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  • VEGF-C promotes the development of esophageal cancer via regulating CNTN-1 expression. 21482472

    Vascular endothelial growth factor C (VEGF-C) is a key regulator of angiogenesis and lymphangiogenesis. VEGF-C is also implicated in the development of esophageal cancer. We investigated the mRNA levels of VEGF-C and its receptors in 38 esophageal squamous cell carcinoma specimens (ESCCs) and matched adjacent normal esophageal tissues via real-time PCR. The mRNA levels of VEGF-C, VEGFR-2 and VEGFR-3 were significantly upregulated in ESCCs versus respective side normal tissues. To explore the influence of VEGF-C on esophageal cancer progression, the expression of VEGF-C was manipulated in esophageal cancer cell lines TE-1 and Eca-109. VEGF-C transcription, translation and secretion were significantly enhanced in cells stably transfected with a VEGF-C overexpression vector or attenuated in VEGF-C shRNA-transfected cell lines. In vitro, TE-1 cells stably transfected with a VEGF-C overexpression vector exhibited an increased rate of cell proliferation, migration and focus formation, whereas knockdown of VEGF-C inhibited cell proliferation, migration and focus formation. Similar results were obtained for Eca-109 cells. VEGF-C mediated biological function through transcription of CNTN-1, which is implicated in tumor invasion and metastasis. The expression of VEGF-C was correlated with that of CNTN-1 and cell proliferation and migration induced by VEGF-C were reversed by silencing of CNTN-1. In addition, nude mice inoculated with VEGF-C shRNA-transfected cells exhibited a significantly decreased tumor size in vivo via reduced VEGFR-2 and VEGFR-3 phosphorylation and microvessel formation. VEGF-C upregulation may be involved in esophageal tumor progression. Vector-based RNA interference (RNAi) targeting VEGF-C is a potential therapeutic method for human esophageal carcinoma.
    Document Type:
    Reference
    Product Catalog Number:
    17-371
    Product Catalog Name:
    EZ-ChIP™

  • VEGF-C, VEGF-D and VEGFR-3 expression in peripheral neuroblastic tumours. 22804730

    Ramani P, Nash R, Radevsky L, Patel A, Luckett M & Rogers C (2012) Histopathology VEGF-C, VEGF-D and VEGFR-3 expression in peripheral neuroblastic tumours Aims:  More than 50% of neuroblastomas (NBs) present with haematogenous and/or lymphatic metastasis; however, little is known about the clinicopathological significance in NBs of the key lymphangiogenesis growth factors vascular endothelial growth factor (VEGF)-C and VEGF-D and the receptor VEGFR-3. Methods and results:  Ninety-three NBs and nine ganglioneuromas (GNs) were immunostained for VEGF-C, VEGF-D and VEGFR-3. VEGF-C and VEGF-D were present in 76% and 82% of the NBs, respectively. There was no significant difference in VEGF-C expression between NBs and GNs. VEGF-D expression was significantly higher in NBs compared with GNs and in MYCN-amplified NBs. VEGFR-3 tumoral cell expression (VEGFR-3c), present in 48% of the NBs, was significantly higher in NBs from children ≥18 months at presentation and those belonging to a high-risk group. VEGFR-3 lymphovascular density was increased significantly in NBs compared with GNs and in NBs associated with adverse clinicopathological and biological factors. Lymphovascular invasion, assessed in VEGFR-3-stained vessels, was present in ∼50% of NBs. Cox regression analyses demonstrated that VEGFR-3c expression was associated with a significantly shorter event-free survival and that its effect was independent of the important pathological variable, mitosis-karyorrhexis index. Conclusions:  VEGF-D and VEGFR-3 up-regulation support tumour progression in NB and VEGFR-3c may provide a useful prognostic marker in NBs.
    Document Type:
    Reference
    Product Catalog Number:
    MAB3757

  • VEGF-C, a lymphatic growth factor, is a RANKL target gene in osteoclasts that enhances osteoclastic bone resorption through an autocrine mechanism. 18359770

