Plasminogen Activator Inhibitor Type 1 Promotes Fibrosarcoma Cell Migration by Modifying Cellular Attachment to Vitronectin via α_vβ₅ Integrin

ABSTRACT

Both urokinase plasminogen activator (u-PA) and plasminogen activator inhibitor type 1 (PAI-1) are associated with a poor prognosis in cancer patients. We demonstrate that PAI-1 inhibits human fibrosarcoma cell (HT-1080) adhesion to vitronectin (Vn) via α_vβ₅ integrin, and stimulates cell migration from Vn toward collagen type IV (Col). The cells attached more strongly to Vn and Col than to fibronectin (Fn), whereas PAI-1 interfered with cell attachment to Vn only. An integrin antagonist, RGD peptide, and anti-α_vβ₅ integrin antibodies, which similarly inhibited cell attachment to Vn, also stimulated cell migration from Vn toward Col. u-PA did not modify cell attachment directly, but reversed the PAI-1-mediated inhibitory effect on cell adhesion to Vn, and its stimulatory effect on cell migration from Vn toward Col. Thus HT-1080 cell migration appears to be modified by u-PA and PAI-1, altering cell adhesion to Vn via α_vβ₅ integrin. This may be related to their tumor-promoting effect.

PAI-1 - u-PA - α_vβ₅ integrin - cell migration

REFERENCES

• 1 Dano K, Behrendt N, Brunner N et al.. The urokinase receptor. Protein structure and role in plasminogen activation and cancer invasion.  Fibrinolysis. 1994;  8(suppl) 189-203
• 2 Blasi F, Vassalli J D, Dano K. Urokinase-type plasminogen activator: proenzyme, receptor, and inhibitors.  J Cell Biol. 1987;  104 801-804
• 3 Grondahl-Hansen J, Christensen I J, Rosenquist C 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 2513-2521
• 4 Pedersen H, Grondahl-Hansen J, Francis D et al.. Urokinase and plasminogen activator inhibitor type 1 in pulmonary adenocarcinoma.  Cancer Res. 1994;  54 120-123
• 5 Pedersen H, Brunner 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
• 6 Kobayashi H, Fujishiro S, Terao T. Impact of urokinase-type plasminogen activator and its inhibitor type 1 on prognosis in cervical cancer of the uterus.  Cancer Res. 1994;  54 6539-6548
• 7 Foekens J A, Buessecker F, Peters H A et al.. Plasminogen activator inhibitor-2: prognostic relevance in 1012 patients with primary breast cancer.  Cancer Res. 1995;  55 1423-1427
• 8 Duggan C, Kennedy S, Kramer M D et al.. Plasminogen activator inhibitor type 2 in breast cancer.  Br J Cancer. 1997;  76 622-627
• 9 Nakamura M, Konno H, Tanaka T et al.. Possible role of plasminogen activator inhibitor 2 in the prevention of the metastasis of gastric cancer tissues.  Thromb Res. 1992;  65 709-719
• 10 Sumiyoshi K, Serizawa K, Urano T et al.. Plasminogen activator system in human breast cancer.  Int J Cancer. 1992;  50 345-348
• 11 Nagayama M, Sato A, Hayakawa H et al.. Plasminogen activators and their inhibitors in non-small cell lung cancer. Low content of type 2 plasminogen activator inhibitor associated with tumor dissemination.  Cancer. 1994;  73 1398-1405
• 12 Wei Y, Waltz D A, Rao N et al.. Identification of the urokinase receptor as an adhesion receptor for vitronectin.  J Biol Chem. 1994;  269 32380-32388
• 13 Deng G, Curriden S A, Wang S et al.. Is plasminogen activator inhibitor-1 the molecular switch that governs urokinase receptor-mediated cell adhesion and release?.  J Cell Biol. 1996;  134 1563-1571
• 14 Stefansson S, Lawrence D A. The serpin PAI-1 inhibits cell migration by blocking integrin alpha V beta 3 binding to vitronectin.  Nature. 1996;  383 441-443
• 15 Deng G, Curriden S A, Hu G et al.. Plasminogen activator inhibitor-1 regulates cell adhesion by binding to the somatomedin B domain of vitronectin.  J Cell Physiol. 2001;  189 23-33
