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  • 1
    Keywords: ANGIOGENESIS ; CELLS ; EXPRESSION ; GROWTH ; carcinoma ; IN-VIVO ; INHIBITION ; MIGRATION ; ADHESION MOLECULE ; MORPHOGENESIS ; RECEPTOR-TYROSINE KINASE ; BREAST-CANCER METASTASIS ; LUNG METASTASIS
    Abstract: The tyrosine kinase receptor EphB4 interacts with its ephrinB2 ligand to act as a bidirectional signaling system that mediates adhesion, migration, and guidance by controlling attractive and repulsive activities. Recent findings have shown that hematopoietic cells expressing EphB4 exert adhesive functions towards endothelial cells expressing ephrinB2. We therefore hypothesized that EphB4/ephrinB2 interactions may be involved in the preferential adhesion of EphB4-expressing tumor cells to ephrinB2-expressing endothelial cells. Screening of a panel of human tumor cell lines identified EphB4 expression in nearly all analyzed tumor cell lines. Human A375 melanoma cells engineered to express either full-length EphB4 or truncated EphB4 variants which lack the cytoplasmic catalytic domain (Delta C-EphB4) adhered preferentially to ephrinB2-expressing endothelial cells. Force spectroscopy by atomic force microscopy confirmed, on the single cell level, the rapid and direct adhesive interaction between EphB4 and ephrinB2. Tumor cell trafficking experiments in vivo using sensitive luciferase detection techniques revealed significantly more EphB4-expressing A375 cells but not Delta C-EphB4-expressing or mock-transduced control cells in the lungs, the liver, and the kidneys. Correspondingly, ephrinB2 expression was detected in the microvessels of these organs. The specificity of the EphB4-mediated tumor homing phenotype was validated by blocking the EphB4/ephrinB2 interaction with soluble EphB4-Fc. Taken together, these experiments identify adhesive EphB4/ephrinB2 interactions between tumor cells and endothelial cells as a mechanism for the site-specific metastatic dissemination of tumor cells.
    Type of Publication: Journal article published
    PubMed ID: 21047731
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  • 2
    Keywords: CELLS ; GROWTH ; BLOOD ; GENE ; MATURATION ; DISRUPTION ; EXPRESSION ANALYSIS ; TUMOR ANGIOGENESIS ; MORPHOGENESIS ; neuropilin-1
    Abstract: OBJECTIVE: To characterize the role of a vascular-expressed class 3 semaphorin (semaphorin 3G [Sema3G]). METHODS AND RESULTS: Semaphorins have been identified as axon guidance molecules. Yet, they have more recently also been characterized as attractive and repulsive regulators of angiogenesis. Through a transcriptomic screen, we identified Sema3G as a molecule of angiogenic endothelial cells. Sema3G-deficient mice are viable and exhibit no overt vascular phenotype. Yet, LacZ expression in the Sema3G locus revealed intense arterial vascular staining in the angiogenic vasculature, starting at E9.5, which was detectable throughout adolescence and downregulated in adult vasculature. Sema3G is expressed as a full-length 100-kDa secreted molecule that is processed by furin proteases to yield 95- and a 65-kDa Sema domain-containing subunits. Full-length Sema3G binds to NP2, whereas processed Sema3G binds to NP1 and NP2. Expression profiling and cellular experiments identified autocrine effects of Sema3G on endothelial cells and paracrine effects on smooth muscle cells. CONCLUSIONS: Although the mouse knockout phenotype suggests compensatory mechanisms, the experiments identify Sema3G as a primarily endothelial cell-expressed class 3 semaphorin that controls endothelial and smooth muscle cell functions in autocrine and paracrine manners, respectively.
