Key Specifications Table
|Species Reactivity||Key Applications||Host||Format||Antibody Type|
|H||FC, IF, IH(P), IP, WB||M||Ascites||Monoclonal Antibody|
|Safety Information according to GHS|
|Material Size||100 µL|
|Reference overview||Application||Pub Med ID|
|Inhibition of FAK and VEGFR-3 binding decreases tumorigenicity in neuroblastoma. |
Stewart, JE; Ma, X; Megison, M; Nabers, H; Cance, WG; Kurenova, EV; Beierle, EA
Molecular carcinogenesis 54 9-23 2015
Neuroblastoma is the most common extracranial solid tumor of childhood and is responsible for over 15% of pediatric cancer deaths. Focal adhesion kinase (FAK) is a nonreceptor tyrosine kinase that is important in many facets of tumor development and progression. Vascular endothelial growth factor receptor-3 (VEGFR-3), another tyrosine kinase, has also been found to be important in the development of many human tumors including neuroblastoma. Recent reports have found that FAK and VEGFR-3 interact, and we have previously shown that both of these kinases interact in neuroblastoma. We have hypothesized that interruption of the FAK-VEGFR-3 interaction would lead to decreased neuroblastoma cell survival. In the current study, we examined the effects of a small molecule, chloropyramine hydrochloride (C4), designed to disrupt the FAK-VEGFR-3 interaction, upon cellular attachment, migration, and survival in two human neuroblastoma cell lines. We also utilized a murine xenograft model to study the impact of C4 upon tumor growth. In these studies, we showed that disruption of the FAK-VEGFR-3 interaction led to decreased cellular attachment, migration, and survival in vitro. In addition, treatment of murine xenografts with chloropyramine hydrochloride decreased neuroblastoma xenograft growth. Further, this molecule acted synergistically with standard chemotherapy to further decrease neuroblastoma xenograft growth. The findings from this current study help to further our understanding of the regulation of neuroblastoma tumorigenesis, and may provide novel therapeutic strategies and targets for neuroblastoma and other solid tumors of childhood.
|Regorafenib (BAY 73-4506): antitumor and antimetastatic activities in preclinical models of colorectal cancer. |
Schmieder, R; Hoffmann, J; Becker, M; Bhargava, A; Müller, T; Kahmann, N; Ellinghaus, P; Adams, R; Rosenthal, A; Thierauch, KH; Scholz, A; Wilhelm, SM; Zopf, D
International journal of cancer. Journal international du cancer 135 1487-96 2014
Regorafenib, a novel multikinase inhibitor, has recently demonstrated overall survival benefits in metastatic colorectal cancer (CRC) patients. Our study aimed to gain further insight into the molecular mechanisms of regorafenib and to assess its potential in combination therapy. Regorafenib was tested alone and in combination with irinotecan in patient-derived (PD) CRC models and a murine CRC liver metastasis model. Mechanism of action was investigated using in vitro functional assays, immunohistochemistry and correlation with CRC-related oncogenes. Regorafenib demonstrated significant inhibition of growth-factor-mediated vascular endothelial growth factor receptor (VEGFR) 2 and VEGFR3 autophosphorylation, and intracellular VEGFR3 signaling in human umbilical vascular endothelial cells (HuVECs) and lymphatic endothelial cells (LECs), and also blocked migration of LECs. Furthermore, regorafenib inhibited proliferation in 19 of 25 human CRC cell lines and markedly slowed tumor growth in five of seven PD xenograft models. Combination of regorafenib with irinotecan significantly delayed tumor growth after extended treatment in four xenograft models. Reduced CD31 staining indicates that the antiangiogenic effects of regorafenib contribute to its antitumor activity. Finally, regorafenib significantly delayed disease progression in a murine CRC liver metastasis model by inhibiting the growth of established liver metastases and preventing the formation of new metastases in other organs. In addition, our results suggest that regorafenib displays antimetastatic activity, which may contribute to its efficacy in patients with metastatic CRC. Combination of regorafenib and irinotecan demonstrated an increased antitumor effect and could provide a future treatment option for CRC patients.
|Inhibition of the focal adhesion kinase and vascular endothelial growth factor receptor-3 interaction leads to decreased survival in human neuroblastoma cell lines. |
Beierle, EA; Ma, X; Stewart, JE; Megison, M; Cance, WG; Kurenova, EV
Molecular carcinogenesis 53 230-42 2014
Neuroblastoma continues to be a devastating childhood solid tumor and is responsible for over 15% of all childhood cancer-related deaths. Focal adhesion kinase (FAK) and vascular endothelial growth factor receptor-3 (VEGFR-3) are protein tyrosine kinases that are overexpressed in a number of human cancers, including neuroblastoma. These two kinases can directly interact and provide survival signals to cancer cells. In this study, we utilized siRNA to VEGFR-3 to demonstrate the biologic importance of this kinase in neuroblastoma cell survival. We also used confocal microscopy and immunoprecipitation to show that FAK and VEGFR-3 bind in neuroblastoma. Finally, employing a 12-amino-acid peptide (AV3) specific to VEGFR-3, we showed that the colocalization between FAK and VEGFR-3 could be disrupted, and that disruption resulted in decreased neuroblastoma cell survival. These studies provide insight to the FAK-VEGFR-3 interaction in neuroblastoma and demonstrate its importance in this tumor type. Focusing upon the FAK-VEGFR-3 interaction may provide a novel therapeutic target for the development of new strategies for treatment of neuroblastoma.
|VEGF-C, VEGF-D and VEGFR-3 expression in peripheral neuroblastic tumours. |
Ramani, Pramila, et al.
