Protease-activated receptors – biology and role in cancer

COMMENTARY ON THE LAW

Protease-activated receptors – biology and role in cancer

Dominika Hempel 1 , Ewa Sierko 1 , Marek Z. Wojtukiewicz 1

1. Klinika Onkologii Uniwersytetu Medycznego w Białymstoku; Białostockie Centrum Onkologii

Published: 2016-07-07
DOI: 10.5604/17322693.1209209
GICID: 01.3001.0009.6855
Available language versions: en pl
Issue: Postepy Hig Med Dosw 2016; 70 : 775-786

 

Abstract

The fact that blood coagulation disorders may accompany malignant disease is well established. However, many studies have shown that components of the haemostatic system may also elicit signaling leading to cancer developement and progression. The potential mechanism by which coagulation factors play a role in cancer invasion is not completely understood, but one hypothesis is that protease-activated receptors (PARs) play a prominent role. PARs are transmembrane G-protein-coupled receptors (GPCRs) that are activated by a unique proteolytic mechanism. They have important functions in haemostasis and inflammation but may also be implicated in cancer cell progression. Thrombin, tissue factor (TF) and matrix metalloproteinases (MMPs) are the main activators of these receptors. The mechanism of persistent activation of PARs was also described in cancer cells. Here, we discuss the physiological and pathological role of PARs with a particular focus on PARs’ contribution to cancer biology. We also present therapeutic options tailored specifically to inhibition of PAR-induced signalling in cancer patients.

References

  • 1. Agarwal A., Covic L., Sevigny L.M., Kaneider N.C., Lazarides K.,Azabdaftari G., Sharifi S., Kuliopulos A.: Targeting a metalloproteasePAR-1signaling system with cell-penetrating pepducins inhibits angiogenesis,ascites, and progression of ovarian cancer. Mol. CancerTher., 2008; 7: 2746-2757
    Google Scholar
  • 2. Al-Eryani K., Cheng J., Abé T., Maruyama S., Yamazaki M., BabkairH., Essa A., Saku T.: Protease-activated receptor 2 modulates proliferationand invasion of oral squamous cell carcinoma cells. Hum.Pathol., 2015; 46: 991-999
    Google Scholar
  • 3. Arora P., Cuevas B.D., Russo A., Johnson G.L., Trejo J.: Persistent transactivationof EGFR and ErbB2/HER2 by protease activated receptor-1promotes breast carcinoma cell invasion. Oncogene, 2008; 27: 4434-4445
    Google Scholar
  • 4. Arora P., Ricks T.K., Trejo J.: Protease-activated receptor signalling,endocytic sorting and dysregulation in cancer. J. Cell. Sci., 2007;120: 921-928
    Google Scholar
  • 5. Austin K.M., Covic L., Kuliopulos A.: Matrix metalloproteases andPAR1 activation. Blood, 2013; 121: 431-439
    Google Scholar
  • 6. Bao Y., Hou W., Yang L., Kong X., Du M., Zheng H., Gao Y., Hua B.:Protease-activated receptor 2 antagonist potentiates analgesic effectsof systemic morphine in a rat model of bone cancer pain. Reg.Anesth. Pain. Med., 2015; 40: 158-165
    Google Scholar
  • 7. Bar-Shavit R., Turm H., Salah Z., Maoz M., Cohen I., Weiss E.,Uziely B., Grisaru-Granovsky S.: PAR-1 plays a role in epithelial malignancies:transcriptional regulation and novel signaling pathway.IUBMB Life., 2011; 63: 397-402
