al. Release of urokinase plasminogen activator receptor during urosepsis and endotoxemia. Kidney Int 2001; 59: 2054-2061.
70. Berg D, Wolff C, Malinowsky K, et al. Profiling signaling pathways in formalin-fixed and paraffin-embedded breast cancer tissues reveals cross-talk between EGFR, HER2, HER3 and uPAR. J Cell Physiol 2011; Epub ahead of print.
71. Eugen-Olsen J, Andersen O, Linneberg A, et al. Circulating soluble urokinase plasminogen activator receptor predicts cancer, cardiovascular disease, diabetes and mortality in the general population. J Intern Med 2010; 268: 296-308.
72. Borrello MG, Degl'Innocenti D, Pierotti MA. Inflammation and cancer: the oncogene-driven connection. Cancer Lett 2008; 267: 262-270.
73. Stewart CE, Hall IP, Parker SG, et al. PLAUR polymorphisms and lung function in UK smokers. BMC Med Genet 2009;10: 112.
74. Mueller JC, Lohmussaar E, Magi R, et al. Linkage disequilibrium patterns and tagSNP transferability among European populations. Am J Hum Genet 2005; 76: 387-398.
75. Di Bernardo MC, Matakidou A, Eisen T, Houlston RS. Plasminogen activator inhibitor variants PAI-1 A15T and PAI-2 S413C influence lung cancer prognosis. Lung Cancer 2009; 65: 237-241.
76. Weng CJ, Tsai CM, Chen YC, et al. Evaluation of the association of urokinase plasminogen activator system gene polymorphisms with susceptibility and pathological development of hepatocellular carcinoma. Ann Surg Oncol 2010; 17: 3394-3401.
77. Weng CJ, Lin CW, Chung TT, Tsai CM, Chen MK, Yang SF. Impact of uPA System Gene Polymorphisms on the Susceptibility of Environmental Factors to Carcinogenesis and the Development of Clinicopathology of Oral Cancer. Ann Surg Oncol 2011; 18: 805-812.
78. Shih CM, Kuo WH, Lin CW, et al. Association of polymorphisms in the genes of the urokinase plasminogen activation system with susceptibility to and severity of non-small cell lung cancer. Clin Chim Acta 2011; 412: 194-198.
79. Manetti M, Allanore Y, Revillod L, et al. A genetic variation located in the promoter region of the UPAR (CD87) gene is associated with the vascular complications of systemic sclerosis. Arthritis Rheum 2011; 63: 247-256.
80. Przybylowska K, Smolarczyk K, Kulig A, et al. Antigen levels of the urokinase-type plasminogen activator and its gene polymorphisms in colorectal cancer. Cancer Lett 2002; 181: 23-30.
81. Pyke C, Eriksen J, Solberg H, et al. An alternatively spliced variant of mRNA for the human receptor for urokinase plasminogen activator. FEBS Lett 1993; 326: 69-74.
82. Luther T, Kotzsch M, Meye A, et al. Identification of a novel urokinase receptor splice variant and its prognostic relevance in breast cancer. Thromb Haemost 2003; 89: 705-717.
83. Van der Veldt AA, Eechoute K, Gelderblom H, et al. Genetic Polymorphisms Associated with a Prolonged Progression-Free Survival in Patients with Metastatic Renal Cell Cancer Treated with Sunitinib. Clin Cancer Res 2011; 17: 620-629.
84. Dunbar SD, Ornstein DL, Zacharski LR. Cancer treatment with inhibitors of urokinase-type plasminogen activator and plasmin. Expert Opin Investig Drugs 2000; 9: 2085-2092.
85. Rømer J, Nielsen BS, Ploug M. The urokinase receptor as a potential target in cancer therapy. Curr Pharm Des 2004; 10: 2359-2376.
86. Nozaki S, Endo Y, Nakahara H, Yoshizawa K, Ohara T, Yamamoto E. Targeting urokinase-type plasminogen activator and its receptor for cancer therapy. Anticancer Drugs 2006; 17: 1109-1117.
87. Mekkawy AH, Morris DL, Pourgholami MH. Urokinase plasminogen activator system as a potential target for cancer therapy. Future Oncol 2009; 5: 1487-1499.
88. Appella E, Blasi F. The growth factor module of urokinase is the binding sequence for its receptor. Ann N Y Acad Sci 1987,511, 192-195.
89. Appella E, Robinson EA, Ullrich SJ, et al. The receptor-binding sequence of urokinase. A biological function for the growth-factor module of proteases. J Biol Chem 1987; 262: 4437-4440.
90. Quax PH, Pedersen N, Masucci MT, et al. Complementation between urokinase-producing and receptor-producing cells in extracellular matrix degradation. Cell Regul 1991; 2: 793-803.
91. Li H, Soria C, Griscelli F, et al. Amino-terminal fragment of urokinase inhibits tumor cell invasion in vitro and in vivo: respective contribution of the urokinase plasminogen activator receptor-dependent or -independent pathway. Hum Gene Ther 2005; 16: 1157-1167.
92. Knör S, Sato S, Huber T, et al. Development and evaluation of peptidic ligands targeting tumour-associated urokinase plasminogen activator receptor (uPAR) for use in alpha-emitter therapy for disseminated ovarian cancer. Eur J Nucl Med Mol Imaging 2008; 35: 53-64.
93. Lu H, Yeh P, Guitton JD, et al. Blockage of the 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: 56-59.
94. Ballance DJ, Marshall JM, Cottingham IR, et al. A hybrid protein of urokinase growth-factor domain and plasminogen-activator inhibitor type 2 inhibits urokinase activity and binds to the urokinase receptor. Eur J Biochem 1992; 207: 177-183.
95. Kobayashi H, Gotoh J, Hirashima Y, Fujie M, Sugino D, Terao T. Inhibitory effect of a conjugate between human urokinase and urinary trypsin inhibitor on tumor cell invasion in vitro. J Biol Chem 1995; 270: 8361-8366.
96. Lefesvre P, Attema J, Van Bekkum D. Adenoviral gene transfer of angiostatic ATF-BPTI inhibits tumour growth. BMC Cancer 2002; 2: 17.
97. Eefting D, Seghers L, Grimbergen, et al. A novel urokinase receptor- targeted inhibitor for plasmin and matrix metalloproteinases suppres vein graft disease. Cardiovasc Res 2010; 88: 367-375.
98. Eefting D, de Vries MR, Grimbergen JM, Karper JC, van Bockel JH, Quax PH. In vivo suppression of vein graft disease by nonviral, electroporation-mediated, gene transfer of tissue inhibitor of metalloproteinase-1 linked to the amino terminal fragment of urokinase (TIMP-1.ATF), a cell-surface directed matrix metalloproteinase inhibitor. J Vasc Surg 2010; 51: 429-437.
