Recombinant human prothrombin kringles have potent anti-angiogenic activities and inhibit Lewis lung carcinoma tumor growth and metastases.

Abstract:

:Prothrombin, a protein involved in blood coagulation, is a plasma glycoprotein composed of the Gla domain, two adjacent kringle domains, and a serine protease domain. Kringles are triple-disulfide-loop folding domains, which are found in several other blood proteins. In this study, we showed that recombinant human prothrombin kringle-1, -2. and -1-2 (rk-1, -2, -1-2) all have potent anti-angiogenic activities, which inhibit Lewis lung carcinoma (LLC) tumor growth and metastases. Recombinant human prothrombin kringles were expressed by an E. coli expression system and purified to apparent homogeneity from crude E. coli extracts. Purified rk-1, -2, -1-2 migrated with a molecular mass of 14, 19, and 31 kDa, respectively, on sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) under reducing conditions. rk-1, -2, -1-2 exhibited potent inhibitory effects on bFGF-stimulated bovine capillary endothelial cell growth with half-maximal concentrations (ED50) of approximately 41, 55, and 156 nM, respectively. All of the recombinant human prothrombin kringles also inhibited angiogenesis in the chorioallantoic membrane (CAM) of chick embryos at a dose of 20 microg. Systemic administration of rk-1, -2, -1-2 at a dose of 0.5 mg/kg/day suppressed the growth of primary LLC and at dose of 0.5 and 1.0 mg/kg/day inhibited LLC metastases in C57BL6/J mice lungs through their anti-angiogenic effects.

journal_name

Angiogenesis

journal_title

Angiogenesis

authors

Kim TH,Kim E,Yoon D,Kim J,Rhim TY,Kim SS

doi

10.1023/a:1023835102832

subject

Has Abstract

pub_date

2002-01-01 00:00:00

pages

191-201

issue

3

eissn

0969-6970

issn

1573-7209

journal_volume

5

pub_type

杂志文章
  • New prospects in the roles of the C-terminal domains of VEGF-A and their cooperation for ligand binding, cellular signaling and vessels formation.

    abstract::VEGF-A is a crucial growth factor for blood vessel homeostasis and pathological angiogenesis. Due to alternative splicing of its pre-mRNA, VEGF-A is produced under several isoforms characterized by the combination of their C-terminal domains, which determines their respective structure, availability and affinity for c...

    journal_title:Angiogenesis

    pub_type: 杂志文章

    doi:10.1007/s10456-012-9320-y

    authors: Delcombel R,Janssen L,Vassy R,Gammons M,Haddad O,Richard B,Letourneur D,Bates D,Hendricks C,Waltenberger J,Starzec A,Sounni NE,Noël A,Deroanne C,Lambert C,Colige A

    更新日期:2013-04-01 00:00:00

  • Semaphorin 4D cooperates with VEGF to promote angiogenesis and tumor progression.

    abstract::The semaphorins and plexins comprise a family of cysteine-rich proteins implicated in control of nerve growth and development and regulation of the immune response. Our group and others have found that Semaphorin 4D (SEMA4D) and its receptor, Plexin-B1, play an important role in tumor-induced angiogenesis, with some n...

    journal_title:Angiogenesis

    pub_type: 杂志文章,收录出版

    doi:10.1007/s10456-012-9268-y

    authors: Zhou H,Binmadi NO,Yang YH,Proia P,Basile JR

    更新日期:2012-09-01 00:00:00

  • Suppression of vascular network formation by chronic hypoxia and prolyl-hydroxylase 2 (phd2) deficiency during vertebrate development.

    abstract::In the adult, new vessels and red blood cells form in response to hypoxia. Here, the oxygen-sensing system (PHD-HIF) has recently been put into focus, since the prolyl-hydroxylase domain proteins (PHD) and hypoxia-inducible factors (HIF) are considered as potential therapeutic targets to treat ischemia, cancers or age...

