Differential inhibition of endothelial cell proliferation and migration by urokinase subdomains: amino-terminal fragment and kringle domain

Kim, Kwang Sei; Hong, Yong-Kil; Lee, Yoon; Shin, J.; Chang, Soo-Ik; Chung, Soo Il; Joe, Yeonsoo

doi:10.1038/emm.2003.76

Cited by 28 publications

(15 citation statements)

References 23 publications

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“…To better characterize the nature of the changes induced by HHV-8, we investigated whether infected HUVEC had undergone an angiogenic switch.To this end, we examined the expression of uPAR, which is involved in the process of extracellular matrix proteins degradation and cell-migration, both processes preliminary to the formation of new vessels (Kim et al, 2003;Trisciuoglio et al, 2004). uPAR expression, as demonstrated by FACS analysis, increased in the early stages of infection (from t0 to t3) (Figure 5a), indicating a propensity of the cells to move, but was lost after one week of HHV-8 infection.…”

Section: Infected Huvec Show Changes Reminiscent Of An Angiogenic Tramentioning

confidence: 99%

Productive infection of HUVEC by HHV-8 is associated with changes compatible with angiogenic transformation

Foglieni¹,

Scabini²,

Belloni³

et al. 2009

Eur J Histochem

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Kaposi's Sarcoma (KS) is an angioproliferative disease associated with human herpesvirus 8 (HHV-8) infection. We have characterized the morphologic and phenotypic modifications of HUVEC in a model of productive HHV-8 infection. HHV-8 replication was associated with ultra-structural changes, flattened soma and a loss of marginal folds and intercellular contacts, and morphologic features, spindle cell conversion and cordon-like structures formation. Phenotypic changes observed on cordon-like structures included partial loss and redistribution of CD31/PECAM-1 and VE-cadherin, uPAR upregulation and de novo expression of CD13/APN. Such changes demonstrate the induction, in HUVEC, of an angiogenic profile. Most of these findings are directly linked to HHV-8-encoded proteins expression, suggesting that HHV-8 itself may participate to the initial steps of the angiogenic transformation in KS.

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Section: Infected Huvec Show Changes Reminiscent Of An Angiogenic Tramentioning

confidence: 99%

Productive infection of HUVEC by HHV-8 is associated with changes compatible with angiogenic transformation

Foglieni¹,

Scabini²,

Belloni³

et al. 2009

Eur J Histochem

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“…Based on this idea, a number of angiogenesis inhibitors have been developed from various sources, including endogenous protein fragments (O'Reilly et al, 1994;Kim et al, 2003), monoclonal antibodies (Brekken et al, 2000) and small molecules originated from natural products and organic synthesis (Ingber et al, 1990;Shim et al, 2003). As a result of our continuing search for new anti-angiogenic agents from chemical spheres, we found cryptotanshinone from the root of Salvia miltiorrhiza Bunge (Labiatae) exhibits a potent anti-angiogenic activity.…”

Section: Introductionmentioning

confidence: 99%

Cryptotanshinone but not tanshinone IIA inhibits angiogenesis in vitro

Hur

Shim²,

Jung³

et al. 2005

Exp Mol Med

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Abbreviations: BAEC, bovine aortic endothelial cells; bFGF, basic fibroblast growth factor; BSA, bovine serum albumin; MTT, 3-(4,5-dimethylthizol-2-yl)-2,5-diphenyl tetrazolium bromide A bstractIn the course of screening of angiogenesis inhibitor from natural products, cryptotanshinone from Salvia m iltiorrhiza w as isolated as a potent sm all m olecule inhibitor of angiogenesis. Cryptotanshinone inhibits bFGF-induced angiogenesis of BAECs at ten m icrom olar ranges in vitro without cytotoxicity. Tanshinone IIA, another tanshinone isolated from S. m iltiorrhiza, w hich is structurally very sim ilar to cryptotanshinone except C-15 position of dihydrofuran ring does not inhibit angiogenesis induced by bFGF. These results dem onstrate that cryptotanshinone is a new anti-angiogenic agent and double bond at C-15 position of the dihydrofuran ring plays a crucial role in the activity.

