Reduction of tumor cell migration and metastasis by adenoviral gene transfer of plasminogen activator inhibitors

Praus, Michael; Wauterickx, K; Collen, D.; Gerard, Robert D.

doi:10.1038/sj.gt.3300802

Cited by 50 publications

(59 citation statements)

References 39 publications

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“…In a mouse model of acute myocardial infarction, blocking plasminogen activation by temporal infusion of PAI-1 prevented rupture of ventricular aneurysm (28), in which ventricular wall destruction by increased MMP activity is thought to be a main mechanism (29). It has also been shown that adenoviral transfer of the PAI-1 gene reduces tumor metastasis (30); in metastasis, extracellular matrix lysis is necessary for movement of transformed cells in tissues. In addition, Allaire et al have reported that, in a rat model of aortic aneurysm, blockade of PAs by local overexpression of PAI-1 prevents formation of aneurysms and arterial rupture by inhibiting MMP activation (9).…”

Section: Discussionmentioning

confidence: 99%

Plasminogen Activator Inhibitor-1 in Patients with Kawasaki Disease: Diagnostic Value for the Prediction of Coronary Artery Lesion and Implication for a New Mode of Therapy

Senzaki¹,

Kobayashi²,

Nagasaka³

et al. 2003

Pediatr Res

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Kawasaki disease (KD) in children takes the form of acute systemic vasculitis, which causes coronary artery dilation and aneurysm formation in 10% to 15% of the patients. We have recently shown that matrix metalloproteinases (MMPs) are intimately involved in coronary arterial wall destruction and the resultant formation of coronary artery lesions (CALs) in this disease. Plasminogen activators (PAs) are known to be a major pathway of MMP activation, and this suggests that their inhibitor, plasminogen activator inhibitor-1 (PAI-1), also plays important roles in the development of CALs in KD. The present study was conducted to test the hypothesis that circulating levels of PAI-I are related to CAL formation in KD. Plasma levels of PAI-1 were measured by enzyme-linked immunoassay in 37 KD patients without CALs (group 1) and 7 KD patients with CALs (group 2). Blood samples were obtained before and after i.v. gammaglobulin therapy (IVGG), and in the convalescent stage. Levels of PAI-1 were significantly higher in KD patients before IVGG than in 18 age-matched healthy control subjects (p Ͻ 0.01). More importantly, both pre-IVGG and post-IVGG levels of PAI-1 were significantly higher in group 2 than in group 1 (p Ͻ 0.01). Furthermore, PAI-1 levels of 9 patients from group 1 who showed pre-IVGG PAI-1 levels higher than the minimum PAI-1 level in group 2 significantly decreased after IVGG, whereas PAI-1 levels of group 2 patients remained persistently elevated, further suggesting a close association between PAI-1 and CAL development in KD. Thus, PAI-1 may be useful as a predictive marker for CAL development in KD. Studies of the effects of PA inhibition on coronary outcome may provide evidence that PA is a viable therapeutic target for the prevention of KD-related CALs. The extracellular matrix of the arterial wall provides a strong structural safety net that resists arterial expansion in a healthy individual. Arterial aneurysm development is thought to be the consequence of degradation of these structural proteins by proteolytic enzymes derived mainly from inflammatory cells infiltrating into media and adventitia (1-3). Matrix metalloproteinases (MMPs) have been implicated in this degradation process, and are thought to play dominant roles in the formation of abdominal aortic aneurysms (3-6).Plasminogen activators (PAs) and plasmin (a serine protease) are known to be activated in response to several inflammatory conditions and to act as triggers activating the MMP pathway (7,8). In addition, recent study of aortic aneurysm in a rat model has demonstrated that blocking PA activity via local overexpression of plasminogen activator inhibitor-1 (PAI-1) prevents formation of arterial aneurysms by inhibiting MMP activation, suggesting a critical role for PA-mediated MMP activation in arterial wall destruction and resultant aneurysm formation (6, 9).Kawasaki disease (KD) in children takes the form of acute systemic vasculitis, which causes coronary artery dilation and aneurysm formation in 10% to 15% of patients during its acute

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Section: Discussionmentioning

confidence: 99%

Plasminogen Activator Inhibitor-1 in Patients with Kawasaki Disease: Diagnostic Value for the Prediction of Coronary Artery Lesion and Implication for a New Mode of Therapy