99. Palwai NR, Zang XP, Harrison RG, Benbrook D, Pento JT. Selective growth inhibition of cancer cells by L-methioninasecontaining fusion protein targeted to the urokinase receptor. Pharmacology 2009; 84: 271-275.
100. Sun QM, Xu QN, Dong XB, et al. A hybrid protein comprising ATF domain of pro-UK and VAS, an angiogenesis inhibitor, is a potent candidate for targeted cancer therapy. International Journal of Cancer 2008; 123: 942-950.
101. Kreitman RJ, Pastan I. Immunotoxins for targeted cancer therapy. Adv Drug Deliv Rev 1998; 31: 53-88.
102. Cavallaro U, Del Vecchio A, Lappi DA, Soria MR. A conjugate between human urokinase and saporin, a type-1 ribosomeinactivating protein, is selectively cytotoxic to urokinase receptorexpressing cells. J Biol Chem 1993; 268: 23186-23190.
103. Liu S, Bugge TH, Leppla SH. Targeting of tumor cells by cell surface urokinase plasminogen activator-dependent anthrax toxin. J Biol Chem 2001; 276: 17976-17984.
104. Rustamzadeh E, Li CB, Doumbia S, Hall WA, Vallera DA. Targeting the over-expressed urokinase-type plasminogen activator receptor on glioblastoma multiforme. Journal of Neuro-Oncology 2003; 65: 63-75.
105. Oh S, Tsai AK, Ohlfest JR, Panoskaltsis-Mortari A, Vallera DA. Evaluation of a bispecific biological drug designed to simultaneously target glioblastoma and its neovasculature in the brain. J Neurosurg 2011; Feb 4; Epub ahead of print.
106. Tressler RJ, Pitot PA, Stratton JR, et al. Urokinase receptor antagonists: discovery and application to in vivo models of tumor growth. APMIS 1999; 107: 168-173.
107. Goodson RJ, Doyle MV, Kaufman SE, Rosenberg S. High-affinity urokinase receptor antagonists identified with bacteriophage peptide display. Proc Natl Acad Sci U S A 1994; 91: 7129-7133.
108. Kobayashi H, Gotoh J, Fujie M, Shinohara H, Moniwa N, Terao T. Inhibition of metastasis of Lewis lung carcinoma by a synthetic peptide within growth factor-like domain of urokinase in the experimental and spontaneous metastasis model. Int J Cancer 1994; 57: 727-733.
109. Rabbani SA, Harakidas P, Davidson DJ, Henkin J, Mazar AP. Prevention of prostate-cancer metastasis in vivo by a novel synthetic inhibitor of urokinase-type plasminogen activator (uPA). Int J Cancer 1995; 63: 840-845.
110. Ploug M, Østergaard S, Gardsvoll H, 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: 12157-12168.
111. Sato S, Kopitz C, Schmalix WA, et al. High-affinity urokinasederived cyclic peptides inhibiting urokinase/urokinase receptorinteraction: effects on tumor growth and spread. FEBS Lett 2002: 528: 212-216.
112. Estreicher A, Wohlwend A, Belin D, Schleuning WD, Vassalli JD. Characterization of the cellular binding site for the urokinase-type plasminogen activator. J Biol Chem 1989; 264: 1180-1189.
113. Quax PH, Grimbergen JM, Lansink M, et al. Binding of human urokinase-type plasminogen activator to its receptor: residues involved in species specificity and binding. Arterioscler Thromb Vasc Biol 1998; 18: 693-701.
114. Corpet DE, Pierre F. How good are rodent models of carcinogenesis in predicting efficacy in humans? A systematic review and meta-analysis of colon chemoprevention in rats, mice and men. Eur J Cancer 2005; 41: 1911-1922.
115. Frese KK, Tuveson DA. Maximizing mouse cancer models. Nat Rev Cancer 2007; 7: 654-658.
116. Hassan R, Bullock S, Premkumar A, et al. Phase I study of SS1P, a recombinant anti-mesothelin immunotoxin given as a bolus I.V. infusion to patients with mesothelin-expressing mesothelioma, ovarian, and pancreatic cancers. Clin Cancer Res 2007; 13: 5144-5149.
117. Luther T, Magdolen V, Albrecht S, 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: 1231-1244.
118. Duriseti S, Goetz DH, Hostetter DR, LeBeau AM, Wei Y, Craik CS. Antagonistic anti-urokinase plasminogen activator receptor (uPAR) antibodies significantly inhibit uPAR-mediated cellular signaling and migration. J Biol Chem 2010; 285: 26878-26888.
119. 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: 2390-2397.
120. Kenny HA, Leonhardt P, Ladanyi A, et al. Targeting the Urokinase Plasminogen Activator Receptor Inhibits Ovarian Cancer Metastasis. Clin Cancer Res 2011; 17: 459-471.
121. van Buren G, Gray MJ, Dallas NA, et al. Targeting the urokinase plasminogen activator receptor with a monoclonal antibody impairs the growth of human colorectal cancer in the liver. Cancer 2009; 115: 3360-3368.
122. Rabbani SA, Ateeq B, Arakelian A, et al. An anti-urokinase plasminogen activator receptor antibody (ATN-658) blocks prostate cancer invasion, migration, growth, and experimental skeletal metastasis in vitro and in vivo. Neoplasia 2010; 12: 778-778.
123. Madsen CD, Sidenius N. The interaction between urokinase receptor and vitronectin in cell adhesion and signalling. Eur J Cell Biol 2008; 87: 617-629.
124. Mekkawy AH, de Bock CE, Lin Z, Morris DL, Wang Y, Pourgholami MH. Novel protein interactors of urokinase-type plasminogen activator receptor. Biochem Biophys Res Commun 2010; 399: 738-743.
125. Huang XH, Peng XH, Wang YQ, et al. A reexamination of active and passive tumor targeting by using rod-shaped gold nanocrystals and covalently conjugated peptide ligands. Acs Nano 2010; 4: 5887-5896.
126. Guthaus E, Schmiedeberg N, Burgle M, Magdolen V, Kessler H, Schmitt M. The urokinase receptor (uPAR, CD87) as a target for tumor therapy: uPA-silica particles (SP-uPA) as a new tool for assessing synthetic peptides to interfere with uPA/uPA-receptor interaction. Recent Results Cancer Res 2003,162, 3-14.