    Osteoclasts are bone-resorbing cells, but they also secrete and respond to cytokines. Here, we test the hypothesis that osteoclasts secrete the lymphatic growth factor, VEGF-C, to increase their resorptive activity. Osteoclasts and osteoclast precursors were generated by culturing splenocytes with macrophage colony-stimulating factor and RANKL from wild-type, NF-kappaBp50(-/-)/p52(-/-), and Src(-/-) mice. Expression of VEGFs was measured by real time reverse transcription-PCR, Western blotting, and immunostaining. The effect of VEGF-C signaling on osteoclast function was determined by osteoclastogenesis and pit assays. RANKL increased the expression of VEGF-C but not of other VEGFs in osteoclasts and their precursors. RANKL-induced VEGF-C expression was reduced in NF-kappaBp50(-/-)/p52(-/-) precursors or wild-type cells treated with an NF-kappaB inhibitor. VEGF-C directly stimulated RANKL-mediated bone resorption, which was reduced by the VEGF-C-specific receptor blocker, VEGFR3:Fc. Osteoclasts express VEGFR3, and VEGF-C stimulated Src phosphorylation in osteoclasts. VEGF-C-mediated bone resorption was abolished in Src(-/-) osteoclasts or cells treated with an Src inhibitor. We conclude that RANKL stimulates osteoclasts and their precursors to release VEGF-C through an NF-kappaB-dependent mechanism, indicating that VEGF-C is a new RANKL target gene in osteoclasts and functions as an autocrine factor regulating osteoclast activity.
    Document Type:
    Reference
    Product Catalog Number:
    17-371
    Product Catalog Name:
    EZ-ChIP™

  • RNAi-mediated silencing of vEGF-C inhibits non-small cell lung cancer progression by simultaneously down-regulating the cXCR4, cCR7, vEGFR-2 and vEGFR-3-dependent axes-in ... 21680174

    Vascular endothelial growth factor C (VEGF-C) expression is associated with the malignant tumour phenotype making it an attractive therapeutic target. We investigated the biological roles of VEGF-C in tumour growth, migration, invasion and explored the possibility of VEGF-C as a potential therapeutic target for the treatment of non-small cell lung cancer (NSCLC). A lentivirus-mediated RNA interference (RNAi) technology was used to specifically knockdown the expression of VEGF-C in A549 cells. Quantitative reverse transcriptase-polymerase chain reaction, flow cytometry, Western blot, immunohistochemistry, cellular growth, migration, invasion and ELISA assays were used to characterise VEGF-C expression in vitro. A lung cancer xenograft model in nude mice was established to investigate whether knockdown of VEGF-C reduced tumour growth in vivo. Silencing of VEGF-C suppressed tumour cell growth, migration and invasion in vitro; suppressed tumour growth, angiogenesis and lymphangiogenesis by tail vein injection of lentivirus encoded shRNA against VEGF-C in vivo. More importantly, silencing of VEGF-C also trapped the VEGFR-2, VEGFR-3, CXCR4, CCR7-dependent axes, and down-regulated the AKT, ERK and p38 signalling pathways. These results suggest that VEGF-C has a multifaceted role in NSCLC growth, migration and invasion; that VEGF-C-mediated autocrine loops with their cognate receptors and chemokine receptors are significant factors affecting tumour progression; and that RNAi-mediated silencing of VEGF-C represents a powerful therapeutic approach for controlling NSCLC growth and metastasis.Copyright © 2011 Elsevier Ltd. All rights reserved.
    Document Type:
    Reference
    Product Catalog Number:
    Multiple
    Product Catalog Name:
    Multiple

  • VEGFR-3 and its ligand VEGF-C are associated with angiogenesis in breast cancer. 10329591

