Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Extensive efforts are under way to identify antiangiogenic therapies for the treatment of human cancers. Many proposed therapeutics target vascular endothelial growth factor (VEGF) or the kinase insert domain receptor (KDR/VEGF receptor-2/FLK-1), the mitogenic VEGF receptor tyrosine kinase expressed by endothelial cells. Inhibition of KDR catalytic activity blocks tumor neoangiogenesis, reduces vascular permeability, and, in animal models, inhibits tumor growth and metastasis. Using a gene expression profiling strategy in rat tumor models, we identified a set of six genes that are selectively overexpressed in tumor endothelial cells relative to tumor cells and whose pattern of expression correlates with the rate of tumor endothelial cell proliferation. In addition to being potential targets for antiangiogenesis tumor therapy, the expression patterns of these genes or their protein products may aid the development of pharmacodynamic assays for small molecule inhibitors of the KDR kinase in human tumors.
Mol Cancer Ther 2005 Mar
PMID:Identification of biomarkers for tumor endothelial cell proliferation through gene expression profiling. 1576 50

Vascular endothelial growth factors (VEGF) and their receptors (VEGFR) have been implicated to play important roles in tumor-associated angiogenesis and lymphangiogenesis, and hence in tumor growth and metastasis. We previously produced a number of fully human antibodies directed against VEGF receptor 2 (VEGFR2) and VEGF receptor 3 (VEGFR3) and showed that these antibodies are capable of inhibiting growth factor (VEGF and VEGF-C)-induced receptor activation, migration, and proliferation of human endothelial cells. In this report, we constructed and produced a bispecific antibody, a diabody, using the variable domain genes of two neutralizing antibodies, IMC-1121 to VEGFR2 and hF4-3C5 to VEGFR3. The diabody binds to both VEGFR2 and VEGFR3 in a dose-dependent manner, and blocks interaction between VEGF/VEGFR2, VEGF-C/VEGFR2, and VEGF-C/VEGFR3. In cell-based assays, the diabody neutralized both VEGF and VEGF-C-stimulated activation of VEGFR2, VEGFR3, and p44/p42 mitogen-activated protein kinase in endothelial cells. Furthermore, the diabody was able to inhibit both VEGF and VEGF-C-induced migration of endothelial cells. Taken together, our results suggest that a dual blockade of both VEGFR2 and VEGFR3 simultaneously may represent a more potent approach to effective cancer therapy.
Mol Cancer Ther 2005 Mar
PMID:A recombinant, fully human, bispecific antibody neutralizes the biological activities mediated by both vascular endothelial growth factor receptors 2 and 3. 1576 51

Anaplastic thyroid carcinoma (ATC) is one of the most aggressive human malignancies with a mean survival of only 6 months. The poor prognosis of patients with ATC reflects the current lack of curative therapeutic options and the need for development of novel therapeutic strategies. In this study, we report the results of a preclinical study of AEE788, a dual inhibitor of epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor (VEGFR) tyrosine kinases, against ATC. AEE788 was able to inhibit the proliferation and induce apoptosis of ATC cell lines in vitro. Administration of AEE788, alone and in combination with paclitaxel, to athymic nude mice bearing s.c. ATC xenografts inhibited the growth of ATC xenografts by 44% and 69%, respectively, compared with the control group. Furthermore, tumors from mice treated with AEE788, alone and in combination with paclitaxel, showed increase in apoptosis of tumor cells by approximately 6- and 8-fold, respectively, compared with the control group. The microvessel density within the ATC xenografts was decreased by >80% in the mice treated with AEE788 alone and in combination with paclitaxel compared with the control group. Lastly, immunofluorescence microscopy showed the inhibition of EGFR autophosphorylation on the tumor cells as well as the inhibition of VEGFR-2 autophosphorylation on tumor endothelium. Considering the fact that curative options seldom exist for patients with ATC, concurrent inhibition of EGFR and VEGFR tyrosine kinases seems to be a valid and promising anticancer strategy for these patients.
Mol Cancer Ther 2005 Apr
PMID:Targeted molecular therapy of anaplastic thyroid carcinoma with AEE788. 1582 37