127. Wang M, Lowik DW, Miller AD, Thanou M. Targeting the urokinase plasminogen activator receptor with synthetic selfassembly nanoparticles. Bioconjug Chem 2009; 20: 32-40.
128. Abdalla MO, Karna P, Sajja HK, et al. Enhanced noscapine delivery using uPAR-targeted optical-MR imaging trackable nanoparticles for prostate cancer therapy. J Control Release 2011; 149: 314-322.
129. Kook YH, Adamski J, Zelent A, Ossowski L. The effect of antisense inhibition of urokinase receptor in human squamous cell carcinoma on malignancy. EMBO J 1994; 13: 3983-3991.
130. Pillay V, Dass CR, Choong PF. The urokinase plasminogen activator receptor as a gene therapy target for cancer. Trends Biotechnol 2007; 25: 33-39.
131. Go Y, Chintala SK, Mohanam S, et al. Inhibition of in vivo tumorigenicity and invasiveness of a human glioblastoma cell line transfected with antisense uPAR vectors. Clin Exp Metastasis 1997; 15: 440-446.
132. Mohan PM, Chintala SK, Mohanam S, et al. Adenovirus-mediated delivery of antisense gene to urokinase-type plasminogen activator receptor suppresses glioma invasion and tumor growth. Cancer Res 1999; 59: 3369-3373.
133. Lakka SS, Rajagopal R, Rajan MK, et al. Adenovirus-mediated antisense urokinase-type plasminogen activator receptor gene transfer reduces tumor cell invasion and metastasis in non-small cell lung cancer cell lines. Clin Cancer Res 2001; 7: 1087-1093.
134. Gondi CS, Lakka SS, Dinh DH, Olivero WC, Gujrati M, Rao JS. RNAi-mediated inhibition of cathepsin B and uPAR leads to decreased cell invasion, angiogenesis and tumor growth in gliomas. Oncogene 2004; 23: 8486-8496.
135. Borgatti M, Boyd DD, Lampronti I, et al. Decoy molecules based on PNA-DNA chimeras and targeting Sp1 transcription factors inhibit the activity of urokinase-type plasminogen activator receptor (uPAR) promoter. Oncol Res 2005; 15: 373-383.
136. Dass CR, Nadesapillai AP, Robin D, et al. Down regulation of uPAR confirms link in growth and metastasis of osteosarcoma. Clin Exp Metastasis 2005; 22: 643-652.
137. Margheri F, D'Alessio S, Serrati S, et al. Effects of blocking urokinase receptor signaling by antisense oligonucleotides in a mouse model of experimental prostate cancer bone metastases. Gene Ther 2005; 12: 702-714.
138. Nair RR, Wang H, Jamaluddin MS, Fokt I, Priebe W, Boyd DD. A bisanthracycline (WP631) represses uPAR gene expression and cell migration of RKO colon cancer cells by interfering with transcription factor binding to a chromatin-accessible -148/-124 promoter region. Oncol Res 2005; 15: 265-279.
139. Nozaki S, Endo Y, Nakahara H, et al. Inhibition of invasion and metastasis in oral cancer by targeting urokinase-type plasminogen activator receptor. Oral Oncol 2005; 41: 971-977.
140. Liang X, Yang X, Tang Y, et al. RNAi-mediated downregulation of urokinase plasminogen activator receptor inhibits proliferation, adhesion, migration and invasion in oral cancer cells. Oral Oncol 2008; 44: 1172-1180.
141. Gondi CS, Rao JS. Therapeutic potential of siRNA-mediated targeting of urokinase plasminogen activator, its receptor, and matrix metalloproteinases. Methods Mol Biol 2009; 487: 267-281.
142. Li C, Cao S, Liu Z, Ye X, Chen L, Meng S. RNAi-mediated downregulation of uPAR synergizes with targeting of HER2 through the ERK pathway in breast cancer cells. Int J Cancer 2010; 127: 1507-1516.
143. Subramanian R, Gondi CS, Lakka SS, Jutla A, Rao JS. SiRNAmediated simultaneous downregulation of uPA and its receptor inhibits angiogenesis and invasiveness triggering apoptosis in breast cancer cells. Int J Oncol 2006; 28: 831-839.
144. Gondi CS, Lakka SS, Dinh DH, Olivero WC, Gujrati M, Rao JS. Intraperitoneal injection of a hairpin RNA-expressing plasmid targeting urokinase-type plasminogen activator (uPA) receptor and uPA retards angiogenesis and inhibits intracranial tumor growth in nude mice. Clin Cancer Res 2007; 13: 4051-4060.
145. Raghu H, Lakka SS, Gondi CS, et al. Suppression of uPA and uPAR attenuates angiogenin mediated angiogenesis in endothelial and glioblastoma cell lines. PLoS ONE 2010,5(8), e12458.
146. Gorantla B, Asuthkar S, Rao JS, Patel J, Gondi CS. Suppression of the uPAR-uPA System Retards Angiogenesis, Invasion and in vivo Tumor Development in Pancreatic Cancer Cells. Mol Cancer Res 2011; 9: 377-389.
147. Malla RR, Gopinath S, Gondi CS, et al. Cathepsin B and uPAR knockdown inhibits tumor-induced angiogenesis by modulating VEGF expression in glioma. Cancer Gene Ther 2011; 18: 419-434.
148. Gondi CS, Rao JS. Therapeutic potential of siRNA-mediated targeting of urokinase plasminogen activator, its receptor, and matrix metalloproteinases. Methods Mol Biol 2009; 487: 267-281.
149. Lips DJ, Koebrugge B, Liefers GJ, et al. The influence of micrometastases on prognosis and survival in stage I-II colon cancer patients: the EnRoute+ Study. BMC Surg 2011 May 11,11(1), 11.
150. Mieog JS, Hutteman M, Van der Vorst JR, et al. Image-guided tumor resection using real-time near-infrared fluorescence in a syngeneic rat model of primary breast cancer. Breast Cancer Res Treat 2010 Sep 7; Epub ahead of print.
151. van der Vorst JR, Hutteman M, Mieog JS, et al. Near-Infrared Fluorescence Imaging of Liver Metastases in Rats using Indocyanine Green. J Surg Res 2011 Feb 2; Epub ahead of print.
152. Hutteman M, Mieog JS, Van der Vorst JR, et al. Intraoperative near-infrared fluorescence imaging of colorectal metastases targeting integrin alpha(v)beta(3) expression in a syngeneic rat model. Eur J Surg Oncol 2011; 37: 252-257.