    journal_title:Angiogenesis

    pub_type: 杂志文章

    doi:10.1007/s10456-015-9492-3

    authors: Metikala S,Neuhaus H,Hollemann T

    更新日期:2016-04-01 00:00:00

  • Angiogenesis and chronic inflammation: cause or consequence?

    abstract::Evidence has been gathered regarding the association between angiogenesis and inflammation in pathological situations. These two phenomena have long been coupled together in many chronic inflammatory disorders with distinct etiopathogenic origin, including psoriasis, rheumatoid arthritis, Crohn's disease, diabetes, an...

    journal_title:Angiogenesis

    pub_type: 杂志文章,评审

    doi:10.1007/s10456-007-9074-0

    authors: Costa C,Incio J,Soares R

    更新日期:2007-01-01 00:00:00

  • Transcriptional regulation of the vascular endothelial glycome by angiogenic and inflammatory signalling.

    abstract::Vascular endothelial cells undergo many molecular changes during pathological processes such as inflammation and tumour development. Tumours such as malignant lymphomas affecting bone marrow are dependent on interactions with endothelial cells for (1) site-specific homing and (2) tumour-induced angiogenesis. Modificat...

    journal_title:Angiogenesis

    pub_type: 杂志文章

    doi:10.1007/s10456-010-9162-4

    authors: Willhauck-Fleckenstein M,Moehler TM,Merling A,Pusunc S,Goldschmidt H,Schwartz-Albiez R

    更新日期:2010-03-01 00:00:00

  • Angiogenesis in arthritis: role in disease pathogenesis and as a potential therapeutic target.

    abstract::Rheumatoid arthritis (RA) is a chronic destructive musculo-skeletal disorder, associated with thickening of the synovial membrane lining the joints, inflammation and hyperproliferation of synovial cells, as well as a pro-inflammatory cytokine cascade, leukocyte infiltration, and tissue damage and bone resorption. An e...

    journal_title:Angiogenesis

    pub_type: 杂志文章

    doi:10.1023/a:1009229508096

    authors: Paleolog EM,Miotla JM

    更新日期:1998-01-01 00:00:00

  • Cyclic GMP protects endothelial progenitors from oxidative stress.

    abstract::Endothelial progenitor cells (EPCs) play a critical role in the repair of damaged blood vessels and/or in the growth of new ones in ischemic tissues. Elevated levels of oxygen radicals, which accumulate in the ischemic tissue, could compromise the angiogenic potential of EPCs. To determine if oxidative stress alters t...

    journal_title:Angiogenesis

    pub_type: 杂志文章

    doi:10.1007/s10456-011-9211-7

    authors: Curatola AM,Xu J,Hendricks-Munoz KD

    更新日期:2011-09-01 00:00:00

  • Characterization of a drug-targetable allosteric site regulating vascular endothelial growth factor signaling.

    abstract::Vascular endothelial growth factors (VEGFs) regulate blood and lymph vessel development upon activation of three receptor tyrosine kinases (VEGFRs). The extracellular domain of VEGFRs consists of seven Ig-homology domains, of which D2-3 form the ligand-binding site, while the membrane proximal domains D4-7 are involve...

    journal_title:Angiogenesis

    pub_type: 杂志文章

    doi:10.1007/s10456-018-9606-9

    authors: Thieltges KM,Avramovic D,Piscitelli CL,Markovic-Mueller S,Binz HK,Ballmer-Hofer K

    更新日期:2018-08-01 00:00:00

  • CLT1 targets angiogenic endothelium through CLIC1 and fibronectin.

    abstract::Angiogenesis is important for tumor growth and metastasis. CLT1 (CGLIIQKNEC), a peptide that binds to tumor interstitial spaces in the presence of fibrin-fibronectin, has structural similarity to the anti-angiogenic β-sheet peptides anastellin and anginex. This similarity is reflected in the ability of CLT1 to form co...

