Structure and Inhibitory Effects on Angiogenesis and Tumor Development of a New Vascular Endothelial Growth Inhibitor

Zilberberg, Lior; Shinkaruk, Svitlana; Lequin, Olivier; Rousseau, Benoı̂t; Hagedorn, Martin; Costa, Francesco; Caronzolo, Dario; Balke, Maurice; Canron, Xavier; Convert, Odile; Laïn, Georges; Gionnet, K.; Gonçalves, Mário A.; Bayle, Mireille; Bello, Lorenzo; Chassaing, Gérard; Déléris, Gérard; Bikfalvi, Andréas

doi:10.1074/jbc.m304435200

Cited by 112 publications

(99 citation statements)

References 58 publications

(62 reference statements)

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“…To test the first possibility, we treated the hMVECs with IL-8 in the presence of the VEGF inhibitor CBO-P11, a cyclic peptide that binds to VEGFR and thus prevents both binding of VEGF to the receptor and receptor activation (Zilberberg et al, 2003), and we examined the phosphorylation/activation of VEGFR2. The results show that inhibition of binding of VEGF to the receptor did not eliminate activation of VEGFR2 by IL-8 ( Figure 3B).…”

Section: Il-8 Stimulates Activation Of Vegfr2 In a Vegf-independent Mmentioning

confidence: 99%

Transactivation of Vascular Endothelial Growth Factor Receptor-2 by Interleukin-8 (IL-8/CXCL8) Is Required for IL-8/CXCL8-induced Endothelial Permeability

Petreaca

Yao²,

Liu³

et al. 2007

MBoC

178

136

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Interleukin-8 (IL-8/CXCL8) is a chemokine that increases endothelial permeability during early stages of angiogenesis. However, the mechanisms involved in IL-8/CXCL8-induced permeability are poorly understood. Here, we show that permeability induced by this chemokine requires the activation of vascular endothelial growth factor receptor-2 (VEGFR2/fetal liver kinase 1/KDR). IL-8/CXCL8 stimulates VEGFR2 phosphorylation in a VEGF-independent manner, suggesting VEGFR2 transactivation. We investigated the possible contribution of physical interactions between VEGFR2 and the IL-8/CXCL8 receptors leading to VEGFR2 transactivation. Both IL-8 receptors interact with VEGFR2 after IL-8/CXCL8 treatment, and the time course of complex formation is comparable with that of VEGFR2 phosphorylation. Src kinases are involved upstream of receptor complex formation and VEGFR2 transactivation during IL-8/CXCL8-induced permeability. An inhibitor of Src kinases blocked IL-8/CXCL8-induced VEGFR2 phosphorylation, receptor complex formation, and endothelial permeability. Furthermore, inhibition of the VEGFR abolishes RhoA activation by IL-8/CXCL8, and gap formation, suggesting a mechanism whereby VEGFR2 transactivation mediates IL-8/CXCL8-induced permeability. This study points to VEGFR2 transactivation as an important signaling pathway used by chemokines such as IL-8/CXCL8, and it may lead to the development of new therapies that can be used in conditions involving increases in endothelial permeability or angiogenesis, particularly in pathological situations associated with both IL-8/CXCL8 and VEGF. INTRODUCTIONAngiogenesis is a multistep process in which quiescent blood vessels give rise to new blood vessels. After endothelial cells are exposed to an angiogenic factor, the endothelium is destabilized, leading to a decrease in endothelial cell adhesion and an increase in vascular permeability. Simultaneously, matrix metalloproteinases are produced and activated, which degrade the basal lamina in discrete regions of the blood vessel. The endothelial cells are then able to proliferate and migrate into surrounding connective tissue, forming a "sprout," or cord of endothelial cells, which subsequently develops a lumen; sprouts from adjacent arterioles and venules fuse to form a network of blood vessels.The nascent vessels then recruit periendothelial cells, smooth muscle-like cells that stabilize the endothelium by promoting basal lamina deposition and intercellular adhesions (Daniel and Abrahamson, 2000;Conway et al., 2001).During inflammation and angiogenesis, multiple factors, including tumor necrosis factor-␣ (Nwariaku et al., 2002), histamine (Leach et al., 1995;van Nieuw Amerongen et al., 1998;Andriopoulou et al., 1999), thrombin (van Nieuw Amerongen et al., 1998;Moldobaeva and Wagner, 2002), and vascular endothelial growth factor (VEGF) (Esser et al., 1998;Kevil et al., 1998;Eliceiri et al., 1999;Chang et al., 2000), increase vascular permeability by altering cell-cell adhesion, gap formation between endothelial cells, or both. Anothe...