153. Schaafsma BE, Mieog JS, Hutteman M, et al. The clinical use of indocyanine green as a near-infrared fluorescent contrast agent for image-guided oncologic surgery. J Surg Oncol 2011 Apr 14; Epub ahead of print.
154. Thakur ML. Genomic biomarkers for molecular imaging: predicting the future. Semin Nucl Med 2009: 39: 236-246.
155. Frangioni JV. New technologies for human cancer imaging. J Clin Oncol 2008; 26: 4012-4021.
156. Allgayer H. Molecular regulation of an invasion-related molecule-- options for tumour staging and clinical strategies. Eur J Cancer 2006; 42: 811-819.
157. del Vecchio S, Stoppelli MP, Carriero MV, et al. In vitro receptor imaging for characterization of human solid tumors. Nucl Med Biol 1994; 21: 771-774.
158. Heiss MM, Allgayer H, Gruetzner KU, 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: 1035-1039.
159. Hong SI, Park IC, Son YS, et al. Expression of urokinase-type plasminogen activator, its receptor, and its inhibitor in gastric adenocarcinoma tissues. J Korean Med Sci 1996; 11: 33-37.
160. van Trappen PO, Pepper MS. Lymphatic dissemination of tumour cells and the formation of micrometastases. Lancet Oncol 2002; 3: 44-52.
161. Yang Y, Adelstein SJ, Kassis AI. General approach to identifying potential targets for cancer imaging by integrated bioinformatics analysis of publicly available genomic profiles. Mol Imaging 2011; 10: 123-134.
162. Myöhänen HT, Stephens RW, Hedman K, et al. Distribution and lateral mobility of the urokinase-receptor complex at the cell surface. J Histochem Cytochem 1993; 41: 1291-1301.
163. Degryse B, Sier CF, Resnati M, Conese M, Blasi F. PAI-1 inhibits urokinase-induced chemotaxis by internalizing the urokinase receptor. FEBS Lett 2001; 505: 249-254.
164. Li ZB, Niu G, Wang H, et al. Imaging of urokinase-type plasminogen activator receptor expression using a 64Cu-labeled linear peptide antagonist by microPET. Clin Cancer Res 2008; 14: 4758-4766.
165. Liu DJ, Overbey D, Watkinson L, Giblin MF. Synthesis and Characterization of an In-111-Labeled Peptide for the in Vivo Localization of Human Cancers Expressing the Urokinase-Type Plasminogen Activator Receptor (uPAR). Bioconjugate Chemistry 2009; 20: 888-894.
166. Yang L, Peng XH, Wang YA, et al. Receptor-targeted nanoparticles for in vivo imaging of breast cancer. Clin Cancer Res 2009; 15: 4722-4732.
167. Yang L, Mao H, Cao Z, et al. Molecular imaging of pancreatic cancer in an animal model using targeted multifunctional nanoparticles. Gastroenterology 2009; 136: 1514-1525.
168. Malik R, Qian S, Law B. Design and synthesis of a near-infrared fluorescent nanofiber precursor for detecting cell-secreted urokinase activity. Anal Biochem 2011; 412: 26-33.
169. Tchouate Gainkam LO, Caveliers V, Devoogdt N, et al. Localization, mechanism and reduction of renal retention of technetium-99m labeled epidermal growth factor receptor-specific nanobody in mice. Contrast Media Mol Imaging 2011; 6: 85-92.
170. Dullin C, Zientkowska M, Napp J, et al. Semiautomatic landmarkbased two-dimensional-three-dimensional image fusion in living mice: correlation of near-infrared fluorescence imaging of Cy5.5-labeled antibodies with flat-panel volume computed tomography. Mol Imaging 2009; 8: 2-14.
171. Llinas P, le Du MH, Gardsvoll H, et al. Crystal structure of the human urokinase plasminogen activator receptor bound to an antagonist peptide. EMBO J 2005; 24: 1655-1663.
172. McGarvey TW, Kariko K, Barnathan ES, Thomas J, Malkowicz SB. The expression of urokinase-related genes in superficial and invasive transitional cell carcinoma. Int J Oncol 1998; 12: 175-180.
173. Nakanishi K, Kawai T, Torikata C, Aurues T, Ikeda T. Urokinasetype plasminogen activator, its inhibitor, and its receptor in patients with upper urinary tract carcinoma. Cancer 1998; 82: 724-732.
174. Champelovier P, Boucard N, Levacher G, Simon A, Seigneurin D, Praloran V. Plasminogen- and colony-stimulating factor-1- associated markers in bladder carcinoma: diagnostic value of urokinase plasminogen activator receptor and plasminogen activator inhibitor type-2 using immunocytochemical analysis. Urol Res 2002; 30: 301-309.
175. Seddighzadeh M, Steineck G, Larsson P, et al. Expression of UPA and UPAR is associated with the clinical course of urinary bladder neoplasms. Int J Cancer 2002; 99: 721-726.
176. Shariat SF, Monoski MA, Andrews B, Wheeler TM, Lerner SP, Slawin KM. Association of plasma urokinase-type plasminogen activator and its receptor with clinical outcome in patients undergoing radical cystectomy for transitional cell carcinoma of the bladder. Urology 2003; 61: 1053-1058.
177. Bhuvarahamurthy V, Schroeder J, Denkert C, et al. In situ gene expression of urokinase-type plasminogen activator and its receptor in transitional cell carcinoma of the human bladder. Oncol Rep 2004; 12: 909-913.
178. El-Kott AF, Khalil AM, El-Kenawy A. Immunohistochemical expressions of uPA and its receptor uPAR and their prognostic significant in urinary bladder carcinoma. Int Urol Nephrol 2004; 36: 417-423.
179. Vivani C, Magi S, Mazzucchelli R, et al. Immunohistochemical evaluation of urokinase plasminogen activator receptor in noninvasive and early invasive urothelial papillary neoplasia. Anal Quant Cytol Histol 2004; 26: 15-21.
180. Bianchi E, Cohen RL, Thor AT, et al. The urokinase receptor is expressed in invasive breast cancer but not in normal breast tissue. Cancer Res 1994; 54: 861-866.
181. Carriero MV, Franco P, Del Vecchio S, et al. Tissue distribution of soluble and receptor-bound urokinase in human breast cancer using a panel of monoclonal antibodies. Cancer Res 1994; 54: 5445-5454.
182. Duggan C, Maguire T, McDermott E, O'Higgins N, Fennelly JJ, Duffy MJ. Urokinase plasminogen activator and urokinase plasminogen activator receptor in breast cancer. Int J Cancer 1995; 61: 597-600.