    journal_title:Angiogenesis

    pub_type: 杂志文章

    doi:10.1007/s10456-011-9247-8

    authors: Knowles LM,Malik G,Hood BL,Conrads TP,Pilch J

    更新日期:2012-03-01 00:00:00

  • Strain differences and inheritance of angiogenic versus angiostatic activity in oestrogen-induced rat pituitary tumours.

    abstract::In this study we investigated the control of the angiogenic/haemorrhagic phenotype of oestrogen-induced rat pituitary tumours of an F1 hybrid (F1) of Fischer 344 (F344) (tumour susceptible) and Brown Norway (tumour resistant) strains. F1 forms a pituitary tumour upon chronic oestrogen treatment, but microvessel count ...

    journal_title:Angiogenesis

    pub_type: 杂志文章

    doi:10.1023/a:1021550211921

    authors: Pandey J,Cracchiolo D,Hansen FM,Wendell DL

    更新日期:2002-01-01 00:00:00

  • Pharmacological intervention of MKL/SRF signaling by CCG-1423 impedes endothelial cell migration and angiogenesis.

    abstract::De novo synthesis of cytoskeleton-regulatory proteins triggered by the megakaryoblastic leukemia (MKL)/serum response factor (SRF) transcriptional system in response to pro-angiogenic growth factors lies at the heart of endothelial cell (EC) migration (a critical element of angiogenesis) and neovascularization. This s...

    journal_title:Angiogenesis

    pub_type: 杂志文章

    doi:10.1007/s10456-017-9560-y

    authors: Gau D,Veon W,Capasso TL,Bottcher R,Shroff S,Roman BL,Roy P

    更新日期:2017-11-01 00:00:00

  • Contrasting effects of sunitinib within in vivo models of metastasis.

    abstract::Sunitinib is a potent and clinically approved tyrosine kinase inhibitor that can suppress tumour growth by inhibiting angiogenesis. However, conflicting data exist regarding the effects of this drug on the growth of metastases in preclinical models. Here we use 4T1 and RENCA tumour cells, which both form lung metastas...

    journal_title:Angiogenesis

    pub_type: 杂志文章

    doi:10.1007/s10456-012-9291-z

    authors: Welti JC,Powles T,Foo S,Gourlaouen M,Preece N,Foster J,Frentzas S,Bird D,Sharpe K,van Weverwijk A,Robertson D,Soffe J,Erler JT,Pili R,Springer CJ,Mather SJ,Reynolds AR

    更新日期:2012-12-01 00:00:00

  • Transcriptional profiling of human microvascular endothelial cells in the proliferative and quiescent state using cDNA arrays.

    abstract::Endothelial cells are known to be a rich source of transcriptional gene expression. Recent technological advances now permit the detailed profiling of mRNA expression using arrays of known cDNAs on blots. We have used such arrays to examine expression of mRNA by primary isolates of human foreskin microvascular endothe...

    journal_title:Angiogenesis

    pub_type: 杂志文章

    doi:10.1023/a:1009085422384

    authors: Zhang HT,Gorn M,Smith K,Graham AP,Lau KK,Bicknell R

    更新日期:1999-01-01 00:00:00

  • STAT1 activation by venous malformations mutant Tie2-R849W antagonizes VEGF-A-mediated angiogenic response partly via reduced bFGF production.

    abstract::A missense mutation from arginine to tryptophan at residue 849 in the kinase domain of Tie2 (Tie2-R849W) is commonly identified in familial venous malformations. The mechanistic action of Tie2-R849W variant expression on angiogenic cascades including smooth muscle cell recruitment, however, remains elusive. To avoid c...

    journal_title:Angiogenesis

    pub_type: 杂志文章

    doi:10.1007/s10456-012-9313-x

    authors: Huang YH,Wu MP,Pan SC,Su WC,Chen YW,Wu LW

    更新日期:2013-01-01 00:00:00

  • Endothelial cells expressing low levels of CD143 (ACE) exhibit enhanced sprouting and potency in relieving tissue ischemia.