    Google Scholar
  • 8. Bäumer N., Krause A., Köhler G., Lettermann S., Evers G., HascherA., Bäumer S., Berdel W.E., Müller-Tidow C., Tickenbrock L.: Proteinase-activatedreceptor 1 (PAR1) regulates leukemic stem cell functions.PLoS One, 2014; 9: e94993
    Google Scholar
  • 9. Boire A., Covic L., Agarwal A., Jacques S., Sherifi S., Kuliopulos A.:PAR-1 is a matrix metalloprotease-1 receptor that promotes invasionand tumorigenesis of breast cancer cells. Cell, 2005; 120: 303-313
    Google Scholar
  • 10. Booden M.A., Eckert L.B., Der C.J., Trejo J.: Persistent signalingby dysregulated thrombin receptor trafficking promotes breast carcinomacell invasion. Mol. Cell. Biol., 2004; 24: 1990-1999
    Google Scholar
  • 11. Borensztajn K.S., Bijlsma M.F., Groot A.P., Brüggemann L.W., VersteegH.H., Reitsma P.H., Peppelenbosch M.P., Spek C.A.: Coagulationfactor Xa drives tumor cells into apoptosis through BH3-only proteinBim up-regulation. Exp. Cell. Res., 2007; 313: 2622-2633
    Google Scholar
  • 12. Camerer E., Huang W., Coughlin S.R.: Tissue factor- and factorX-dependent activation of protease-activated receptor 2 by factorVIIa. Proc. Natl. Acad. Sci. USA, 2000; 97: 5255-5260
    Google Scholar
  • 13. Camerer E., Qazi A.A., Duong D.N., Cornelissen I., Advincula R.,Coughlin S.R.: Platelets, protease-activated receptors, and fibrinogenin hematogenous metastasis. Blood, 2004; 104: 397-401
    Google Scholar
  • 14. Carney D.H., Cunningham D.D.: Initiation of chick cell divisionby trypsin action at the cell surface. Nature, 1977; 268: 602-606
    Google Scholar
  • 15. Coughlin S.R.: Protease-activated receptors in hemostasis, thrombosisand vascular biology. J. Thromb. Haemost., 2005; 3: 1800-1814
    Google Scholar
  • 16. Dardik R., Savion N., Kaufmann Y. Varon D.: Thrombin promotesplatelets-mediated melanoma cell adhesion to endothelial cells underflow conditions: role of platelet glycoproteins P-selectin andGPIIb-IIIa. Br. J. Cancer, 1998; 77: 2069-2075
    Google Scholar
  • 17. DeFea K.A., Zalevsky J., Thoma M.S., Déry O., Mullins R.D., BunnettN.W.: β-arrestin-dependent endocytosis of proteinase-activatedreceptor 2 is required for intracellular targeting of activated ERK1/2.J. Cell. Biol., 2000; 148: 1267-1281
    Google Scholar
  • 18. Du X., Wang S., Lu J., Cao Y., Song N., Yang T., Dong R., Zang L.,Yang Y., Wu T., Li J.: Correlation between MMP1-PAR1 axis and clinicaloutcome of primary gallbladder carcinoma. Jpn. J. Clin. Oncol.,2011; 41: 1086-1093
    Google Scholar
  • 19. Dvorak H.F.: Tumors: wounds that do not heal. N. Engl. J. Med.,1986; 315: 1650-1659
    Google Scholar
  • 20. Esumi N., Fan D., Fidler I.J.: Inhibition of murine melanoma experimentalmetastasis by recombinant desulfatohirudin, a highlyspecific thrombin inhibitor. Cancer Res., 1991; 51: 4549-4556
    Google Scholar
  • 21. Even-Ram S.C., Maoz M., Pokroy E., Reich R., Katz B.Z., GutweinP., Altevogt P., Bar-Shavit R.: Tumor cell invasion is promoted byactivation of protease activated receptor-1 in cooperation with theαvβ5 integrin. J. Biol. Chem., 2001; 276: 10952-10962