183. Grøndahl-Hansen J, Peters HA, Van Putten WL, et al. Prognostic significance of the receptor for urokinase plasminogen activator in breast cancer. Clin Cancer Res 1995; 1: 1079-1087.
184. Costantini V, Sidoni A, Deveglia R, et al. Combined overexpression of urokinase, urokinase receptor, and plasminogen activator inhibitor-1 is associated with breast cancer progression: an immunohistochemical comparison of normal, benign, and malignant breast tissues. Cancer 1996; 77: 1079-1088.
185. Kim SJ, Shiba E, Taguchi T, et al. Urokinase type plasminogen activator receptor is a novel prognostic factor in breast cancer. Anticancer Res 1997; 17: 1373-1378.
186. Kennedy S, Duffy MJ, Duggan C, Barnes C, Rafferty R, Kramer MD. Semi-quantitation of urokinase plasminogen activator and its receptor in breast carcinomas by immunocytochemistry. Br J Cancer 1998; 77: 1638-1641.
187. Hildenbrand R, Glienke W, Magdolen V, Graeff H, Stutte HJ, Schmitt M. Urokinase receptor localization in breast cancer and benign lesions assessed by in situ hybridization and immunohistochemistry. Histochem Cell Biol 1998; 110: 27-32.
188. Dublin E, Hanby A, Patel NK, Liebman R, Barnes D. Immunohistochemical expression of uPA, uPAR, and PAI-1 in breast carcinoma. Fibroblastic expression has strong associations with tumor pathology. Am J Pathol 2000; 157: 1219-1227.
189. Fisher JL, Field CL, Zhou H, Harris TL, Henderson MA, Choong PF. Urokinase plasminogen activator system gene expression is increased in human breast carcinoma and its bone metastases-a comparison of normal breast tissue, non-invasive and invasive carcinoma and osseous metastases. Breast Cancer Res Treat 2000; 61: 1-12.
190. Gong SJ, Rha SY, Chung HC, et al. Tissue urokinase-type plasminogen activator receptor levels in breast cancer. Int J Mol Med 2000; 6: 301-305.
191. Guyton DP, Evans DM, Sloan-Stakleff KD. Urokinase Plasminogen Activator Receptor (uPAR): A Potential Indicator of Invasion for In Situ Breast Cancer. Breast J 2000; 6: 130-136.
192. Meijer-Van Gelder ME, Look MP, Bolt-de Vries J, Peters HA, Klijn JG, Foekens JA. Clinical relevance of biologic factors in male breast cancer. Breast Cancer Res Treat 2001; 68: 249-260.
193. Pacheco MM, Nishimoto IN, Mourao NM, Mantovani EB, Brentani MM. Prognostic significance of the combined expression of matrix metalloproteinase-9, urokinase type plasminogen activator and its receptor in breast cancer as measured by Northern blot analysis. Int J Biol Markers 2001; 16: 62-68.
194. Riisbro R, Christensen IJ, Piironen T, 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: 1132-1141.
195. Giannopoulou I, Mylona E, Kapranou A, et al. The prognostic value of the topographic distribution of uPAR expression in invasive breast carcinomas. Cancer Lett 2007; 246: 262-267.
196. Hurd TC, Sait S, Kohga S, et al. Plasminogen activator system ocalization in 60 cases of ductal carcinoma in situ. Ann Surg Oncol 2007; 14: 3117-3124.
197. Hildenbrand R, Schaaf A. The urokinase-system in tumor tissue stroma of the breast and breast cancer cell invasion. Int J Oncol 2009; 34: 15-23.
198. Kotzsch M, Bernt K, Friedrich K, et al. Prognostic relevance of tumour cell-associated uPAR expression in invasive ductal breast carcinoma. Histopathology 2010; 57: 461-471.
199. Yamamoto M, Sawaya R, Mohanam S, et al. Expression and localization of urokinase-type plasminogen activator receptor in human gliomas. Cancer Res 1994; 54: 5016-5020.
200. Yamamoto M, Ikeda K, Ohshima K, Tsugu H, Kimura H, Tomonaga M. Expression and cellular localization of low-density lipoprotein receptor-related protein/alpha 2-macroglobulin receptor in human glioblastoma in vivo. Brain Tumor Pathol 1998; 15: 23-30.
201. Garcia-Monco JC, Coleman JL, Benach JL. Soluble urokinase receptor (uPAR, CD 87) is present in serum and cerebrospinal fluid in patients with neurologic diseases. J Neuroimmunol 2002; 129: 216-223.
202. Knappe UJ, Hagel C, Lisboa BW, Wilczak W, Ludecke DK, Saeger W. Expression of serine proteases and metalloproteinases in human pituitary adenomas and anterior pituitary lobe tissue. Acta Neuropathol 2003; 106: 471-478.
203. Salajegheh M, Rudnicki A, Smith TW. Expression of urokinasetype plasminogen activator receptor (uPAR) in primary central nervous system neoplasms. Appl Immunohistochem Mol Morphol 2005; 13: 184-189.
204. Abe J, Urano T, Konno H, et al. Larger and more invasive colorectal carcinoma contains larger amounts of plasminogen activator inhibitor type 1 and its relative ratio over urokinase receptor correlates well with tumor size. Cancer 1999; 86: 2602-2611.
205. Stephens RW, Nielsen HJ, Christensen IJ, et al. Plasma urokinase receptor levels in patients with colorectal cancer: relationship to prognosis. J Natl Cancer Inst 1999; 91: 869-874.
206. Saito K, Takeha S, Shiba K, et al. Clinicopathologic significance of urokinase receptor- and MMP-9- positive stromal cells in human colorectal cancer: functional multiplicity of matrix degradation on hematogenous metastasis. Int J Cancer 2000; 86: 24-29.
207. Yang JL, Seetoo D, Wang Y, et al. Urokinase-type plasminogen activator and its receptor in colorectal cancer: independent prognostic factors of metastasis and cancer- specific survival and potential therapeutic targets. Int J Cancer 2000; 89: 431-439.
208. Fernebro E, Madsen RR, Fernö M, et al. Prognostic importance of the soluble plasminogen activator receptor, suPAR, in plasma from rectal cancer patients. Eur J Cancer 2001; 37: 486-491.
209. Konno H, Abe J, Kaneko T, 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: 516-523.
210. Baker EA, Leaper DJ. The plasminogen activator and matrix metalloproteinase systems in colorectal cancer. relationship to tumour pathology. Eur J Cancer 2003; 39: 981-988.
211. Seetoo DQ, Crowe PJ, Russell PJ, Yang JL. Quantitative expression of protein markers of plasminogen activation system in prognosis of colorectal cancer. J Surg Oncol 2003; 82: 184-193.
