The urokinase-type plasminogen activator, its receptor and u-PA inhibitor type-1 affect in vitro growth and invasion of Kaposi's sarcoma and capillary endothelial cells: role of HIV-Tat protein.
The aggressive and malignant nature of AIDS-associated Kaposi's sarcoma (KS) lesions have largely been ascribed to Tat, the HIV-1 transactivator protein. Among other activities, HIV-Tat induces the migration and invasion of KS and endothelial cells. Since cell invasion is strictly correlated to the activity of lytic enzymes, we elucidated the role of the cell-associated plasminogen activation system in Tat-dependent and in constitutive invasion and proliferation of KS and of microvascular endothelial cells (MVEC). We demonstrate that KS cells and MVEC express the u-PA receptor (u-PAR) and release plasminogen activators and plasminogen activator inhibitor type-1 (PAI-1). The urokinase-type plasminogen activator (u-PA) is chemotactic, chemoinvasive and mitogenic for KS cells and for MVEC. Conditioned medium from KS cells induced invasion and proliferation of MVEC through the u-PA/u-PAR system. Tat is motogenic and mitogenic on KS cells and MVEC, and stimulates morphogenesis of MVEC. These activities were inhibited following antagonization of u-PA and u-PAR, which also reduced constitutive proliferation and invasion of KS cells and MVEC. These data indicate that the u-PA/u-PAR/PAI-1 system is involved in KS-induced endothelial cell invasion, proliferation, and differentiation. Further, exogenous Tat protein could up-regulate the fibrinolytic system, increasing its influence on KS and endothelial cell proliferation and migration, potentially promoting KS progression. These observations suggest the potential for application of u-PA/u-PAR system inhibitors for control of AIDS-associated KS, that has a high risk of recurrence with highly active antiretroviral therapy failure, and of other KS forms.
Margheri
Francesca
F
Department of Experimental Pathology and Oncology, University of Florence, Italy.
D'Alessio
Silvia
S
Serratì
Simona
S
Pucci
Marco
M
Del Rosso
Angela
A
Benelli
Roberto
R
Ferrari
Nicoletta
N
Noonan
Douglas M
DM
Albini
Adriana
A
Fibbi
Gabriella
G
Del Rosso
Mario
M
D000911:Antibodies, Monoclonal / Q000737:chemistry; D023241:Antiretroviral Therapy, Highly Active; D002196:Capillaries / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003094:Collagen / Q000494:pharmacology; D017077:Culture Media, Conditioned / Q000494:pharmacology; D004338:Drug Combinations; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology*; D004797:Enzyme-Linked Immunosorbent Assay; D015696:Gene Products, tat / Q000378:metabolism; D006801:Humans; D007797:Laminin / Q000494:pharmacology; D008833:Microcirculation; D011509:Proteoglycans / Q000494:pharmacology; D011956:Receptors, Cell Surface / Q000378:metabolism*; D055293:Receptors, Urokinase Plasminogen Activator; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012514:Sarcoma, Kaposi / Q000378:metabolism / Q000473:pathology* / Q000821:virology*; D013696:Temperature; D013997:Time Factors; D014568:Urokinase-Type Plasminogen Activator / Q000037:antagonists & inhibitors* / Q000378:metabolism*
D000911:Antibodies, Monoclonal; D017077:Culture Media, Conditioned; D004338:Drug Combinations; D015696:Gene Products, tat; D007797:Laminin; C524898:PLAUR protein, human; D011509:Proteoglycans; D011956:Receptors, Cell Surface; D055293:Receptors, Urokinase Plasminogen Activator; C059485:matrigel; D003094:Collagen; D014568:Urokinase-Type Plasminogen Activator