Absence of host plasminogen activator inhibitor 1 prevents cancer invasion and vascularization

Abstract

Acquisition of invasive/metastatic potential through protease expression is an essential event in tumor progression. High levels of components of the plasminogen activation system, including urokinase, but paradoxically also its inhibitor, plasminogen activator inhibitor 1 (PAI1), have been correlated with a poor prognosis for some cancers. We report here that deficient PAI1 expression in host mice prevented local invasion and tumor vascularization of transplanted malignant keratinocytes. When this PAI1 deficiency was circumvented by intravenous injection of a replication-defective adenoviral vector expressing human PAI1, invasion and associated angio-genesis were restored. This experimental evidence demonstrates that host-produced PAI is essential for cancer cell invasion and angiogenesis.Tumor cell invasion and metastatic processes require the coordinated and temporal regulation of a series of adhesive, proteolytic and migratory events 1 . The plasminogen activator (PA)-plasmin proteolytic system has been implicated in these processes. Urokinase-type (uPA) and tissue-type (tPA) plasminogen activators are serine proteases that catalyze the conversion of inactive plasminogen into plasmin, a broadly acting enzyme able to degrade a variety of extracellular matrix proteins and to activate metalloproteinases and growth factors 2,3 . Plasminogen and uPA bind to their specific receptors directing plasmin activity to the migrating tumor cell surface. The activities of PA are directly controlled by specific inhibitors, the PA inhibitors 1 and 2 (PAI1 and PAI2) (ref. 4).Many studies have focused on the role of uPA in cellular invasion and metastasis. Much of the data supporting the role of uPA in these events derives from in vitro and in vivo experiments demonstrating a correlation between uPA expression and cell invasion and metastasis as well as reduction of metastatic potential by using natural or synthetic serine protease inhibitors, neutralizing antibodies to uPA or antisense oligonucleotides 5,6 . PAI1 may also be directly involved in cancer progression. Both tumor cells and capillary endothelial cells express higher levels of PAI1 than other cell types [7][8][9] . Surprisingly, this inhibitor is necessary for optimal invasion of cultured lung cancer cells 10 , and an increasing number of clinical studies have demonstrated that high PAI1 levels indicate a poor prognosis for the survival of patients suffering from a variety of cancers [11][12][13] . However, as PAI1 is an acute-phase reactant 14 , it remains undetermined whether the increased PAI1 levels causally contribute to, or rather are the consequence of, the malignancy.Various observations indicate that the PA system may provide both surface-associated protease activity and an adhesion mechanism for cells through interaction with vitronectin. Deng et al. suggested that the balance between cell adhesion and cell detachment is governed by PAI1 (ref. 15). The PAI1-mediated release of cells attached to vitronectin seems to occur independently of the abili...

Cooperation between monocytes and breast cancer cells promotes factors involved in cancer aggressiveness

“…This pathogenic effect of PAI-1 in cancer aggressiveness was confirmed by the report that cancer invasion and neovascularisation are abolished in PAI-1-deficient mice, and can be restored by local induction of PAI-1 expression (Bajou et al, 1998). This increase in PAI-1 allows a critical balance of u-PA associated to its cell surface receptor, as it could represent a key molecule in the rapid attachment/detachment events occurring at the cell leading edge that are required for migration.…”

Independent prognostic value of angiogenesis and the level of plasminogen activator inhibitor type 1 in breast cancer patients

“…This could further facilitate the capillary networking of the new tumour blood vessels. Accordingly, it has been reported that tumour angiogenesis is drastically impaired in mice with targeted disruption of the PAI-1 gene (Bajou et al, 1998. A few other model system studies have also suggested a proangiogenic role of PAI-1 (Lambert et al, 2001;McMahon et al, 2001;Devy et al, 2002).…”

“…In several cell culture and animal model systems, PAI-1 has been found to have a proangiogenic effect (Bajou et al, 1998Lambert et al, 2001;McMahon et al, 2001;Devy et al, 2002). However, the clinical significance of the biological interaction of angiogenesis and the plasminogen activator system is unknown.…”

Modeling metastasis in the mouse

“…For example, host de®ciency for the plasminogen activator inhibitor (PAI1), paradoxically prevented tumor invasion and angiogenesis of malignant keratinocyte but not melanoma tumor cell xenografts (Bajou et al, 1998). This could re¯ect a requirement for the serine protease plasminogen during the neovascularization process.…”