Angiostatin generation by human tumor cell lines: Involvement of plasminogen activators

Westphal, Johan R.; Hullenaar, Rianne Van't; Geurts-Moespot, Anneke; Sweep, Fred C.G.J.; Verheijen, J.H.; Bussemakers, Marion M.G.; Askaa, Jon; Clemmensen, Inge; Eggermont, Alexander; Ruiter, Dirk J.; Waal, R.M.W. de

doi:10.1002/(sici)1097-0215(20000615)86:6<760::aid-ijc2>3.0.co;2-4

Cited by 48 publications

(27 citation statements)

References 33 publications

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“…Human angiostatin K1-4 (aa 97-454), containing the first four disulfide-linked structures of plasminogen, which was the first protein described, is generated following hydrolysis of plasminogen by a metalloelastase. 3,[8][9][10] In vitro, angiostatin K1-4 (aa 97-454) inhibits endothelial cell growth with an ED 50 of 135 nM, 11 and endothelial cell migration in a specific manner. 12 In vivo, angiostatin K1-4 (aa 97-454) inhibits neovascularization in chick chorioallantoic membrane and mouse corneal assays, and suppresses subsequent tumor growth in different murine models.…”

Section: Introductionmentioning

confidence: 99%

Full kringles of plasminogen (aa 1–566) mediate complete regression of human MDA-MB-231 breast tumor xenografted in nude mice

et al. 2005

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Since kringle (K)5, not present in the angiostatin molecule, was shown to be a key functional domain possessing potent antiangiogenic activity, we have evaluated a new plasminogen-derived fragment, consisting of the N-terminal part of human plasminogen, that included the complete secondary structure of K1-5 (aa 1-566). In contrast to other fragments described to date, K1-5 includes cysteine residues at positions 543, 555 and 560 allowing the formation of the three disulfide bonds lying within K5. Vascular endothelial cell proliferation and migration assays revealed that a replication-defective adenovirus (AdK1-5(1-566)), expressing K1-5 (aa 1-566), was dose dependently more potent that AdK1-3(1-354), an adenovirus that expresses only the first three kringles. In contrast to AdK1-3(1-354), a single intratumoral injection of AdK1-5(1-566) into MDA-MB-231 breast human carcinoma tumors was followed by a total regression of 40% of the tumor and by significant arrest of tumor growth (90%), which was correlated with a drastic decrease of functional neovascularization into the tumors. Furthermore, systemic delivery of AdK1-5(1-566) in mice inhibited the lung invasion of melanoma B16-F10 cells by 87%. Our findings provide evidence that the full kringles of plasminogen (aa 1-566) may be much more potent than K1-3 (aa 1-354), for the suppression of angiogenesis, tumor growth and metastatic dissemination. Gene Therapy (2005) 12, 831-842.

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Section: Introductionmentioning

confidence: 99%

Full kringles of plasminogen (aa 1–566) mediate complete regression of human MDA-MB-231 breast tumor xenografted in nude mice

et al. 2005

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“…All of these angiostatinrelated proteins exert similar endothelial cell inhibitory activities including apoptosis induction and migration inhibition, as well as tumor growth inhibition in experimental neoplasia, with various degrees of effectiveness (4). To our knowledge, only macrophages and tumor cells have been reported to generate angiostatin, mainly as angiostatin K1-4 and/or K1-5, depending on the enzymatic activities released by these cells (10,(12)(13)(14).…”

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confidence: 99%

Generation of Biologically Active Angiostatin Kringle 1–3 by Activated Human Neutrophils

