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

Francesca Margheri, Silvia D'Alessio, Simona Serrati, Marco Pucci, Angela Del Rosso, Roberto Benelli, Nicoletta Ferrari, Douglas M. Noonan, Adriana Albini, Gabriella Fibbi, Mario Del Rosso

Research output: Contribution to journalArticle

Abstract

The aggressive and malignant nature of AIDSassociated 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.

Original languageEnglish
Pages (from-to)223-235
Number of pages13
JournalInternational Journal of Oncology
Volume27
Issue number1
Publication statusPublished - Jul 2005

Keywords

  • Angiogenesis
  • HIV-1
  • Kaposi's sarcoma
  • Plasminogen activator inhibitor type-1
  • Tat
  • u-PA receptor
  • Urokinase-type plasminogen activator

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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