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Section: Il-8 Stimulates Activation Of Vegfr2 In a Vegf-independent Mmentioning

confidence: 99%

Transactivation of Vascular Endothelial Growth Factor Receptor-2 by Interleukin-8 (IL-8/CXCL8) Is Required for IL-8/CXCL8-induced Endothelial Permeability

Petreaca

Yao²,

Liu³

et al. 2007

MBoC

178

136

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“…24 The immunoblots were visualized with the enhanced chemiluminescence (ECL plus) Western blotting detection system (Amersham Pharmacia Biotech, Uppsala, Sweden). 24 For enzyme-linked immunosorbent assay (ELISA) quantification of CXCL4/CXCL4L1 in supernatants and in lysates of different cell types, cells were plated at a density of 1 ϫ 10 6 cells/mL. After overnight culture in serum-free media, media were changed and cells cultured for additional 24 hours in serum-free media.…”

Section: Western Blot and Elisamentioning

confidence: 99%

PF-4/CXCL4 and CXCL4L1 exhibit distinct subcellular localization and a differentially regulated mechanism of secretion

Lasagni

Grépin

Mazzinghi

et al. 2007

Blood

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PF-4/CXCL4 is a member of the CXC chemokine family, which is mainly produced by platelets and known for its pleiotropic biological functions. Recently, the proteic product of a nonallelic variant gene of CXCL4 was isolated from human platelets and named as CXCL4L1. CXCL4L1 shows only 4.3% amino acid divergence in the mature protein, but exhibits a 38% amino acid divergence in the signal peptide region. We hypothesized that this may imply a difference in the cell type in which CXCL4L1 is expressed or a difference in its mode of secretion. In different types of transfected cells, CXCL4 and CXCL4L1 exhibited a distinct subcellular localization and a differential regulation of secretion, CXCL4 being stored in secretory granules and released in response to protein kinase C activation, whereas CXCL4L1 was continuously synthesized and secreted through a constitutive pathway. A protein kinase C-regulated CXCL4 secretion was observed also in lymphocytes, a cell type expressing mainly CXCL4 mRNA, whereas smooth muscle cells, which preferentially expressed CXCL4L1, exhibited a constitutive pathway of secretion. These results demonstrate that CXCL4 and CXCL4L1 exhibit a distinct subcellular localization and are secreted in a differentially regulated manner, suggesting distinct roles in inflammatory or homeostatic processes. IntroductionPF-4/CXCL4 is a member of the CXC chemokine family produced by cells of the megakaryocytic lineage. In megakaryocytes CXCL4 is synthesized, enclosed in vesicles, and transferred to the ␣ granules from which it is secreted following platelet activation. 1 More recently, CXCL4 expression was also found in monocytes. 2 The first biological function described for CXCL4 is its antiheparin activity, responsible for the important role of CXCL4 in the regulation of coagulation processes. 3 In addition, CXCL4 has a role in heparin-induced thrombocytopenia (HIT), a common immune-mediated disorder characterized by an immune response against epitopes within circulating heparin-CXCL4 complexes, which leads to a reduction of circulating platelets counts and is recognized as a risk factor for thromboembolic complications. 4,5 Subsequent studies have defined an array of apparently unrelated CXCL4 activities. CXCL4 exhibits antiangiogenic properties in vitro and in vivo and inhibits tumor neovascularization through a variety of mechanisms. [6][7][8] First, CXCL4 is able to interact directly with angiogenic growth factors, such as fibroblast growth factors (FGFs) and vascular endothelial growth factor (VEGF), and inhibits their interaction with the cell surface receptor. 6,9 Second, CXCL4 may bind proteoglycans and interfere with the proteoglycan-bystander effect on growth factor activity. 10 Furthermore, a cell surface receptor that is expressed by human endothelial cells (ECs) in a cell cycle-dependent manner 11 and mediates the antiangiogenic effects of CXCL4 has been recently identified and named as Besides the antiangiogenic properties, CXCL4 expresses immunomodulatory activities, such as down-regulatio...