Scapini

Nesi

Morini

et al. 2002

The Journal of Immunology

124

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The contribution of polymorphonuclear neutrophils (PMN) to host defense and natural immunity extends well beyond their traditional role as professional phagocytes. In this study, we demonstrate that upon stimulation with proinflammatory stimuli, human PMN release enzymatic activities that, in vitro, generate bioactive angiostatin fragments from purified plasminogen. We also provide evidence that these angiostatin-like fragments, comprising kringle domain 1 to kringle domain 3 (kringle 1–3) of plasminogen, are generated as a byproduct of the selective proteolytic activity of neutrophil-secreted elastase. Remarkably, affinity-purified angiostatin kringle 1–3 fragments generated by neutrophils inhibited basic fibroblast growth factor plus vascular endothelial growth factor-induced endothelial cell proliferation in vitro, and both vascular endothelial growth factor-induced angiogenesis in the matrigel plug assay and fibroblast growth factor-induced angiogenesis in the chick embryo chorioallantoic membrane assay, in vivo. These results represent the first demonstration that biologically active angiostatin-like fragments can be generated by inflammatory human neutrophils. Because angiostatin is a potent inhibitor of angiogenesis, tumor growth, and metastasis, the data suggest that activated PMN not only act as potent effectors of inflammation, but might also play a critical role in the inhibition of angiogenesis in inflammatory diseases and tumors, by generation of a potent anti-angiogenic molecule.

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“…19 The degree of angiostatin formation was determined semiquantitatively by the time point at which angiostatin formation was first observed, the intensity of angiostatin bands, and decrease of plasminogen band intensity as described. 19 Angiogenesis in BPH and prostate cancer S-J Shih et al…”

Section: Digestion Of Plasminogen To Angiostatin By Cell-culture Supementioning

confidence: 99%

“…A cell line inducing complete conversion of plasminogen to angiostatin after 24 h and/or formation of angiostatin after 8 or even 3 h of incubation was considered to be a potent angiostatin generator. 19 Immunohistochemistry for MVD CaP and BPH originating from the same radical prostatectomy specimen were immunostained. Four micron tissue sections were deparaffinized in xylene, dehydrated and incubated with 3% H 2 O 2 in absolute methanol for 10 min.…”

Section: Digestion Of Plasminogen To Angiostatin By Cell-culture Supementioning

confidence: 99%

“…18 The plasminogen-activator system is involved in converting plasminogen to angiostatin in vitro. It has been demonstrated that angiostatin can be generated by established human cell lines of melanoma, bladder, colon, cervical, breast, and ovarian carcinomas, 19 the CaP cell line PC-3, a pancreatic-cancer cell line, 20 as well as activated macrophages. 21,22 The proteolytic enzymes, u-PA, tPA, elastase, metalloproteinases (MMPs), 23 and prostate-specific antigen 24 can also be involved in angiostatin generation.…”

Section: Introductionmentioning

confidence: 99%

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Elements regulating angiogenesis and correlative microvessel density in benign hyperplastic and malignant prostate tissue

Shih

Dall′Era

Westphal³

et al. 2003

Prostate Cancer Prostatic Dis

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Purpose: To quantify the ex vivo production of proangiogenic proteins (vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), urokinase-type plasminogen activator (u-PA), tissue-type plasminogen activator (tPA)) and angiogenesis inhibitors (plasminogen activator inhibitor type-1 (PAI-1) and angiostatin) from epithelial and stromal components of primary prostate cancer (CaP) and benign prostatic hyperplasia (BPH) cultures. To perform microvessel density (MVD) counts on sections of BPH and CaP from the same prostatectomy specimens. Scope: Angiogenic cytokine expression was measured by immunoassays and in vitro angiostatin generating capacities assessed using immunoblotting. CaP and BPH tissue was immunostained using factor VIII antibody to determine MVD. Conclusions: Elements regulating angiogenesis are present in both primary cultures of CaP and BPH, suggesting that angiogenic ability is well established in the absence of carcinoma.

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Angiostatin generation by human tumor cell lines: Involvement of plasminogen activators

Cited by 48 publications

References 33 publications

Full kringles of plasminogen (aa 1–566) mediate complete regression of human MDA-MB-231 breast tumor xenografted in nude mice

Full kringles of plasminogen (aa 1–566) mediate complete regression of human MDA-MB-231 breast tumor xenografted in nude mice

Generation of Biologically Active Angiostatin Kringle 1–3 by Activated Human Neutrophils

Elements regulating angiogenesis and correlative microvessel density in benign hyperplastic and malignant prostate tissue

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