212. Kim TD, Song KS, Li G, et al. Activity and expression of urokinase-type plasminogen activator and matrix metalloproteinases in human colorectal cancer. BMC Cancer 2006; 6: 211.
213. Kaneko I, Tanaka S, Oka S, et al. Immunohistochemical molecular markers as predictors of curability of endoscopically resected submucosal colorectal cancer. World J Gastroenterol 2007; 13: 3829-3835.
214. Lomholt AF, Høyer-Hansen G, Nielsen HJ, Christensen IJ. Intact and cleaved forms of the urokinase receptor enhance discrimination of cancer from non-malignant conditions in patients presenting with symptoms related to colorectal cancer. Br J Cancer 2009; 101: 992-997.
215. Lomholt AF, Christensen IJ, Høyer-Hansen G, Nielsen HJ. Prognostic value of intact and cleaved forms of the urokinase plasminogen activator receptor in a retrospective study of 518 colorectal cancer patients. Acta Oncol 2010; 49: 805-811.
216. Foca C, Rice GE, Quinn MA, Moses EK. Identification and partial characterization of differentially expressed mRNAs in normal human endometria and endometrial carcinomas by differential display RT-PCR. Mol Hum Reprod 2000; 6: 712-718.
217. Tecimer C, Doering DL, Goldsmith LJ, Meyer JS, Abdulhay G, Wittliff JL. Clinical relevance of urokinase-type plasminogen activator, its receptor, and its inhibitor type 1 in endometrial cancer. Gynecol Oncol 2001; 80: 48-55.
218. Memarzadeh S, Kozak KR, Chang L, et al. Urokinase plasminogen activator receptor: Prognostic biomarker for endometrial cancer. Proc Natl Acad Sci U S A 2002; 99: 10647-10652.
219. Nordengren J, Fredstorp LM, Bendahl PO, et al. High tumor tissue concentration of plasminogen activator inhibitor 2 (PAI-2) is an independent marker for shorter progression-free survival in patients with early stage endometrial cancer. Int J Cancer 2002; 97: 379-385.
220. Hewin DF, Savage PB, Alderson D, Vipond MN. Plasminogen activators in oesophageal carcinoma. Br J Surg 1996; 83: 1152-1155.
221. Shiomi H, Eguchi Y, Tani T, Kodama M, Hattori T. Cellular distribution and clinical value of urokinase-type plasminogen activator, its receptor, and plasminogen activator inhibitor-2 in esophageal squamous cell carcinoma. Am J Pathol 2000; 156: 567-575.
222. Swiercz R, Wolfe JD, Zaher A, Jankun J. Expression of the plasminogen activation system in kidney cancer correlates with its aggressive phenotype. Clin Cancer Res 1998; 4: 869-877.
223. Bhuvarahamurthy V, Schroeder J, Kristiansen G, et al. Differential gene expression of urokinase-type plasminogen activator and its receptor in human renal cell carcinoma. Oncol Rep 2005; 14: 777-782.
224. Ohba K, Miyata Y, Kanda S, Koga S, Hayashi T, Kanetake H. Expression of urokinase-type plasminogen activator, urokinasetype plasminogen activator receptor and plasminogen activator inhibitors in patients with renal cell carcinoma: correlation with tumor associated macrophage and prognosis. J Urol 2005: 174: 461-465.
225. Plesner T, Ralfkiaer E, Wittrup M, 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: 835-841.
226. Lopez-Pedrera C, Jardi M, Del Mar MM, et al. Tissue factor (TF) and urokinase plasminogen activator receptor (uPAR) and bleeding complications in leukemic patients. Thromb Haemost 1997; 77: 62-70.
227. Lanza F, Castoldi GL, Castagnari B, et al. Expression and functional role of urokinase-type plasminogen activator receptor in normal and acute leukaemic cells. Br J Haematol 1998; 103: 110-123.
228. Mustjoki S, Alitalo R, Stephens RW, Vaheri A. Blast cell-surface and plasma soluble urokinase receptor in acute leukemia patients: relationship to classification and response to therapy. Thromb Haemost 1999; 81: 705-710.
229. Scherrer A, Wohlwend A, Kruithof EK, Vassalli JD, Sappino AP. Plasminogen activation in human acute leukaemias. Br J Haematol 1999; 105: 920-927.
230. Aref S, El-Sherbiny M, Mabed M, Menessy A, El-Refaei M. Urokinase plasminogen activator receptor and soluble matrix metalloproteinase-9 in acute myeloid leukemia patients: a possible relation to disease invasion. Hematology 2003; 8: 385-391.
231. Graf M, Reif S, Hecht K, Pelka-Fleischer R, Pfister K, Schmetzer H. High expression of urokinase plasminogen activator receptor (uPA-R) in acute myeloid leukemia (AML) is associated with worse prognosis. Am J Hematol 2005; 79: 26-35.
232. Morita Y, Hayashi Y, Wang Y, et al. Expression of urokinase-type plasminogen activator receptor in hepatocellular carcinoma. Hepatology 1997; 25: 856-861.
233. Akahane T, Ishii M, Ohtani H, Nagura H, Toyota T. Stromal expression of urokinase-type plasminogen activator receptor (uPAR) is associated with invasive growth in primary liver cancer. Liver 1998; 18: 414-419.
234. de Petro G, Tavian D, Copeta A, Portolani N, Giulini SM, Barlati S. Expression of urokinase-type plasminogen activator (u-PA), u- PA receptor, and tissue-type PA messenger RNAs in human hepatocellular carcinoma. Cancer Res 1998; 58: 2234-2239.
235. 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: 190-195.
236. Zheng Q, Tang ZY, Xue Q, Shi DR, Song HY, Tang HB. Invasion and metastasis of hepatocellular carcinoma in relation to urokinasetype plasminogen activator, its receptor and inhibitor. J Cancer Res Clin Oncol 2000; 126: 641-646.
237. Zhou L, Hayashi Y, Itoh T, Wang W, Rui J, Itoh H. Expression of urokinase-type plasminogen activator, urokinase-type plasminogen activator receptor, and plasminogen activator inhibitor-1 and -2 in hepatocellular carcinoma. Pathol Int 2000; 50: 392-397.
238. Schoedel KE, Tyner VZ, Kim TH, Michalopoulos GK, Mars WM. HGF, MET, and matrix-related proteases in hepatocellular carcinoma, fibrolamellar variant, cirrhotic and normal liver. Mod Pathol 2003; 16: 14-21.