    abstract::The sprouting of endothelial cells from pre-existing blood vessels represents a critical event in the angiogenesis cascade. However, only a fraction of cultured or transplanted endothelial cells form new vessels. Moreover, it is unclear whether this results from a stochastic process or instead relates to certain endot...

    journal_title:Angiogenesis

    pub_type: 杂志文章

    doi:10.1007/s10456-014-9414-9

    authors: Silva EA,Eseonu C,Mooney DJ

    更新日期:2014-07-01 00:00:00

  • Tumor vasculogenic mimicry predicts poor prognosis in cancer patients: a meta-analysis.

    abstract:BACKGROUND:Vasculogenic mimicry (VM) is the formation of vascular channels by tumor cells or tumor cell-derived, trans-differentiated cells in highly aggressive, solid tumors. However, the disease features and prognostic value of VM for overall survival of cancer patients remain controversial. METHOD:To systematically...

    journal_title:Angiogenesis

    pub_type: 杂志文章,meta分析

    doi:10.1007/s10456-016-9500-2

    authors: Yang JP,Liao YD,Mai DM,Xie P,Qiang YY,Zheng LS,Wang MY,Mei Y,Meng DF,Xu L,Cao L,Yang Q,Yang XX,Wang WB,Peng LX,Huang BJ,Qian CN

    更新日期:2016-04-01 00:00:00

  • Time-dependent LXR/RXR pathway modulation characterizes capillary remodeling in inflammatory corneal neovascularization.

    abstract::Inflammation in the normally immune-privileged cornea can initiate a pathologic angiogenic response causing vision-threatening corneal neovascularization. Inflammatory pathways, however, are numerous, complex and are activated in a time-dependent manner. Effective resolution of inflammation and associated angiogenesis...

    journal_title:Angiogenesis

    pub_type: 杂志文章

    doi:10.1007/s10456-018-9604-y

    authors: Mukwaya A,Lennikov A,Xeroudaki M,Mirabelli P,Lachota M,Jensen L,Peebo B,Lagali N

    更新日期:2018-05-01 00:00:00

  • Antiangiogenic tyrosine kinase inhibition related gastrointestinal perforations: a case report and literature review.

    abstract::Anti-VEGF (vascular endothelial growth factor) therapy with the monoclonal antibody bevacizumab can cause gastrointestinal (GI) perforations. In recent years it became apparent that GI perforations also occur during treatment with antiangiogenic tyrosine kinase inhibitors (TKIs). It is of clinical importance to consid...

    journal_title:Angiogenesis

    pub_type: 杂志文章,评审

    doi:10.1007/s10456-010-9197-6

    authors: Walraven M,Witteveen PO,Lolkema MP,van Hillegersberg R,Voest EE,Verheul HM

    更新日期:2011-05-01 00:00:00

  • Angiogenic desmoplastic histopathological growth pattern as a prognostic marker of good outcome in patients with colorectal liver metastases.

    abstract:BACKGROUND:In patients with resectable colorectal liver metastases (CRLM), distinct histopathological growth patterns (HGPs) develop at the interface between the tumour and surrounding tissue. The desmoplastic (d) HGP is characterised by angiogenesis and a peripheral fibrotic rim, whereas non-angiogenic HGPs co-opt end...

    journal_title:Angiogenesis

    pub_type: 杂志文章

    doi:10.1007/s10456-019-09661-5

    authors: Galjart B,Nierop PMH,van der Stok EP,van den Braak RRJC,Höppener DJ,Daelemans S,Dirix LY,Verhoef C,Vermeulen PB,Grünhagen DJ

    更新日期:2019-05-01 00:00:00

  • Identification of soluble CD146 as a regulator of trophoblast migration: potential role in placental vascular development.