    Google Scholar
  • 22. Even-Ram S., Uziely B., Cohen P., Grisaru-Granovsky S., Maoz M.,Ginzburg Y., Reich R., Vlodavsky I., Bar-Shavit R.: Thrombin receptoroverexpression in malignant and physiological invasion processes.Nat. Med., 1998; 4: 909-994
    Google Scholar
  • 23. Folkman J.: Angiogenesis in cancer, vascular, rheumatoid andother disease. Nat. Med., 1995; 1: 27-31
    Google Scholar
  • 24. Furie B., Furie B.C.: The molecular basis of blood coagulation.Cell, 1988; 53: 505-518
    Google Scholar
  • 25. Gieseler F., Ungefroren H., Settmacher U., Hollenberg M.D.,Kaufmann R.: Proteinase-activated receptors (PARs) – focus on receptor-receptor-interactionsand their physiological and pathophysiologicalimpact. Cell. Commun. Signal., 2013; 11: 86
    Google Scholar
  • 26. Griffin C.T., Srinivasan Y., Zheng Y.W., Huang W., Coughlin S.R.:A role for thrombin receptor signaling in endothelial cells duringembryonic development. Science, 2001; 293: 1666-1670
    Google Scholar
  • 27. Grimsey N., Lin H., Trejo J.: Endosomal signaling by proteaseactivatedreceptors. Methods Enzymol., 2014; 535: 389-401
    Google Scholar
  • 28. Gullapalli A., Wolfe B.L., Griffin C.T., Magnuson T., Trejo J.: An essentialrole for SNX1 in lysosomal sorting protease-activated receptor-1:evidence for retromer, Hrs- and Tsg101-independent functionsof sorting nexins. Mol. Biol. Cell, 2006: 17: 1228-1238
    Google Scholar
  • 29. Guo H., Liu D., Gelbard H., Cheng T., Insalaco R., Fernández J.A.,Griffin J.H., Zlokovic B.V.: Activated protein C prevents neuronalapoptosis via protease activated receptors 1 and 3. Neuron, 2004;41: 563-572
    Google Scholar
  • 30. Jaber M., Maoz M., Kancharla A., Agranovich D., Peretz T., Grisaru-GranovskyS., Uziely B., Bar-Shavit R.: Protease-activated-receptor-2affects protease-activated-receptor-1-driven breast cancer.Cell. Mol. Life Sci., 2014; 71: 2517-2533
    Google Scholar
  • 31. Koizume S., Jin M.S., Miyagi E., Hirahara F., Nakamura Y., PiaoJ.H., Asai A., Yoshida A., Tsuchiya E., Ruf W., Miyagi Y.: Activation ofcancer cell migration and invasion by ectopic synthesis of coagulationfactor VII. Cancer Res., 2006; 66: 9453-9460
    Google Scholar
  • 32. Li S.M., Jiang P., Xiang Y., Wang W.W., Zhu Y.C., Feng W.Y., LiS.D., Yu G.Y.: Protease-activated receptor (PAR)1, PAR2 and PAR4expressions in esophageal squamous cell carcinoma. DongwuxueYanjiu, 2014; 35: 420-425
    Google Scholar
  • 33. Li X., Tai H.H.: Thromboxane A2 receptor-mediated release ofmatrix metalloproteinase-1 (MMP-1) induces expression of monocytechemoattractant protein-1 (MCP-1) by activation of proteaseactivatedreceptor 2 (PAR2) in A549 human lung adenocarcinomacells. Mol. Carcinog., 2014; 53: 659-666
    Google Scholar
  • 34. Liao M., Tong P., Zhao J., Zhang Y., Li Z., Wang J., Feng X., Hu M.,Pan Y.: Prognostic value of matrix metalloproteinase-1/proteinaseactivatedreceptor-1 signaling axis in hepatocellular carcinoma.Pathol. Oncol. Res., 2012; 18: 397-403
    Google Scholar
  • 35. Lin H., Liu A.P., Smith T.H., Trejo J.: Cofactoring and dimerizationof proteinase-activated receptors. Pharmacol Rev., 2013; 65:1198-1213