Senzaki¹,

Kobayashi²,

Nagasaka³

et al. 2003

Pediatr Res

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“…High expression of PAI-1 and uPA characterizes malignant astrocytic tumors (Yamamoto et al, 1994). Antisense against uPA or transfer of the PAI-1 gene reduced the invasiveness of glioma cells in vitro and decreased tumorigenicity (Praus et al, 1999).…”

Section: Discussionmentioning

confidence: 99%

Microglia-derived TGF-β as an important regulator of glioblastoma invasion—an inhibition of TGF-β-dependent effects by shRNA against human TGF-β type II receptor

et al. 2007

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The invasion of tumor cells into brain tissue is a pathologic hallmark of malignant gliomas and contributes to treatment failures. Diffuse glioblastomas contain numerous microglial cells, which enhance the progression of gliomas; however, factors responsible for invasionpromoting role of microglia are unknown. Transforming growth factor-b (TGF-b) can enhance tumor growth, invasion, angiogenesis and immunosuppression. Antagonizing TGF-b activity has been shown to inhibit tumor invasion in vitro and tumorigenicity, but a systemic inhibition or lack of TGF-b signaling results in acute inflammation and disruption of immune system homeostasis. We developed plasmid-transcribed small hairpin RNAs (shRNAs) to downregulate the TGF-b type II receptor (TbIIR) expression, which effectively inhibited cytokine-induced signaling pathways and transcriptional responses in transiently transfected human glioblastoma cells. Silencing of TbIIR abolished TGF-b-induced glioblastoma invasiveness and migratory responses in vitro. Moreover, tumorigenicity of glioblastoma cells stably expressing TbIIR shRNAs in nude mice was reduced by 50%. Microglia strongly enhanced glioma invasiveness in the co-culture system, but this invasion-promoting activity was lost in glioma cells stably expressing shTbRII, indicating a crucial role of microglia-derived TGF-b in tumor-host interactions. Our results demonstrate a successful targeting of TGF-b-dependent invasiveness and tumorigenicity of glioblastoma cells by RNAi-mediated gene silencing.

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“…Adenovirus-mediated delivery of anti-sense targeting uPAR induces the regression of pre-established glioblastoma tumors in vivo [105]. Although adenoviral transfer of PAI-1 reduces metastatic dissemination in mice with intraocular melanoma [120] or HT1080 tumors [121], the dose-dependent effect of PAI-1, pro-angiogenic at low concentration and antiangiogenic at higher ones [92,96] (Fig. 2), raises questions about the use of PAI-1 or PAI-1 antagonists for inhibition of tumoral angiogenesis.…”

Section: Delivery Of Viral Vectors To Suppress the Plasminogen Systemmentioning

confidence: 99%

Role of plasminogen activator-plasmin system in tumor angiogenesis

Rakic¹,

Maillard²,

Jost³

et al. 2003

Cellular and Molecular Life Sciences (CMLS)

119

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New blood formation or angiogenesis has become a key target in therapeutic strategies aimed at inhibiting tumor growth and other diseases associated with neovascularization. Angiogenesis is associated with important extracellular remodeling involving different proteolytic systems among which the plasminogen system plays an essential role. It belongs to the large serine proteinase family and can act directly or indirectly by activating matrix metalloproteinases or by liberating growth factors and cytokines sequestered within the extracellular matrix. Migration of endothelial cells is associated with significant upregulation of proteolysis and conversely, immunoneutralization or chemical inhibition of the system reduces angiogenesis in vitro. On the other hand genetically altered mice developed normally without overt vascular anomalies indicating the possibility of compensation by other proteases in vivo. Nevertheless, they have in some experimental settings revealed unanticipated roles for previously characterized proteinases or their inhibitors. In this review, the complex mechanisms of action of the serine proteases in pathological angiogenesis are summarized alongside possible therapeutic applications.

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Reduction of tumor cell migration and metastasis by adenoviral gene transfer of plasminogen activator inhibitors

Cited by 50 publications

References 39 publications

Plasminogen Activator Inhibitor-1 in Patients with Kawasaki Disease: Diagnostic Value for the Prediction of Coronary Artery Lesion and Implication for a New Mode of Therapy

Plasminogen Activator Inhibitor-1 in Patients with Kawasaki Disease: Diagnostic Value for the Prediction of Coronary Artery Lesion and Implication for a New Mode of Therapy

Microglia-derived TGF-β as an important regulator of glioblastoma invasion—an inhibition of TGF-β-dependent effects by shRNA against human TGF-β type II receptor

Role of plasminogen activator-plasmin system in tumor angiogenesis

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