    Type of Publication: Journal article published
    PubMed ID: 20947821
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  • 3
    Keywords: RECEPTOR ; ANGIOGENESIS ; CELLS ; ENDOTHELIAL-CELLS ; GROWTH ; proliferation ; CELL ; ENDOTHELIAL GROWTH-FACTOR ; TYROSINE KINASE ; MICE ; TRANSDUCTION ; COMPLEX ; COMPLEXES ; MECHANISM ; BINDING ; BIOLOGY ; MOLECULAR-BIOLOGY ; PHOSPHORYLATION ; signal transduction ; SIGNAL ; FORM ; ISOFORM ; MUTANT ; SIGNAL-TRANSDUCTION ; EFFICIENT ; DISPLAY ; TUMOR ANGIOGENESIS ; AFFINITY ; VEGF ; LACKING ; BINDS ; signaling ; molecular biology ; molecular ; ENHANCER ; RE ; INCREASE ; endothelial cells ; AMINO-ACID ; ENHANCEMENT ; USA ; function ; vascular endothelial growth factor ; ENDOTHELIAL-CELL ; INHIBIT ; vasculogenesis ; neuropilin-1 ; ENDOTHELIAL GROWTH ; KDR ; binding affinity ; semaphorin
    Abstract: The neuropilin-1 (np1) receptor binds the 165 amino-acid form of vascular endothelial growth factor(165) (VEGF(165)) and functions as an enhancer that potentiates VEGF(165) signaling via the VEGFR-2 tyrosine-kinase receptor. To study the mechanism by which neuropilins potentiate VEGF activity we produced a VEGF(165) mutant (VEGF(165KF)) that binds to neuropilins but displays a much lower affinity toward VEGFR-1 and VEGFR-2. VEGF(165KF) failed to induce VEGFR-2 phosphorylation in cells lacking neuropilins. However, in the presence of np1, VEGF(165KF) bound weakly to VEGFR-2, induced VEGFR-2 phosphorylation, and activated ERK1/2. Interestingly, VEGF(165KF) did not promote formation of VEGFR-2/np1 complexes nor did high concentrations of VEGF(165KF) inhibit VEGF165 induced formation of such complexes, suggesting that VEGF(165) does not stabilize VEGFR-2/np1 complexes by forming bridges spanning VEGFR-2 and np1. VEGF(121) is a VEGF form that does not bind to neuropilins. Surprisingly, both np1 and neuropilin-2 (np2) enhanced VEGF(121)-induced phosphorylation of VEGFR-2 and VEGF121-induced proliferation of endothelial cells. The enhancement of VEGF(121) activity by np1 was accompanied by a 10-fold increase in binding affinity. to, VEGFR-2 and was not associated with the formation of new VEGFR-2/np1 complexes. These observations suggest that neuropilins enhance the activity of VEGF forms that do not bind to neuropilins, indicate that np2 is a functional VEGF receptor, and imply that spontaneously formed VEGFR-2/np1 complexes suffice for efficient neuropilin mediated enhancement of VEGF activity
    Type of Publication: Journal article published
    PubMed ID: 17185751
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  • 4
    Abstract: Neuropilin-1 (NRP1) regulates developmental and pathological angiogenesis, arteriogenesis, and vascular permeability, acting as a coreceptor for semaphorin 3A (Sema3A) and the 165-amino acid isoform of vascular endothelial growth factor A (VEGF-A165). NRP1 is also the receptor for the CendR peptides, a class of cell- and tissue-penetrating peptides with a specific R-x-x-R carboxyl-terminal motif. Because the cytoplasmic domain of NRP1 lacks catalytic activity, NRP1 is mainly thought to act through the recruitment and binding to other receptors. We report here that the NRP1 intracellular domain mediates vascular permeability. Stimulation with VEGF-A165, a ligand-blocking antibody, and a CendR peptide led to NRP1 accumulation at cell-cell contacts in endothelial cell monolayers, increased cellular permeability in vitro and vascular leakage in vivo. Biochemical analyses, VEGF receptor-2 (VEGFR-2) silencing, and the use of a specific VEGFR blocker established that the effects induced by the CendR peptide and the antibody were independent of VEGFR-2. Moreover, leakage assays in mice expressing a mutant NRP1 lacking the cytoplasmic domain revealed that this domain was required for NRP1-induced vascular permeability in vivo. Hence, these data define a vascular permeability pathway mediated by NRP1 but independent of VEGFR-2 activation.
    Type of Publication: Journal article published
    PubMed ID: 27117252
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  • 5
    Abstract: The vascular endothelial growth factor (VEGF) isoform VEGF165 stimulates vascular growth and hyperpermeability. Whereas blood vessel growth is essential to sustain organ health, chronic hyperpermeability causes damaging tissue edema. By combining in vivo and tissue culture models, we show here that VEGF165-induced vascular leakage requires both VEGFR2 and NRP1, including the VEGF164-binding site of NRP1 and the NRP1 cytoplasmic domain (NCD), but not the known NCD interactor GIPC1. In the VEGF165-bound receptor complex, the NCD promotes ABL kinase activation, which in turn is required to activate VEGFR2-recruited SRC family kinases (SFKs). These results elucidate the receptor complex and signaling hierarchy of downstream kinases that transduce the permeability response to VEGF165. In a mouse model with choroidal neovascularisation akin to age-related macular degeneration, NCD loss attenuated vessel leakage without affecting neovascularisation. These findings raise the possibility that targeting NRP1 or its NCD interactors may be a useful therapeutic strategy in neovascular disease to reduce VEGF165-induced edema without compromising vessel growth.