    abstract::Both vasculogenesis and angiogenesis occur during normal placental vascular development. Additionally, the placenta undergoes a process of vascular mimicry (pseudo-vasculogenesis) where the placental extravillous trophoblast (EVT) that invade the spiral arteries convert from an epithelial to an endothelial phenotype d...

    journal_title:Angiogenesis

    pub_type: 杂志文章

    doi:10.1007/s10456-012-9317-6

    authors: Kaspi E,Guillet B,Piercecchi-Marti MD,Alfaidy N,Bretelle F,Bertaud-Foucault A,Stalin J,Rambeloson L,Lacroix O,Blot-Chabaud M,Dignat-George F,Bardin N

    更新日期:2013-04-01 00:00:00

  • The role of the fibrinolytic system in corneal angiogenesis.

    abstract::The plasminogen activation system has been implicated in angiogenesis and angiogenesis-dependent diseases such as cancer, atherosclerosis and ocular diseases. The identification and development of inhibitors of angiogenesis offer new possibilities for the treatment of these diseases. To clarify the role of proteins in...

    journal_title:Angiogenesis

    pub_type: 杂志文章

    doi:10.1023/B:AGEN.0000029414.24060.fe

    authors: Vogten JM,Reijerkerk A,Meijers JC,Voest EE,Borel Rinkes IH,Gebbink MF

    更新日期:2003-01-01 00:00:00

  • TM4SF1: a tetraspanin-like protein necessary for nanopodia formation and endothelial cell migration.

    abstract::Transmembrane-4-L-six-family-1 (TM4SF1) is a tetraspanin-like membrane protein that is highly and selectively expressed by cultured endothelial cells (EC) and, in vivo, by EC lining angiogenic tumor blood vessels. TM4SF1 is necessary for the formation of unusually long (up to a 50 μm), thin (~100-300 nm wide), F-actin...

    journal_title:Angiogenesis

    pub_type: 杂志文章

    doi:10.1007/s10456-011-9218-0

    authors: Zukauskas A,Merley A,Li D,Ang LH,Sciuto TE,Salman S,Dvorak AM,Dvorak HF,Jaminet SC

    更新日期:2011-09-01 00:00:00

  • CMTM4 regulates angiogenesis by promoting cell surface recycling of VE-cadherin to endothelial adherens junctions.

    abstract::Vascular endothelial (VE) cadherin is a key component of endothelial adherens junctions (AJs) and plays an important role in maintaining vascular integrity. Endocytosis of VE-cadherin regulates junctional strength and a decrease of surface VE-cadherin reduces vascular stability. However, disruption of AJs is also a re...

    journal_title:Angiogenesis

    pub_type: 杂志文章

    doi:10.1007/s10456-018-9638-1

    authors: Chrifi I,Louzao-Martinez L,Brandt MM,van Dijk CGM,Bürgisser PE,Zhu C,Kros JM,Verhaar MC,Duncker DJ,Cheng C

    更新日期:2019-02-01 00:00:00

  • Visualization of endothelial cell cycle dynamics in mouse using the Flt-1/eGFP-anillin system.

    abstract::Endothelial cell proliferation is a key process during vascular growth but its kinetics could only be assessed in vitro or ex vivo so far. To enable the monitoring and quantification of cell cycle kinetics in vivo, we have generated transgenic mice expressing an eGFP-anillin construct under control of the endothelial-...

    journal_title:Angiogenesis

    pub_type: 杂志文章

    doi:10.1007/s10456-018-9601-1

    authors: Herz K,Becker A,Shi C,Ema M,Takahashi S,Potente M,Hesse M,Fleischmann BK,Wenzel D

    更新日期:2018-05-01 00:00:00

  • Genetic markers of bevacizumab-induced hypertension.

    abstract:PURPOSE:There are currently no validated biomarkers predicting bevacizumab treatment outcome or toxicity. We combined biomarker data from six phase III trials of bevacizumab to assess whether genetic variation in vascular endothelial growth factor-A (VEGF-A) pathway or hypertension-related genes are associated with bev...