• 16 Dear A E, Medcalf R L. The cellular and molecular biology of plasminogen activator inhibitor type-2.  Fibrinolysis. 1995;  9 321-330
• 17 Kumar S, Baglioni C. Protection from tumor necrosis factor-mediated cytolysis by overexpression of plasminogen activator inhibitor type-2.  J Biol Chem. 1991;  266 20960-20964
• 18 Gan H, Newman G W, Remold H G. Plasminogen activator inhibitor type 2 prevents programmed cell death of human macrophages infected with Mycobacterium avium, serovar 4.  J Immunol. 1995;  155 1304-1315
• 19 Hibino T, Matsuda Y, Takahashi T, Goetinck P F. Suppression of keratinocyte proliferation by plasminogen activator inhibitor-2.  J Invest Dermatol. 1999;  112 85-90
• 20 Ploug M, Ronne E, Behrendt N et al.. Cellular receptor for urokinase plasminogen activator. Carboxyl-terminal processing and membrane anchoring by glycosyl-phosphatidylinositol.  J Biol Chem. 1991;  266 1926-1933
• 21 Urano T, Strandberg L, Johansson L B, Ny T. A substrate-like form of plasminogen-activator-inhibitor type 1. Conversions between different forms by sodium dodecyl sulphate.  Eur J Biochem. 1992;  209 985-992
• 22 Mikus P, Urano T, Liljestrom P, Ny T. Plasminogen-activator inhibitor type 2 (PAI-2) is a spontaneously polymerising SERPIN. Biochemical characterisation of the recombinant intracellular and extracellular forms.  Eur J Biochem. 1993;  218 1071-1082
• 23 Waltz D A, Natkin L R, Fujita R M et al.. Plasmin and plasminogen activator inhibitor type 1 promote cellular motility by regulating the interaction between the urokinase receptor and vitronectin.  J Clin Invest. 1997;  100 58-67
• 24 Duffy M J, Reilly D, O'Sullivan C et al.. Urokinase-plasminogen activator, a new and independent prognostic marker in breast cancer.  Cancer Res. 1990;  50 6827-6829
• 25 Foekens J A, Schmitt M, van Putten W L et al.. Prognostic value of urokinase-type plasminogen activator in 671 primary breast cancer patients.  Cancer Res. 1992;  52 6101-6105
• 26 Sugiura Y, Ma L, Sun B et al.. The plasminogen-plasminogen activator (PA) system in neuroblastoma: role of PA inhibitor-1 in metastasis.  Cancer Res. 1999;  59 1327-1336
• 27 Isogai C, Laug W E, Shimada H et al.. Plasminogen activator inhibitor-1 promotes angiogenesis by stimulating endothelial cell migration toward fibronectin.  Cancer Res. 2001;  61 5587-5594
• 28 Lawrence D A, Palaniappan S, Stefansson S et al.. Characterization of the binding of different conformational forms of plasminogen activator inhibitor-1 to vitronectin. Implications for the regulation of pericellular proteolysis.  J Biol Chem. 1997;  272 7676-7680
• 29 Liotta L A. Cancer cell invasion and metastasis.  Sci Am. 1992;  266 34-41
• 30 Bajou K, Noel A, Gerard R D et al.. Absence of host plasminogen activator inhibitor 1 prevents cancer invasion and vascularization.  Nat Med. 1998;  4 923-928
• 31 Gutierrez L S, Schulman A, Brito-Robinson T et al.. Tumor development is retarded in mice lacking the gene for urokinase-type plasminogen activator or its inhibitor, plasminogen activator inhibitor-1.  Cancer Res. 2000;  60 5839-5847
• 32 Olson D, Pollanen J, Hoyer-Hansen G et al.. Internalization of the urokinase-plasminogen activator inhibitor type-1 complex is mediated by the urokinase receptor.  J Biol Chem. 1992;  267 9129-9133
• 33 Degryse B, Sier C F, Resnati M et al.. PAI-1 inhibits urokinase-induced chemotaxis by internalizing the urokinase receptor.  FEBS Lett. 2001;  505 249-254
• 34 Ellis V, Wun T C, Behrendt N et al.. Inhibition of receptor-bound urokinase by plasminogen-activator inhibitors.  J Biol Chem. 1990;  265 9904-9908
• 35 Zhou H M, Bolon I, Nichols A et al.. Overexpression of plasminogen activator inhibitor type 2 in basal keratinocytes enhances papilloma formation in transgenic mice.  Cancer Res. 2001;  61 970-976