    Type of Publication: Journal article published
    PubMed ID: 28289053
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  • 6
    Keywords: RECEPTOR ; ANGIOGENESIS ; APOPTOSIS ; CANCER ; CELLS ; GROWTH ; GROWTH-FACTOR ; IN-VITRO ; proliferation ; tumor ; carcinoma ; CELL ; CELL-PROLIFERATION ; ENDOTHELIAL GROWTH-FACTOR ; Germany ; human ; IN-VIVO ; MICROVESSEL DENSITY ; PERFUSION ; VITRO ; VIVO ; DENSITY ; SYSTEM ; DIFFERENTIATION ; TUMORS ; MEMBER ; SUSCEPTIBILITY ; MOUSE ; PROGRESSION ; ASSAY ; CARCINOMA CELLS ; TUMOR PROGRESSION ; FIBROBLAST-GROWTH-FACTOR ; CARCINOMA-CELLS ; Jun ; RECRUITMENT ; ANTAGONIST ; BINDING PROTEIN ; CELL-GROWTH ; CELL CARCINOMA ; renal cell carcinoma ; ONCOLOGY ; RE ; TUMOR-GROWTH ; TUMORIGENESIS ; antiangiogenic therapy ; cell proliferation ; analysis ; TUMOR-CELL ; ROLES ; human renal cell carcinoma ; MAMMARY-CARCINOMA ; cancer research ; in vivo ; CAPILLARIES ; INHIBIT ; TUBULOGENESIS ; mammary ; activin ; FOLLICLE-STIMULATING-HORMONE ; HUMAN-PREGNANCY
    Abstract: The transforming growth factor-P superfamily member activin and its antagonist, follistatin, act as a pleiotropic growth factor system that controls cell proliferation, differentiation, and apoptosis. Activin inhibits fibroblast growth factor 2-induced sprouting angiogenesis in vitro (spheroidal angiogenesis assay) and in vivo (Matrigel assay). To further study the role of the activin/follistatin system during angiogenesis and tumor progression, activin- and follistatin-expressing R30C mammary carcinoma cells were studied in mouse tumor experiments. Surprisingly, activin-expressing tumors grew much faster than follistatin-expressing tumors although they failed to induce increased angiogenesis (as evidenced by low microvessel density counts). Conversely, follistatin-expressing tumors were much smaller but had a dense network of small-diameter capillaries. Qualitative angioarchitectural analyses (mural cell recruitment, perfusion) revealed no major functional differences of the tumor neovasculature. Analysis of activin- and follistatin-expressing R30C cells identified a cell autonomous role of this system in controlling tumor cell growth. Whereas proliferation of R30C cells was not altered, follistatin-expressing R30C cells had an enhanced susceptibility to undergo apoptosis. These findings in experimental tumors are complemented by an intriguing case report of a human renal cell carcinoma that similarly shows a dissociation of angiogenesis and tumorigenesis during tumor progression. Collectively, the data shed further light into the dichotomous stimulating and inhibiting roles that the activin/follistatin system can exert during angiogenesis and tumor progression. Furthermore, the experiments provide a critical proof-of-principle example for the dissociation of angiogenesis and tumorigenesis, supporting the concept that tumor growth may not be dependent on increased angiogenesis as long as a minimal intratumoral microvessel density is maintained
    Type of Publication: Journal article published
    PubMed ID: 16740706
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  • 7
    Keywords: RECEPTOR ; CELLS ; ENDOTHELIAL-CELLS ; EXPRESSION ; GROWTH ; GROWTH-FACTOR ; CELL ; ENDOTHELIAL GROWTH-FACTOR ; Germany ; INHIBITION ; MOLECULES ; COMPLEX ; LIGAND ; MECHANISM ; DOMAIN ; BINDING ; BIOLOGY ; MOLECULAR-BIOLOGY ; PHOSPHORYLATION ; MOLECULE ; NERVOUS-SYSTEM ; RECEPTORS ; VEGF ; signaling ; molecular biology ; molecular ; RE ; KINASE-ACTIVITY ; SWITCH ; USA ; vascular endothelial growth factor ; CYTOPLASMIC DOMAIN ; ENDOTHELIAL GROWTH ; CRUCIAL ROLE ; C-TERMINUS ; CONTAINING PROTEIN ; RGS-GAIP
    Abstract: Vascular endothelial growth factor (VEGF) acts as a hierarchically high switch of the angiogenic cascade by interacting with its high affinity VEGF receptors and with neuropilin co-receptors. VEGF(165) binds to both Neuropilin-1 (NP-1) and VEGFR-2, and it is believed that ligand binding forms an extracellular bridge between both molecules. This leads to complex formation, thereby enhancing VEGFR-2 phosphorylation and subsequent signaling. We found that inhibition of VEGF receptor (VEGFR) phosphorylation reduced complex formation between NP-1 and VEGFR-2, suggesting a functional role of the cytoplasmic domain of VEGFR-2 for complex formation. Correspondingly, deleting the PDZ-binding domain of NP-1 decreased complex formation, indicating that extracellular VEGF165 binding is not sufficient for VEGFR-2-NP-1 interaction. Synectin is an NP-1 PDZ-binding domain-interacting molecule. Experiments in Synectin-deficient endothelial cells revealed reduced VEGFR-2-NP-1 complex formation, suggesting a role for Synectin in VEGFR-2-NP-1 signaling. Taken together, the experiments have identified a novel mechanism of NP-1 interaction with VEGFR-2, which involves the cytoplasmic domain of NP-1
    Type of Publication: Journal article published
    PubMed ID: 18628209
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