    journal_title:Angiogenesis

    pub_type: 杂志文章

    doi:10.1007/s10456-014-9424-7

    authors: Lambrechts D,Moisse M,Delmar P,Miles DW,Leighl N,Escudier B,Van Cutsem E,Bansal AT,Carmeliet P,Scherer SJ,de Haas S,Pallaud C

    更新日期:2014-07-01 00:00:00

  • Pazopanib may reduce bleeding in hereditary hemorrhagic telangiectasia.

    abstract::Pazopanib (Votrient) is an orally administered tyrosine kinase inhibitor that blocks VEGF receptors potentially serving as anti-angiogenic treatment for hereditary hemorrhagic telangiectasia (HHT). We report a prospective, multi-center, open-label, dose-escalating study [50 mg, 100 mg, 200 mg, and 400 mg], designed as...

    journal_title:Angiogenesis

    pub_type: 临床试验,杂志文章,多中心研究

    doi:10.1007/s10456-018-9646-1

    authors: Faughnan ME,Gossage JR,Chakinala MM,Oh SP,Kasthuri R,Hughes CCW,McWilliams JP,Parambil JG,Vozoris N,Donaldson J,Paul G,Berry P,Sprecher DL

    更新日期:2019-02-01 00:00:00

  • Matrix Gla protein regulates differentiation of endothelial cells derived from mouse embryonic stem cells.

    abstract::Matrix Gla protein (MGP) is an antagonist of bone morphogenetic proteins and expressed in vascular endothelial cells. Lack of MGP causes vascular abnormalities in multiple organs in mice. The objective of this study is to define the role of MGP in early endothelial differentiation. We find that expression of endotheli...

    journal_title:Angiogenesis

    pub_type: 杂志文章

    doi:10.1007/s10456-015-9484-3

    authors: Yao J,Guihard PJ,Blazquez-Medela AM,Guo Y,Liu T,Boström KI,Yao Y

    更新日期:2016-01-01 00:00:00

  • Angiogenesis and endothelium phenotype expression in embryonic adrenal gland and cerebellum grafted onto chorioallantoic membrane.

    abstract::Vascularization and endothelial phenotype were investigated in embryonic tissues grafted onto chorioallantoic membrane (CAM) by means of immunocytochemistry and electron microscopy. Single grafts of adrenal gland or cerebellum and double grafts of adrenal gland plus cerebellum were performed, using tissues from chick ...

    journal_title:Angiogenesis

    pub_type: 杂志文章

    doi:10.1023/a:1026550510585

    authors: Bertossi M,Virgintino D,Coltey P,Errede M,Mancini L,Roncali L

    更新日期:1999-01-01 00:00:00

  • Inhibition of angiogenesis by vitamin D-binding protein: characterization of anti-endothelial activity of DBP-maf.

    abstract::Angiogenesis is a complex process involving coordinated steps of endothelial cell activation, proliferation, migration, tube formation and capillary sprouting with participation of intracellular signaling pathways. Regulation of angiogenesis carries tremendous potential for cancer therapy. Our earlier studies showed t...

    journal_title:Angiogenesis

    pub_type: 杂志文章

    doi:10.1007/s10456-005-9024-7

    authors: Kalkunte S,Brard L,Granai CO,Swamy N

    更新日期:2005-01-01 00:00:00

  • Early contribution of pericytes to angiogenic sprouting and tube formation.

    abstract::Immunostaining with endothelial and pericyte markers was used to evaluate the cellular composition of angiogenic sprouts in several types of tumors and in the developing retina. Confocal microscopy revealed that, in addition to conventional endothelial tubes heavily invested by pericytes, all tissues contained small p...

    journal_title:Angiogenesis

    pub_type: 杂志文章

    doi:10.1023/B:AGEN.0000021401.58039.a9

    authors: Ozerdem U,Stallcup WB

    更新日期:2003-01-01 00:00:00