    Google Scholar
  • 36. Lin H., Trejo J.: Transactivation of the PAR1-PAR2 heterodimerby thrombin elicits β-arrestin-mediated endosomal signaling. J. Biol.Chem., 2013; 288: 11203-11215
    Google Scholar
  • 37. Lin Z.M., Zhao J.X., Duan X.N., Zhang L.B., Ye J.M., Xu L., LiuY.H.: Effects of tissue factor, PAR-2 and MMP-9 expression on humanbreast cancer cell line MCF-7 invasion. Asian Pac. J. Cancer.Prev., 2014; 15: 643-646
    Google Scholar
  • 38. Martin C.B., Mahon G.M., Klinger M.B., Kay R.J., Symons M., DerC.J., Whitehead I.P.: The thrombin receptor, PAR-1, causes transformationby activation of Rho-mediated signaling pathways. Oncogene,2001; 20: 1953-1963
    Google Scholar
  • 39. McLaughlin J.N., Patterson M.M., Malik A.B.: Protease-activatedreceptor‑3 (PAR3) regulates PAR1 signaling by receptor dimerization.Proc. Natl. Acad. Sci. USA, 2007; 104: 5662-5667
    Google Scholar
  • 40. Mußbach F., Henklein P., Westermann M., Settmacher U., BöhmerF.D., Kaufmann R.: Proteinase-activated receptor 1- and 4-promotedmigration of Hep3B hepatocellular carcinoma cells dependson ROS formation and RTK transactivation. J. Cancer Res. Clin. Oncol.,2015; 141: 813-825
    Google Scholar
  • 41. Nakanishi-Matsui M., Zheng Y.W., Sulciner D.J., Weiss E.J., LudemanM.J. Coughlin S.R.: PAR3 is a cofactor for PAR4 activation bythrombin. Nature, 2000; 404: 609-613
    Google Scholar
  • 42. Nierodzik M.L., Chen K., Takeshita K., Li J.J., Huang Y.Q., FengX.S., D’Andrea M.R., Andrade-Gordon P., Karpatkin S.: Protease-activatedreceptor 1 (PAR-1) is required and rate-limiting for thrombin-enhancedexperimental pulmonary metastasis. Blood, 1998;92: 3694-3700
    Google Scholar
  • 43. Nierodzik M.L., Kajumo F., Karpatkin S.: Effect of thrombin treatmentof tumor cells on adhesion of tumor cells to platelets in vitroand tumor metastasis in vivo. Cancer Res., 1992; 52: 3267-3272
    Google Scholar
  • 44. Nierodzik M.L., Karpatkin S.: Thrombin induces tumor growth,metastasis, and angiogenesis: Evidence for a thrombin-regulateddormant tumor phenotype. Cancer Cell, 2006; 10: 355-362
    Google Scholar
  • 45. Nishibori M., Mori S., Takahashi H.K.: Physiology and pathophysiologyof proteinase-activated receptors (PARs): PAR-2-mediatedproliferation of colon cancer cell. J. Pharmacol. Sci., 2005; 97: 25-30
    Google Scholar
  • 46. Nystedt S., Emilsson K., Wahlestedt C., Sundelin J.: Molecularcloning of a potential novel proteinase activated receptor. Proc. Natl.Acad. Sci. USA, 1994; 91: 9208-9212
    Google Scholar
  • 47. Olejar T., Vetvicka D., Zadinova M., Pouckova P., Kukal J., JezekP., Matej R.: Dual role of host Par2 in a murine model of spontaneousmetastatic B16 melanoma. Anticancer Res., 2014; 34: 3511-3515
    Google Scholar
  • 48. Ossovskaya V.S., Bunnett N.W.: Protease-activated receptors: contributionto physiology and disease. Physiol Rev., 2004; 84: 579-621
    Google Scholar
  • 49. Otsuki T., Fujimoto D., Hirono Y., Goi T., Yamaguchi A.: Thrombinconducts epithelial mesenchymal transition via protease-activatedreceptor-1 in human gastric cancer. Int. J. Oncol., 2014; 45: 2287-2294
