Increased proteolytic activity is responsible for the aberrant morphogenetic behavior of endothelial cells expressing the middle T oncogene

Montesano, Roberto; Pepper, Michael Sean; Möhle-Steinlein, Uta; Risau, Werner; Wagner, Erwin F.; Orci, Lelio

doi:10.1016/0092-8674(90)90009-4

Cited by 423 publications

(273 citation statements)

References 35 publications

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“…The molecular basis of this intriguing effect has been clarified recently. In agreement with previous in vitro studies (70), an optimal level of extracellular matrix degradation was found to be required for efficient tumor invasion and capillary formation (65). Therefore, this observation attributes the protumorigenic effect of PAI-1 to the counterbalancing of excessive plasmin generation.…”

Section: Discussionsupporting

confidence: 79%

Urokinase Plasminogen Activator and Plasmin Efficiently Convert Hemofiltrate CC Chemokine 1 into Its Active [9–74] Processed Variant

Vakili

Ständker

Detheux

et al. 2001

The Journal of Immunology

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We have previously isolated from human hemofiltrate an N-terminally truncated form of the hemofiltrate CC chemokine 1 (HCC-1), and characterized HCC-1[9–74] as a strong agonist of CCR1, CCR5, and to a lower extent CCR3. In this study, we show that conditioned media from human tumor cell lines PC-3 and 143B contain proteolytic activities that convert HCC-1 into the [9–74] form. This activity was fully inhibited by inhibitors of urokinase-type plasminogen activator (uPA), including PA inhibitor-1, an anti-uPA mAb, and amiloride. Pure preparations of uPA processed HCC-1 with high efficiency, without further degrading HCC-1[9–74]. Plasmin could also generate HCC-1[9–74], but degraded the active product as well. The kinetics of HCC-1 cleavage by uPA and plasmin (Michaelis constant, Km, of 0.76 ± 0.4 μM for uPA, and 0.096 ± 0.05 μM for plasmin; catalytic rate constant, kcat: 3.36 ± 0.96 s−1 for uPA and 6 ± 3.6 s−1 for plasmin) are fully compatible with a role in vivo. The activation of an abundant inactive precursor into a broad-spectrum chemokine by uPA and plasmin directly links the production of uPA by numerous tumors and their ability to recruit mononuclear leukocytes, without the need for the transcriptional activation of chemokine genes.

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Section: Discussionsupporting

confidence: 79%

Urokinase Plasminogen Activator and Plasmin Efficiently Convert Hemofiltrate CC Chemokine 1 into Its Active [9–74] Processed Variant

Vakili

Ständker

Detheux

et al. 2001

The Journal of Immunology

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“…Inhibition of plasmin restores normal morphogenic properties. These findings clearly implicate increased plasminogen activator-plasmin-mediated proteolysis in aberrant vascular morphogenesis [74]. Injection of End.…”

Section: The Plasminogen System and Angiogenesismentioning

confidence: 76%

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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“…Murine brain endothelioma cells (bEnd.5) 17,18 were cultured in complete Dulbecco's modified Eagle's medium (supplemented with 10% fetal calf serum, 1 mM sodium pyruvate, 100 U/mL penicillin, 100 g/mL streptomycin, 2 mM L-glutamine, 1% nonessential amino acid solution, and 0.1% ␤-mercaptoethanol). Murine mesenteric lymph node-derived endothelioma cells (mlEnd), 19,20 kindly provided by Ru-pert Hallmann (Münster, Germany), were cultured in complete RPMI 1640 (supplemented with 10% fetal calf serum, 1 mM sodium pyruvate, 100 U/mL penicillin, 100 g/mL streptomycin, and 0.1% ␤-mercaptoethanol).…”

Section: Methodsmentioning

confidence: 99%

Enhanced T cell transmigration across the murine liver sinusoidal endothelium is mediated by transcytosis and surface presentation of chemokines†

et al. 2008

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Transmigration through the liver endothelium is a prerequisite for the homeostatic balance of intrahepatic T cells and a key regulator of inflammatory processes within the liver. Extravasation into the liver parenchyma is regulated by the distinct expression patterns of adhesion molecules and chemokines and their receptors on the lymphocyte and endothelial cell surface. In the present study, we investigated whether liver sinusoidal endothelial cells ( H omeostatic extravasation into the liver parenchyma and transmigration of T cells into sites of inflammation under pathological conditions such as hepatitis and cholangitis are mediated by multiple steps involving activation and firm adhesion followed by egress. The process is closely regulated by the distinct expression patterns of adhesion molecules and chemokines and their receptors on the cell surface. 1,2 Within the liver, lymphocyte adhesion, a prerequisite for transmigration, occurs mainly within the sinusoidal circulation. Thus, T cell immigration into the liver is presumed to happen predominantly via the sinusoids. 3 Liver sinusoidal endothelial cells (LSEC) lining the sinusoids form a morphologically and functionally distinct endothelium that lacks a basement membrane, fails to form tight junctions, and displays fenestrae grouped to sieve plates. 4 In contrast to other tissues, selectins are not necessary for the initial adhesion of leukocytes to the liver microvasculature. The

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Increased proteolytic activity is responsible for the aberrant morphogenetic behavior of endothelial cells expressing the middle T oncogene

Cited by 423 publications

References 35 publications

Urokinase Plasminogen Activator and Plasmin Efficiently Convert Hemofiltrate CC Chemokine 1 into Its Active [9–74] Processed Variant

Urokinase Plasminogen Activator and Plasmin Efficiently Convert Hemofiltrate CC Chemokine 1 into Its Active [9–74] Processed Variant

Role of plasminogen activator-plasmin system in tumor angiogenesis

Enhanced T cell transmigration across the murine liver sinusoidal endothelium is mediated by transcytosis and surface presentation of chemokines†

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