Histopathology, 61: 1006-16 (2012) 2012
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.
|Different patterns of NF-κB and Notch1 signaling contribute to tumor-induced lymphangiogenesis of esophageal squamous cell carcinoma. |
Su, C; Chen, Z; Luo, H; Su, Y; Liu, W; Cai, L; Wang, T; Lei, Y; Zhong, B
Journal of experimental & clinical cancer research : CR 30 85 2011
Lymph node involvement and tumor-induced lymphangiogenesis appear as the earliest features of esophageal squamous cell carcinoma (ESCC), although the molecular regulatory mechanisms involved have remained unclear. Our aim was to investigate the contribution of NF-κB and Notch1 signaling to lymph node involvement and tumor-induced lymphangiogenesis in ESCC.NF-κB and Notch1 expression in 60 tissue samples of ESCC were assessed by immunohistochemical staining. The correlations of NF-κB and Notch1 with lymph node involvement, lymphatic vessel density (LVD), podoplanin, and vascular endothelial growth factor-C (VEGF-C) were further evaluated to determine the association of NF-κB and Notch1 expression with tumor-induced lymphangiogenesis.Chi-square tests revealed that NF-κB and Notch1 expression in ESCC tissues were significant associated with lymph node metastasis, LVD, podoplanin, and VEGF-C expression. Strong expression of NF-κB, but weak expression of Notch1, was observed in tumor tissues with lymph nodes involvement (P less than 0.05 for both). The mean histoscores of LVD, podoplanin, and VEGF-C staining were higher in high-NF-κB-expressing tissue than in low-expressing tissue (P less than 0.05 for each). In contrast, the mean histoscores of LVD and VEGF-C staining were lower in high-Notch1-expressing tissue than in low-expressing tissue (P less than 0.05 for both). A multiple factors analysis of LVD and VEGF-C further demonstrated that LVD and VEGF-C status were significantly correlated with NF-κB and Notch1 expression in tumors. NF-κB and Notch1 expression were also significantly inversely correlated (P less than 0.05).These results suggest that different patterns of NF-κB and Notch1 signaling contribute to lymph nodes metastasis and tumor-induced lymphangiogenesis of ESCC, and reveal that up-regulation of NF-κB is associated with down-regulation of Notch1 in tumor tissue.Full Text Article
|Vascular endothelial growth factor receptor-3 promotes breast cancer cell proliferation, motility and survival in vitro and tumor formation in vivo. |
Elena V Kurenova,Darrell L Hunt,Dihua He,Ann D Fu,Nicole A Massoll,Vita M Golubovskaya,Christopher A Garces,William G Cance
Cell cycle (Georgetown, Tex.) 8 2009
Vascular endothelial growth factor receptor-3 is a receptor tyrosine kinase that is overexpressed in some human carcinomas, but its role in tumorigenesis has not been fully elucidated. We examined VEGFR-3 expression in normal, nonneoplastic and early stage malignant breast tissues and have shown that VEGFR-3 upregulation in breast cancer preceded tumor cell invasion, suggesting that VEGFR-3 may function as a survival signal. We characterized the biological effects of VEGFR-3 over-expression in human breast cancer cells based on two approaches: gain of function by overexpressing VEGFR-3 in MCF-7 breast cancer cells and loss of function by RNAi-mediated silencing of VEGFR-3 in MCF-7-VEGFR-3 and BT474 cells. VEGFR-3 overexpression increased cellular proliferation by 40% when MCF7-VEGFR-3 cells were compared to parental MCF7 cells, and proliferation was reduced by more than 40% when endogenous VEGFR-3 was downregulated in BT474 cells. VEGFR-3 overexpression promoted a three-fold increase in motility and invasion and both motility and invasion were inhibited by downregulation of VEGFR-3. Furthermore, VEGFR-3 overexpression promoted cellular survival under stress conditions induced by staurosporine treatment and led to anchorage-independent growth. VEGFR-3 overexpression dramatically increased tumor formation in both hormone-dependent and independent xenograft models. With estrogen stimulation, MCF7-VEGFR-3 xenografts were ten times larger than control xenografts. Finally, downregulation of VEGFR-3 expression in both xenograft model cell lines led to a significant reduction of tumor growth. For the first time, we have demonstrated that VEGFR-3 overexpression promotes breast cancer cell proliferation, motility, survival, anchorage-independent growth and tumorogenicity in the absence of ligand expression.
|VEGFR-3 and its ligand VEGF-C are associated with angiogenesis in breast cancer. |
Valtola, R, et al.
Am. J. Pathol., 154: 1381-90 (1999) 1999
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.
|Advancing cancer research: From hallmarks & biomarkers to tumor microenvironment progression|
|Anti-VEGF Receptor-3, extracellular domain, clone 9D9F9 - Data Sheet|