    Google Scholar
  • 50. Palumbo J.S., Kombrinck K.W., Drew A.F., Grimes T.S., Kiser J.H.,Degen J.L., Bugge T.H.: Fibrinogen is an important determinant ofthe metastatic potential of circulating tumor cells. Blood, 2000; 96:3302-3309
    Google Scholar
  • 51. Ramachandran R., Noorbakhsh F., Defea K., Hollenberg M.D.:Targeting proteinase-activated receptors: therapeutic potential andchallenges. Nat. Rev. Drug Discov., 2012; 11: 69-86
    Google Scholar
  • 52. Rasmussen U.B., Vouret-Craviari V., Jallat S., Schlesinger Y.,Pages G., Pavirani A., Lecocq J.P., Pouysségur J., Van ObberghenSchillingE.: cDNA cloning and expression of a hamster α-thrombinreceptor coupled to Ca2+ mobilization. FEBS Lett., 1991; 288: 123-128
    Google Scholar
  • 53. Rieser P.: The insulin-like action of pepsin and pepsinogen. ActaEndocrinol., 1967: 54, 375-379
    Google Scholar
  • 54. Riewald M., Petrovan R.J., Donner A., Mueller B.M., Ruf W.: Activationof endothelial cell protease activated receptor 1 by theprotein C pathway. Science, 2002; 296: 1880-1882
    Google Scholar
  • 55. Riewald M, Ruf W.: Mechanistic coupling of protease signalingand initiation of coagulation by tissue factor. Proc. Natl. Acad. Sci.USA, 2001; 98: 7742-7747
    Google Scholar
  • 56. Rydén L, Grabau D., Schaffner F., Jönsson P.E., Ruf W., BeltingM.: Evidence for tissue factor phosphorylation and its correlationwith protease-activated receptor expression and the prognosis ofprimary breast cancer. Int. J. Cancer, 2010; 126: 2330-2340
    Google Scholar
  • 57. Sánchez-Hernández P.E., Ramirez-Dueñas M.G., Albarran-SomozaB., García-Iglesias T., del Toro-Arreola A., Franco-Topete R.,Daneri-Navarro A.: Protease-activated receptor-2 (PAR-2) in cervicalcancer proliferation. Gynecol. Oncol., 2008; 108: 19-26
    Google Scholar
  • 58. Sedda S., Marafini I., Caruso R., Pallone F., Monteleone G.: Proteinaseactivated-receptors-associated signaling in the control ofgastric cancer. World J. Gastroenterol., 2014; 20: 11977-11984
    Google Scholar
  • 59. Shapiro M.J., Weiss E.J., Faruqi T.R., Coughlin S.R.: Proteaseactivatedreceptors 1 and 4 are shut off with distinct kinetics afteractivation by thrombin. J. Biol. Chem., 2000; 275: 25216-25221
    Google Scholar
  • 60. Shi K., Queiroz K.C., Roelofs J.J., van Noesel C.J., Richel D.J., SpekC.A.: Protease-activated receptor 2 suppresses lymphangiogenesisand subsequent lymph node metastasis in a murine pancreatic cancermodel. J. Pathol., 2014; 234: 398-409
    Google Scholar
  • 61. Shi X., Gangadharan B., Brass L.F., Ruf W., Mueller B.M.: Proteaseactivatedreceptors (PAR1 and PAR2) contribute to tumor cell motilityand metastasis. Mol. Cancer Res., 2004; 2: 395-402
    Google Scholar
  • 62. Sierko E., Wojtukiewicz M.Z.: Inhibition of platelet function:does it offer a chance of better cancer progression control? Semin.Thromb. Hemost., 2007; 33: 712-721
    Google Scholar
  • 63. Sierko E., Wojtukiewicz M.Z., Zimnoch L., Thorpe P.E., BrekkenR.A., Kisiel W.: Co-localization of prothrombin fragment F1+2and VEGF-R2-bound VEGF in human colon cancer. Anticancer Res.,2011; 31: 843-847