    Recently, monoclonal antibodies against the human vascular endothelial growth factor receptor VEGFR-3 were shown to provide a specific antigenic marker for lymphatic endothelium in various normal tissues. In this study we have investigated the expression of VEGFR-3 and its ligand VEGF-C in normal breast tissue and in breast tumors by immunohistochemistry. VEGFR-3 was weakly expressed in capillaries of normal breast tissue and in fibroadenomas. In intraductal breast carcinomas, VEGFR-3 was prominent in the "necklace" vessels adjacent to the basal lamina of the tumor-filled ducts. VEGF receptor 1 and 2 as well as blood vessel endothelial and basal lamina markers were colocalized with VEGFR-3 in many of these vessels. Antibodies against smooth muscle alpha-actin gave a weak staining of the necklace vessels, suggesting that they were incompletely covered by pericytes/smooth muscle cells. A highly elevated number of VEGFR-3 positive vessels was found in invasive breast cancer in comparison with histologically normal breast tissue (P < 0.0001, the Mann-Whitney test). VEGF-C was located in the cytoplasm of intraductal and invasive cancer cells. The results demonstrate that the expression of VEGFR-3 becomes up-regulated in the endothelium of angiogenic blood vessels in breast cancer. The results also suggest that VEGF-C secreted by the intraductal carcinoma cells acts predominantly as an angiogenic growth factor for blood vessels, although this paracrine signaling network between the cancer cells and the endothelium may also be involved in modifying the permeabilities of both blood and lymphatic vessels and metastasis formation.
    Document Type:
    Reference
    Product Catalog Number:
    MAB3757

  • The Schlemm's canal is a VEGF-C/VEGFR-3-responsive lymphatic-like vessel. 25061878

    In glaucoma, aqueous outflow into the Schlemm's canal (SC) is obstructed. Despite striking structural and functional similarities with the lymphatic vascular system, it is unknown whether the SC is a blood or lymphatic vessel. Here, we demonstrated the expression of lymphatic endothelial cell markers by the SC in murine and zebrafish models as well as in human eye tissue. The initial stages of SC development involved induction of the transcription factor PROX1 and the lymphangiogenic receptor tyrosine kinase VEGFR-3 in venous endothelial cells in postnatal mice. Using gene deletion and function-blocking antibodies in mice, we determined that the lymphangiogenic growth factor VEGF-C and its receptor, VEGFR-3, are essential for SC development. Delivery of VEGF-C into the adult eye resulted in sprouting, proliferation, and growth of SC endothelial cells, whereas VEGF-A obliterated the aqueous outflow system. Furthermore, a single injection of recombinant VEGF-C induced SC growth and was associated with trend toward a sustained decrease in intraocular pressure in adult mice. These results reveal the evolutionary conservation of the lymphatic-like phenotype of the SC, implicate VEGF-C and VEGFR-3 as critical regulators of SC lymphangiogenesis, and provide a basis for further studies on therapeutic manipulation of the SC with VEGF-C in glaucoma treatment.
    Document Type:
    Reference
    Product Catalog Number:
    Multiple
    Product Catalog Name:
    Multiple

  • Migration-promoting role of VEGF-C and VEGF-C binding receptors in human breast cancer cells. 17912247

    Vascular endothelial growth factor C (VEGF-C) is a lymphangiogenic factor over-expressed in highly metastatic, cyclooxygenase (COX)-2 expressing breast cancer cells. We tested the hypothesis that tumour-derived VEGF-C may play an autocrine role in metastasis by promoting cellular motility through one or more VEGF-C-binding receptors VEGFR-2, VEGFR-3, neuropilin (NRP)-1, NRP-2, and integrin alpha9beta1. We investigated the expression of these receptors in several breast cancer cell lines (MDA-MB-231, Hs578T, SK-BR-3, T-47D, and MCF7) and their possible requirement in migration of two VEGF-C-secreting, highly metastatic lines MDA-MB-231 and Hs578T. While cell lines varied significantly in their expression of above VEGF-C receptors, migratory activity of MDA-MB-231 and Hs578T cells was linked to one or more of these receptors. Depletion of endogenous VEGF-C by treatments with a neutralising antibody, VEGF-C siRNA or inhibitors of Src, EGFR/Her2/neu and p38 MAP kinases which inhibited VEGF-C production, inhibited cellular migration, indicating the requirement of VEGF-C for migratory function. Migration was differentially attenuated by blocking or downregulation of different VEGF-C receptors, for example treatment with a VEGFR-2 tyrosine kinase inhibitor, NRP-1 and NRP-2 siRNA or alpha9beta1 integrin antibody, indicating the participation of one or more of the receptors in cell motility. This novel role of tumour-derived VEGF-C indicates that breast cancer metastasis can be promoted by coordinated stimulation of lymphangiogenesis and enhanced migratory activity of breast cancer cells.
    Document Type:
    Reference
    Product Catalog Number:
    Multiple
    Product Catalog Name:
    Multiple