239. Pedersen H, Brünner N, Francis D, 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: 4671-4675.
240. Morita S, Sato A, Hayakawa H, et al. 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 1998; 78: 286-292.
241. Ferrier CM, De Witte HH, Straatman H, et al. Comparison of immunohistochemistry with immunoassay (ELISA) for the detection of components of the plasminogen activation system in human tumour tissue. Br J Cancer 1999; 79: 1534-1541.
242. Volm M, Mattern J, Koomagi R. Relationship of urokinase and urokinase receptor in non-small cell lung cancer to proliferation, angiogenesis, metastasis and patient survival. Oncol Rep 1999; 6: 611-615.
243. Jumper C, Cobos E, Lox C. The circulating urokinase plasminogen activator (uPA) and its soluble receptor (suPAR) are not upregulated by the circulating P105 fraction of the HER-2/neu protooncogene: in vivo evidence from patients with advanced non-small cell lung cancer (NSCLC). Anticancer Res 2002; 22: 2073-2076.
244. Montuori N, Mattiello A, Mancini A, et al. Urokinase-mediated posttranscriptional regulation of urokinase-receptor expression in non small cell lung carcinoma. Int J Cancer 2003; 105: 353-360.
245. Cobos E, Jumper C, Lox C. Pretreatment determination of the serum urokinase plasminogen activator and its soluble receptor in advanced small-cell lung cancer or non-small-cell lung cancer. Clin Appl Thromb Hemost 2003; 9: 241-246.
246. Almasi CE, Høyer-Hansen G, Christensen IJ, Danø 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: 349-355.
247. de Vries TJ, Quax PH, Denijn M, et al. Plasminogen activators, their inhibitors, and urokinase receptor emerge in late stages of melanocytic tumor progression. Am J Pathol 1994; 144: 70-81.
248. Weidle UH, Wollisch E, Rønne E, et al. Studies on functional and structural role of urokinase receptor and other components of the plasminogen activation system in malignancy. Ann Biol Clin (Paris); 52: 775-782.
249. de Vries TJ, Mooy CM, van Balken MR, et al. Components of the plasminogen activation system in uveal melanoma--a clinicopathological study. J Pathol 1995; 175: 59-67.
250. Maguire T, Chin D, Soutar D, Duffy MJ. Low levels of urokinase plasminogen activator components in basal cell carcinoma of the skin. Int J Cancer 2000; 85: 457-459.
251. Rømer J, Pyke C, Lund LR, Ralfkiaer E, Danø K. Cancer cell expression of urokinase-type plasminogen activator receptor mRNA in squamous cell carcinomas of the skin. J Invest Dermatol 2001; 116: 353-358.
252. Ferrier CM, van Geloof WL, Straatman H, van de Molengraft FJ, van Muijen GN, Ruiter DJ. Spitz naevi may express components of the plasminogen activation system. J Pathol 2002; 198: 92-99.
253. Nozaki S, Endo Y, Kawashiri S, et al. Immunohistochemical localization of a urokinase-type plasminogen activator system in squamous cell carcinoma of the oral cavity: association with mode of invasion and lymph node metastasis. Oral Oncol 1998; 34: 58-62.
254. Lindberg P, Larsson A, Nielsen BS. Expression of plasminogen activator inhibitor-1, urokinase receptor and laminin gamma-2 chain is an early coordinated event in incipient oral squamous cell carcinoma. Int J Cancer 2006; 118: 2948-2956.
255. Baker EA, Leaper DJ, Hayter JP, Dickenson AJ. Plasminogen activator system in oral squamous cell carcinoma. Br J Oral Maxillofac Surg 2007; 45: 623-627.
256. Kumamoto H, Ooya K. Immunohistochemical detection of uPA, uPAR, PAI-1, and maspin in ameloblastic tumors. J Oral Pathol Med 2007; 36: 488-494.
257. Chambers SK, Gertz RE, Jr., Ivins CM, Kacinski BM. The significance of urokinase- type plasminogen activator, its inhibitors, and its receptor in ascites of patients with epithelial ovarian cancer. Cancer 1995; 75: 1627-1633.
258. Chambers SK, Ivins CM, Carcangiu ML. Urokinase-type plasminogen activator in epithelial ovarian cancer - A poor prognostic factor, associated with advanced stage. Int J Gynecol Cancer 1998; 8: 242-250.
259. Cantero D, Friess H, Deflorin J, et al. Enhanced expression of urokinase plasminogen activator and its receptor in pancreatic carcinoma. Br J Cancer 1997; 75: 388-395.
260. Harvey SR, Hurd TC, Markus G, et al. Evaluation of urinary plasminogen activator, its receptor, matrix metalloproteinase-9, and von Willebrand factor in pancreatic cancer. Clin Cancer Res 2003; 9: 4935-4943.
261. Xue A, Scarlett CJ, Jackson CJ, Allen BJ, Smith RC. Prognostic significance of growth factors and the urokinase-type plasminogen activator system in pancreatic ductal adenocarcinoma. Pancreas 2008; 36: 160-167.
262. Wood M, Fudge K, Mohler JL, et al. In situ hybridization studies of metalloproteinases 2 and 9 and TIMP-1 and TIMP-2 expression in human prostate cancer. Clin Exp Metastasis 1997; 15: 246-258.
263. Miyake H, Hara I, Yamanaka K, Arakawa S, Kamidono S. 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 1999; 14: 535-541.
264. 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: 123-129.
265. McCabe NP, Angwafo FF, Zaher A, Selman SH, Kouinche A, Jankun J. Expression of soluble urokinase plasminogen activator receptor may be related to outcome in prostate cancer patients. Oncol Rep 2000; 7: 879-882.
266. Gavrilov D, Kenzior O, Evans M, Calaluce R, Folk WR. Expression of urokinase plasminogen activator and receptor in conjunction with the ets family and AP-1 complex transcription factors in high grade prostate cancers. Eur J Cancer 2001; 37: 1033-1040.
267. Riddick AC, Shukla CJ, Pennington CJ, et al. Identification of degradome components associated with prostate cancer progression by expression analysis of human prostatic tissues. Br J Cancer 2005; 92: 2171-2180.
268. Usher PA, Thomsen OF, Iversen P, et al. Expression of urokinase plasminogen activator, its receptor and type-1 inhibitor in malignant and benign prostate tissue. Int J Cancer 2005; 113: 870-880.
269. Cozzi PJ, Wang J, Delprado W, et al. Evaluation of urokinase plasminogen activator and its receptor in different grades of human prostate cancer. Hum Pathol 2006; 37: 1442-1451.