    Google Scholar
  • 64. Smorenburg S.M., Hettiarachchi R.J., Vink R., Büller H.R.: Theeffects of unfractionated heparin on survival in patients with malignancy-a systematic review. Thromb. Haemost., 1999; 82: 1600-1604
    Google Scholar
  • 65. Trejo J., Connolly A.J., Coughlin S.R.: The cloned thrombin receptoris necessary and sufficient for activation of mitogen-activatedprotein kinase and mitogenesis in mouse lung fibroblasts. Loss ofresponses in fibroblasts from receptor knockout mice. J. Biol. Chem.,1996; 271: 21536-21541
    Google Scholar
  • 66. Trousseau A.: Phlegmasia dolens. Clinique Medicale de l`HotelDieude Paris, 1865; 3: 490-515
    Google Scholar
  • 67. Tsopanoglou N.E., Maragoudakis M.E.: On the mechanism ofthrombin-induced angiogenesis: Potentiation of vascular endothelialgrowth factor activity on endothelial cells by upregulation ofits receptors. J. Biol. Chem., 1999; 274: 23969-23976
    Google Scholar
  • 68. Tsopanoglou N.E., Maragoudakis M.E.: Role of thrombin in angiogenesisand tumor progression. Semin. Thromb. Hemost., 2004; 30: 63-69
    Google Scholar
  • 69. Ünlü B., Versteeg H.H.: Effects of tumor-expressed coagulationfactors on cancer progression and venous thrombosis: is there a keyfactor? Thromb. Res., 2014; 133 (Suppl. 2): S76-S84
    Google Scholar
  • 70. Uzunoglu F.G., Kolbe J., Wikman H., Güngör C., Bohn B.A., NentwichM.F., Reeh M., König A.M., Bockhorn M., Kutup A., Mann O.,Izbicki J.R., Vashist Y.K.: VEGFR-2, CXCR-2 and PAR-1 germline polymorphismsas predictors of survival in pancreatic carcinoma. AnnOncol., 2013; 24: 1282-1290
    Google Scholar
  • 71. Uzunoglu F.G., Yavari N., Bohn B.A., Nentwich M.F., Reeh M., PantelK., Perez D., Tsui T.Y., Bockhorn M., Mann O., Izbicki J.R., WikmanH., Vashist Y.K.: C-X-C motif receptor 2, endostatin and proteinaseactivatedreceptor 1 polymorphisms as prognostic factors in NSCLC.Lung Cancer, 2013; 81: 123-129
    Google Scholar
  • 72. Vu T.K., Hung D.T., Wheaton V.I., Coughlin S.R.: Molecular cloningof a functional thrombin receptor reveals a novel proteolyticmechanism of receptor activation. Cell, 1991; 64: 1057-1068
    Google Scholar
  • 73. Vu T.K., Wheaton V.I., Hung D.T., Coughlin S.R.: Domains specifyingthrombin-receptor interaction. Nature, 1991; 353: 674-677
    Google Scholar
  • 74. Walz D.A., Fenton J.W.: The role of thrombin in tumor cell metastasis.Invasion Metastasis, 1994-1995; 14: 303-308
    Google Scholar
  • 75. Wang J., Boerma M., Kulkarni A., Hollenberg M.D., Hauer-JensenM.: Activation of protease activated receptor 2 by exogenous agonistexacerbates early radiation injury in rat intestine. Int. J. Radiat.Oncol. Biol. Phys., 2010; 77: 1206-1212
    Google Scholar
  • 76. Wang J., Kulkarni A., Chintala M., Fink L.M., Hauer-Jensen M.:Inhibition of protease-activated receptor 1 ameliorates intestinalradiation mucositis in a preclinical rat model. Int. J. Radiat. Oncol.Biol. Phys., 2013; 85: 208-214
    Google Scholar