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“…(12) Interestingly, in our previous study, we demonstrated that the kringle domain (Asp 45 -Lys 135 ), a subdomain of ATF, possesses an antiangiogenic activity, possibly with a different mechanism of ATF. (13,14) Thus, it warrants further investigation for its antitumor effect and action mechanisms.…”

mentioning

confidence: 99%

The recombinant kringle domain of urokinase plasminogen activator inhibits in vivo malignant glioma growth

et al. 2006

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In a previous report, the recombinant kringle domain (UK1) of the urokinase type plasminogen activator (uPA) showed antiangiogenic activity. Here, we investigated in vivo antitumor effects of the UK1 of human uPA employing a brain tumor model. The systemic administration of UK1 purified from pichia expression (10 and 50 mg/kg/day intraperitoneally for 25 days) led to suppress the growth of a U87 human glioma xenograft, implanted into the brains of male BALB/cSlc nude mice, by 35% and 80%, respectively. In the immunohistochemical analysis, the tumors treated with UK1 showed decreased vascularity and expression of angiogenesis-related factors including vascular endothelial growth factor (VEGF), angiogenin, M alignant gliomas, the most common primary brain tumors, are extremely aggressive and highly angiogenic tumors with a very poor prognosis despite available intensive therapies including surgery, irradiation and chemotherapy.(1,2) Angiogenesis is an important feature associated with malignant glioma growth and progression.(3) The blood-brain barrier or blood-tumor barrier, which hinders drug delivery to brain tumors, is considered to be one of the main problems associated with systemic chemotherapy of brain tumors.(1,4) Angiogenesis inhibition, targeting endothelial cells rather than tumor cells, may especially be suitable for the treatment of malignant gliomas. Several antiangiogenic therapies have shown antitumor effects only in the preclinical setting but not in clinical studies. (5,6) It is important to investigate a new antiangiogenic molecule and its action mechanism for the development of antiangiogenic tumor therapy.Urokinase-type plasminogen activator (uPA) belonging to a protein family that contains a kringle domain plays an important role in inflammation, invasion, angiogenesis, and tumor metastasis by pericellular plasminogen activation.(7-9) uPA is a multidomain protein composed of a carboxyl-terminal protease domain and an amino-terminal fragment (ATF) which can be further subdivided into a growth factor-like domain (aa 4 -43) and a kringle domain (aa 45-135, UK1). uPA is highly expressed in malignant brain tumors;(10) its binding to the uPA receptor (uPAR) is enhanced by tumor progression and invasion by proteolysis of the extracellular matrix.(11) The ATF fragment of uPA has been reported to inhibit glioma growth and invasion properties in vivo.(12) Interestingly, in our previous study, we demonstrated that the kringle domain (Asp 45 -Lys 135 ), a subdomain of ATF, possesses an antiangiogenic activity, possibly with a different mechanism of ATF. (13,14) Thus, it warrants further investigation for its antitumor effect and action mechanisms.Here, we report that systemic administration of UK1 efficiently suppressed in vivo malignant glioma growth in nude mice, and reduced the expression of angiogenesis-related factors in tumor tissues. Materials and MethodsCell culture. Human malignant glioma cell lines U87, A172 and U373 were purchased from the American Type Culture Collection (ATCC, Manassas, VA)....

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Differential inhibition of endothelial cell proliferation and migration by urokinase subdomains: amino-terminal fragment and kringle domain

Cited by 28 publications

References 23 publications

Productive infection of HUVEC by HHV-8 is associated with changes compatible with angiogenic transformation

Productive infection of HUVEC by HHV-8 is associated with changes compatible with angiogenic transformation

Cryptotanshinone but not tanshinone IIA inhibits angiogenesis in vitro

The recombinant kringle domain of urokinase plasminogen activator inhibits in vivo malignant glioma growth

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