270. Shariat SF, Roehrborn CG, McConnell JD, et al. Association of the circulating levels of the urokinase system of plasminogen activation with the presence of prostate cancer and invasion, progression, and metastasis. J Clin Oncol 2007; 25: 349-355.
271. Steuber T, Vickers A, Haese A, et al. Free PSA isoforms and intact and cleaved forms of urokinase plasminogen activator receptor in serum improve selection of patients for prostate cancer biopsy. Int J Cancer 2007; 120: 1499-1504.
272. Gupta A, Lotan Y, Ashfaq R, et al. Predictive value of the differential expression of the urokinase plasminogen activation axis in radical prostatectomy patients. Eur Urol 2009; 55: 1124-1133.
273. Kogianni G, Walker MM, Waxman J, Sturge J. Endo180 expression with cofunctional partners MT1-MMP and uPAR-uPA is correlated with prostate cancer progression. Eur J Cancer 2009; 45: 685-693.
274. Kumano M, Miyake H, Muramaki M, Furukawa J, Takenaka A, Fujisawa M. Expression of urokinase-type plasminogen activator system in prostate cancer: correlation with clinicopathological outcomes in patients undergoing radical prostatectomy. Urol Oncol 2009; 27: 180-186.
275. Thomas C, Wiesner C, Melchior SW, et al. Urokinaseplasminogen- activator receptor expression in disseminated tumour cells in the bone marrow and peripheral blood of patients with clinically localized prostate cancer. BJU Int 2009; 104: 29-34.
276. Kjellman A, Akre O, Gustafsson O, et al. Soluble urokinase plasminogen activator receptor as a prognostic marker in men participating in prostate cancer screening. J Intern Med 2011; 269: 299-305.
277. Taubert H, Wurl P, Greither T, et al. Co-detection of members of the urokinase plasminogen activator system in tumour tissue and serum correlates with a poor prognosis for soft-tissue sarcoma patients. Br J Cancer 2010; 102: 731-737.
278. Ganesh S, Sier CF, Heerding MM, et al. Prognostic value of the plasminogen activation system in patients with gastric carcinoma. Cancer 1996; 77: 1035-1043.
279. Allgayer H, Babic R, Grutzner KU, et al. An immunohistochemical assessment of cathepsin D in gastric carcinoma: its impact on clinical prognosis. Cancer 1997 Jul 15,80(2), 179-187.
280. Plebani M, Herszenyi L, Carraro P, et al. Urokinase-type plasminogen activator receptor in gastric cancer: tissue expression and prognostic role. Clin Exp Metastasis 1997 Jul,15(4), 418-425.
281. Allgayer H, Babic R, Grutzner KU, et al. Tumor-associated proteases and inhibitors in gastric cancer: analysis of prognostic impact and individual risk protease patterns. Clin Exp Metastasis 1998; 16: 62-73.
282. Kawasaki K, Hayashi Y, Wang Y, et al. Expression of urokinasetype plasminogen activator receptor and plasminogen activator inhibitor-1 in gastric cancer. J Gastroenterol Hepatol 1998; 13: 936-944.
283. Ho CH, Chao Y, Lee SD, Chau WK, Wu CW, Liu SM. Diagnostic and prognostic values of plasma levels of fibrinolytic markers in gastric cancer. Thromb Res 1998; 91: 23-27.
284. Taniguchi K, Yonemura Y, Nojima N, et al. The relation between the growth patterns of gastric carcinoma and the expression of hepatocyte growth factor receptor (c-met), autocrine motility factor receptor, and urokinase-type plasminogen activator receptor. Cancer 1998; 82: 2112-2122.
285. Migita T, Sato E, Saito K, et al. Differing expression of MMPs-1 and -9 and urokinase receptor between diffuse- and intestinal-type gastric carcinoma. Int J Cancer 1999; 84: 74-79.
286. Heiss MM, Simon EH, Beyer BC, 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: 2005-2016.
287. Kaneko T, Konno H, Baba M, Tanaka T, Nakamura S. Urokinasetype plasminogen activator expression correlates with tumor angiogenesis and poor outcome in gastric cancer. Cancer Sci 2003; 94: 43-49.
288. Lee KH, Bae SH, Lee JL, et al. Relationship between urokinasetype plasminogen receptor, interleukin-8 gene expression and clinicopathological features in gastric cancer. Oncology 2004; 66: 210-217.
289. Beyer BC, Heiss MM, Simon EH, et al. Urokinase system expression in gastric carcinoma: prognostic impact in an independent patient series and first evidence of predictive value in preoperative biopsy and intestinal metaplasia specimens. Cancer 2006; 106: 1026-1035.
290. Zhang L, Zhao ZS, Ru GQ, Ma J. Correlative studies on uPA mRNA and uPAR mRNA expression with vascular endothelial growth factor, microvessel density, progression and survival time of patients with gastric cancer. World J Gastroenterol 2006; 12: 3970-3976.
291. Kita Y, Fukagawa T, Mimori K, et al. Expression of uPAR mRNA in peripheral blood is a favourite marker for metastasis in gastric cancer cases. Br J Cancer 2009; 100: 153-159.
292. Alpizar-Alpizar W, Nielsen BS, Sierra R, et al. Urokinase plasminogen activator receptor is expressed in invasive cells in gastric carcinomas from high- and low-risk countries. Int J Cancer 2010; 126: 405-415.
293. Ulisse S, Baldini E, Mottolese M, et al. Increased expression of urokinase plasminogen activator and its cognate receptor in human seminomas. BMC Cancer 2010;10: 151.
294. Kim SJ, Shiba E, Taguchi T, et al. UPA receptor expression in benign and malignant thyroid tumors. Anticancer Res 2002; 22: 387-393.
295. Ulisse S, Baldini E, Toller M, et al. Differential expression of the components of the plasminogen activating system in human thyroid tumour derived cell lines and papillary carcinomas. Eur J Cancer 2006; 42: 2631-2638.
296. Buergy D, Weber T, Maurer GD, et al. Urokinase receptor, MMP-1 and MMP-9 are markers to differentiate prognosis, adenoma and carcinoma in thyroid malignancies. Int J Cancer 2009; 125: 894-901.
297. Nowicki TS, Kummer NT, Iacob C, et al. Inhibition of uPAR and uPA reduces invasion in papillary thyroid carcinoma cells. Laryngoscope 2010; 120: 1383-1390.
298. Ulisse S, Baldini E, Sorrenti S, et al. High expression of the urokinase plasminogen activator and its cognate receptor associates with advanced stages and reduced disease-free interval in papillary thyroid carcinoma. J Clin Endocrinol Metab 2011; 96: 504-508.