  • 77. Wang J., Zheng H., Ou X., Albertson C.M., Fink L.M., Herbert J.M.,Hauer-Jensen M.: Hirudin ameliorates intestinal radiation toxicityin the rat: support for thrombin inhibition as strategy to minimizeside-effects after radiation therapy and as countermeasure againstradiation exposure. J. Thromb. Haemost., 2004; 2: 2027-2035
    Google Scholar
  • 78. Wojtukiewicz M.Z., Ciarelli J.J., Snyder D.A., Nelson K.K., WalzD.A., Honn K.V.: Increased tumor cell adhesiveness and experimentalmetastasis following exposure to alpha-thrombin, its precursorand analogues. American Cancer Society Michigan Division Inc., Cancer Research Conference, Ypsilanti, MI, USA, 1990, Abstract 22
    Google Scholar
  • 79. Wojtukiewicz M.Z., Ciarelli J.J., Snyder D., Nelson K.K., Walz D.A.,Honn K.V.: Thrombin increases tumor cell adhesiveness via a nonproteolyticpathway. First Regional Meeting of the American Societyfor Cell Biology, Chicago, IL, USA, 1990, Abstract 91
    Google Scholar
  • 80. Wojtukiewicz M.Z., Ciarelli J.J., Walz D.A., Honn K.V.: Thrombinenhances cancer cell expression of an integrin receptor and increasesadhesion. 81st Annual Meeting of the Americsan Associationfor Cancer Research, 1990, Proceedings of AACR, 31, Abstract 476
    Google Scholar
  • 81. Wojtukiewicz M.Z., Rucinska M., Zacharski L.R., Kozlowski L.,Zimnoch L., Piotrowski Z., Kudryk B.J., Kisiel W.: Localization of bloodcoagulation factors in situ in pancreatic carcinoma. Thromb. Haemost.,2001; 86: 1416-1420
    Google Scholar
  • 82. Wojtukiewicz M.Z., Sierko E., Rak J.: Contribution of the hemostaticsystem to angiogenesis in cancer. Semin. Thromb. Hemost.,2004; 30: 5-20
    Google Scholar
  • 83. Wojtukiewicz M.Z., Sierko E., Zacharski L.R., Zimnoch L., KudrykB., Kisiel W.: Tissue factor-dependent coagulation activation andimpaired fibrinolysis in situ in gastric cancer. Semin. Thromb. Hemost.,2003; 29: 291-300
    Google Scholar
  • 84. Wojtukiewicz M.Z., Tang D.G., Ben-Josef E., Renaud C., Walz D.A.,Honn K.V.: Solid tumor cells express functional “tethered ligand”thrombin receptor. Cancer Res., 1995; 55: 698-704
    Google Scholar
  • 85. Wojtukiewicz M.Z., Tang D.G., Ciarelli J.J., Nelson K.K., WalzD.A., Diglio C.A., Mammen E.F., Honn K.V.: Thrombin increases themetastatic potential of tumor cells. Int. J. Cancer, 1993; 54: 793-806
    Google Scholar
  • 86. Wojtukiewicz M.Z., Tang D.G., Nelson K.K., Walz D.A., DiglioC.A., Honn K.V.: Thrombin enhances tumor cell adhesive and metastaticproperties via increased αIIbβ3 expression on the cell surface.Thromb. Res., 1992; 68: 233-245
    Google Scholar
  • 87. Wojtukiewicz M.Z., Zacharski L.R., Rucińska M., Zimnoch L., JarominJ., Rózańska-Kudelska M., Kisiel W., Kudryk B.J.: Expression oftissue factor and tissue factor pathway inhibitor in situ in laryngealcarcinoma. Thromb. Haemost., 1999; 82: 1659-1662
    Google Scholar
  • 88. Xie L., Duan Z., Liu C., Zheng Y., Zhou J.: Protease-activated receptor 2 agonist increases cell proliferation and invasion of humanpancreatic cancer cells. Exp. Ther. Med., 2015; 9: 239-244
    Google Scholar
  • 89. Xie L., Zheng Y., Li X., Zhao J., Chen X., Chen L., Zhou J., Hai O.,Li F.: Enhanced proliferation of human hepatoma cells by PAR-2agonists via the ERK/AP-1 pathway. Oncol. Rep., 2012; 28: 1665-1672