  • The balance of autocrine VEGF-A and VEGF-C determines podocyte survival. 19828679

    Podocytes are an important component of the glomerular filtration barrier and are the major source of vascular endothelial growth factor (VEGF) in the glomerulus. The role of VEGF for the phenotype of the glomerular endothelium has been intensely studied; however, the direct effects of autocrine VEGF on the podocyte are largely unknown. In this study we characterized the expression of VEGF isoforms and VEGF receptors in cultured human podocytes and examined direct effects on cell signaling and apoptosis after stimulation with exogenous VEGF or ablation of autocrine VEGF. We identified VEGF-A and VEGF-C as the dominant isoforms in human podocytes and showed that autocrine levels of both are important for the intracellular activation of antiapoptotic phosphoinositol 3-kinase/AKT and suppression of the proapoptotic p38MAPK via VEGFR-2. We demonstrated that ablation of VEGF-A or VEGF-C as well as treatment with bevacizumab or a VEGFR-2/-3 tyrosine kinase inhibitor led to reduced podocyte survival. In contrast, ablation of VEGF-B had no effect on podocyte survival. Treatment with exogenous VEGF-C reversed the effect of VEGF-A neutralization, and exogenous VEGF-A abrogated the effect of VEGF-C ablation in human podocytes. Our results underline the importance of autocrine VEGF for podocyte survival and indicate the delicate balance of VEGF-A and VEGF-C to influence progression of glomerular diseases.
    Document Type:
    Reference
    Product Catalog Number:
    S7165
    Product Catalog Name:
    ApopTag® Red In Situ Apoptosis Detection Kit

  • MT1-MMP sheds LYVE-1 on lymphatic endothelial cells and suppresses VEGF-C production to inhibit lymphangiogenesis. 26926389

    Lymphangiogensis is involved in various pathological conditions, such as arthritis and cancer metastasis. Although many factors have been identified to stimulate lymphatic vessel growth, little is known about lymphangiogenesis inhibitors. Here we report that membrane type 1-matrix metalloproteinase (MT1-MMP) is an endogenous suppressor of lymphatic vessel growth. MT1-MMP-deficient mice exhibit spontaneous corneal lymphangiogenesis without concomitant changes in angiogenesis. Mice lacking MT1-MMP in either lymphatic endothelial cells or macrophages recapitulate corneal lymphangiogenic phenotypes observed in Mmp14(-/-) mice, suggesting that the spontaneous lymphangiogenesis is both lymphatic endothelial cells autonomous and macrophage associated. Mechanistically, MT1-MMP directly cleaves LYVE-1 on lymphatic endothelial cells to inhibit LYVE-1-mediated lymphangiogenic responses. In addition, MT1-MMP-mediated PI3Kδ signalling restrains the production of VEGF-C from prolymphangiogenic macrophages through repressing the activation of NF-κB signalling. Thus, we identify MT1-MMP as an endogenous inhibitor of physiological lymphangiogenesis.
    Document Type:
    Reference
    Product Catalog Number:
    17-371
    Product Catalog Name:
    EZ-ChIP™