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“…Two different antiangiogenic drugs have been evaluated: thalidomide-which induces apoptosis of endothelial cells-and a cyclopeptidic vascular endothelial growth inhibitor (VEGF)-CBOP11-which inhibits VEGF-induced endothelial cell proliferation (19,20). A significant part of the study focused on the determination of the best relative timing for radioimmunotherapy and antiangiogenic treatment.…”

mentioning

confidence: 99%

Comparative Toxicity and Efficacy of Combined Radioimmunotherapy and Antiangiogenic Therapy in Carcinoembryonic Antigen–Expressing Medullary Thyroid Cancer Xenograft

Kraeber-Bodéré¹,

Bodet-Milin²,

Niaudet³

et al. 2010

J Nucl Med

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A significant antitumor effect was previously observed with radioimmunotherapy using anti-carcinoembryonic antigen 131 I-F6 monoclonal antibody in medullary thyroid cancer-bearing nude mice. Nevertheless, no complete response was observed. As seen with chemotherapy, drugs targeting the tumor microenvironment might improve radioimmunotherapy efficacy. This study evaluated the toxicity and efficacy of combining radioimmunotherapy with thalidomide or a cyclopeptidic vascular endothelial growth inhibitor (CBOP11) in mice grafted with the TT human medullary thyroid cancer cell line. Methods: Six to 10 nude mice treated with 92.5 MBq of 131 I-F6 in association with 200 mg/kg/d of oral thalidomide during 20 d by force-feeding or 0.45 mg/kg/d of CBOP11 during 25 d using subcutaneous minipumps were compared with control mice receiving either treatment or naked F6 or nonspecific 131 I-734. Combined therapies included 131 I-F6 at day 0 followed by thalidomide between days 20 and 40, thalidomide between days 0 and 20 followed by 131 I-F6 at day 25, 131 I-F6 at day 0 and CBOP11 between days 0 and 25, CBOP11 between days 0 and 25 followed by 131 I-F6 at day 25, and 131 I-F6 at day 0 followed by CBOP11 between days 20 and 45. Animal weight, hematologic toxicity, tumor volume, and serum calcitonin were monitored for the following 3 mo. Improvement of 125 I-F6 tumor biodistribution by antiangiogenic drug was studied after pretreatment by thalidomide. Follow-up of the tumor after combined antiangiogenic and radioimmunotherapy therapies was performed by histology studies. Results: Combined associations, as compared with radioimmunotherapy alone, increased leukopenia but not thrombocytopenia. Tumor volume-quadrupling time (TVQT) was 22.8 6 3.3 d in the control group, 29.9 6 3.6 d in the group treated with thalidomide, 34.6 6 4.4 d in the group treated with CBOP11, and 51.0 6 2.8 d after radioimmunotherapy alone. As compared with radioimmunotherapy, TVQT was significantly longer (P , 0.01) after thalidomide followed by radioimmunotherapy (69.83 6 3.9), CBOP11 followed by radioimmunotherapy (71.3 6 6.1), and CBOP11-radioimmunotherapy in concomitance (64.2 6 6.1). Nevertheless, TVQT was not increased after radioimmunotherapy followed by thalidomide (48.8 6 4) and radioimmunotherapy followed by CBOP11 (56.8 6 4.8). Surprisingly, pretreatment by CBOP11 or thalidomide sensitized larger tumors (.300 mm 3 ) to radioimmunotherapy. Change in calcitonin levels confirmed morphologic tumor response. Tumor uptake 24 h after injection of 125 I-F6 was 4.5 6 0.6 percentage injected dose per gram (%ID/g) without pretreatment and 8.7 6 1.3 %ID/g with pretreatment by thalidomide. An increase of the antitumor effect observed using the antiangiogenic drug combined with radioimmunotherapy was correlated with a decrease of blood vessels shown by von Willebrand immunostaining. Conclusion: Pretreatment with antiangiogenic therapies improved radioimmunotherapy efficacy, with acceptable toxicity. Future investigations will be performed to understand how antia...

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Structure and Inhibitory Effects on Angiogenesis and Tumor Development of a New Vascular Endothelial Growth Inhibitor

Cited by 112 publications

References 58 publications

Transactivation of Vascular Endothelial Growth Factor Receptor-2 by Interleukin-8 (IL-8/CXCL8) Is Required for IL-8/CXCL8-induced Endothelial Permeability

Transactivation of Vascular Endothelial Growth Factor Receptor-2 by Interleukin-8 (IL-8/CXCL8) Is Required for IL-8/CXCL8-induced Endothelial Permeability

PF-4/CXCL4 and CXCL4L1 exhibit distinct subcellular localization and a differentially regulated mechanism of secretion

Comparative Toxicity and Efficacy of Combined Radioimmunotherapy and Antiangiogenic Therapy in Carcinoembryonic Antigen–Expressing Medullary Thyroid Cancer Xenograft

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