    Google Scholar
  • 90. Xie Q., Bao X., Chen Z.H., Xu Y., Keep R.F., Muraszko K.M., Xi G.,Hua Y.: Role of protease-activated receptor-1 in glioma growth. ActaNeurochir. Suppl., 2016; 121: 355-360
    Google Scholar
  • 91. Yamahata H., Takeshima H., Kuratsu J., Sarker K.P., Tanioka K.,Wakimaru N., Nakata M., Kitajima I., Maruyama I.: The role of thrombinin the neo-vascularization of malignant gliomas: an intrinsicmodulator for the up-regulation of vascular endothelial growthfactor. Int. J. Oncol., 2002; 20: 921-928
    Google Scholar
  • 92. Yang E., Boire A., Agarwal A., Nguyen N., O’Callaghan K., Tu P.,Kuliopulos A., Covic L.: Blockade of PAR1 signaling with cell-penetratingpepducins inhibits Akt survival pathways in breast cancercells and suppresses tumor survival and metastasis. Cancer Res.,2009; 69: 6223-6231
    Google Scholar
  • 93. Yin Y.J., Salah Z., Grisaru-Granovsky S., Cohen I., Even-Ram S.C.,Maoz M., Uziely B., Peretz T., Bar-Shavit R.: Human protease-activatedreceptor 1 expression in malignant epithelia: a role in invasivness.Aterioscler. Thromb. Vasc. Biol., 2003; 23: 940-944
    Google Scholar
  • 94. Yin Y.J., Salah Z., Maoz M., Even-Ram S.C., Ochayon S., NeufeldG., Katzav S., Bar-Shavit R.: Oncogenic transformation induces tumorangiogenesis: a role for PAR-1 activation. FASEB J., 2003; 17: 163-174
    Google Scholar
  • 95. Yuan L., Liu X.: Platelets are associated with xenograft tumorgrowth and the clinical malignancy of ovarian cancer through an angiogenesis-dependentmechanism. Mol. Med. Rep., 2015: 11: 2449-2458
    Google Scholar
  • 96. Zacharski L.R., Memoli V.A., Morain W.D., Schlaeppi J.M., RousseauS.M.: Cellular localization of enzymatically active thrombin inintact human tissues by hirudin binding. Thromb. Haemost., 1995;73: 793-797
    Google Scholar
  • 97. Zain J., Huang Y.Q., Feng X., Nierodzik M.L., Li J.J., KarpatkinS.: Concentration-dependent dual effect of thrombin on impairedgrowth/apoptosis or mitogenesis in tumor cells. Blood, 2000; 95:3133-3138
    Google Scholar
  • 98. Zania P., Kritikou S., Flordellis C.S., Maragoudakis M.E., TsopanoglouN.E.: Blockade of angiogenesis by small molecule antagoniststo protease-activated receptor-1: association with endothelial cellgrowth suppression and induction of apoptosis. J Pharmacol. Exp.Ther., 2006; 318: 246-254
    Google Scholar
  • 99. Zheng Y.M., Xie L.Q., Li X., Zhao J.Y., Chen X.Y., Chen L., ZhouJ., Li F.: Effect of ERK/AP-1 signaling pathway on proliferation ofhepatoma cells induced by PAR-2 agonists. Zhonghua Yi Xue ZaZhi, 2009; 89: 3116-3121
    Google Scholar
  • 100. Zhu L., Wang X., Wu J., Mao D., Xu Z., He Z., Yu A.: Cooperationof protease-activated receptor 1 and integrin ανβ5 in thrombinmediatedlung cancer cell invasion. Oncol. Rep., 2012; 28: 553-560
    Google Scholar
  • 101. Zhu Q., Luo J., Wang T., Ren J., Hu K., Wu G.: The activation ofprotease-activated receptor 1 mediates proliferation and invasionof nasopharyngeal carcinoma cells. Oncol. Rep., 2012; 28: 255-261
    Google Scholar

Full text

Skip to content