The Ras-Raf-MEK-ERK (ERK) pathway is a logical therapeutic target because it represents a common downstream pathway for several key growth factor tyrosine kinase receptors which are often mutated or overexpressed in human cancers. Although considered mainly growth-promoting, in certain contexts, this pathway also seems to be apoptosis-suppressing. Several novel agents targeting this pathway have now been developed and are in clinical trials. One of the most interesting new agents is BAY 43-9006. Although initially developed as a Raf kinase inhibitor, it can also target several other important tyrosine kinases including VEGFR-2, Flt-3, and c-Kit, which contributes to its antiproliferative and antiangiogenic properties. To date, encouraging results have been seen with BAY 43-9006, particularly in renal cell cancers which are highly vascular tumors. This review will provide an overview of the ERK signaling pathway in normal and neoplastic tissue, with a specific focus on novel therapies targeting the ERK pathway at the level of Raf kinase.
Mol Cancer Ther 2005 Apr
PMID:Raf kinase as a target for anticancer therapeutics. 1582 42

CD117 (KIT) is a type III receptor tyrosine kinase operating in cell signal transduction in several cell types. Normally KIT is activated (phosphorylated) by binding of its ligand, the stem cell factor. This leads to a phosphorylation cascade ultimately activating various transcription factors in different cell types. Such activation regulates apoptosis, cell differentiation, proliferation, chemotaxis, and cell adhesion. KIT-dependent cell types include mast cells, some hematopoietic stem cells, germ cells, melanocytes, and Cajal cells of the gastrointestinal tract, and neoplasms of these cells are examples of KIT-positive tumors. Other KIT-positive normal cells include epithelial cells in skin adnexa, breast, and subsets of cerebellar neurons. KIT positivity has been variably reported in sarcomas such as angiosarcoma, Ewing sarcoma, synovial sarcoma, leiomyosarcoma, and MFH; results of the last three are controversial. The variations in published data may result from incomplete specificity of some polyclonal antibodies, possibly contributed by too high dilutions. Also, KIT is expressed in pulmonary and other small cell carcinomas, adenoid cystic carcinoma, renal chromophobe carcinoma, thymic, and some ovarian and few breast carcinomas. A good KIT antibody reacts with known KIT positive cells, and smooth muscle cells and fibroblasts are negative. KIT deficiency due to hereditary nonsense/missense mutations leads to disruption of KIT-dependent functions such as erythropoiesis, skin pigmentation, fertility, and gastrointestinal motility. Conversely, pathologic activation of KIT through gain-of-function mutations leads to neoplasia of KIT-dependent and KIT-positive cell types at least in three different systems: mast cells/myeloid cells--mastocytosis/acute myeloid leukemia, germ cells--seminoma, and Cajal cells--gastrointestinal stromal tumors (GISTs). KIT tyrosine kinase inhibitors such as imatinib mesylate are the generally accepted treatment of metastatic GISTs, and their availability has prompted an active search for other treatment targets among KIT-positive tumors such as myeloid leukemias and small cell carcinoma of the lung, with variable and often nonconvincing results.
Appl Immunohistochem Mol Morphol 2005 Sep
PMID:KIT (CD117): a review on expression in normal and neoplastic tissues, and mutations and their clinicopathologic correlation. 1608 45

To identify genes important to the process of vasculogenesis, we evaluated embryonic vascular anomalies from 100 mouse knockout studies using a novel meta-analysis approach. By applying this method, termed approach for ranking of embryonic vascular anomalies (AREVA), rank scores were calculated for each knockout based on the occurrence of vascular defects during periods of vasculogenesis in specific embryonic regions. As a result, 12 genes (fibronectin, VEGFR-1/Flt-1, VEGFR-2/Flk-1, alpha 5 integrin, Tek/Tie2, VE-cadherin, VEGFA, connexin 45, ShcA, cytochrome P450 reductase, CD148/DEP-1, and EphrinB2) were determined to play critical roles in vasculogenesis. Functional categorization of these genes revealed the fundamental importance of VEGF signaling since 10 of the 12 genes (fibronectin, VEGFR-1/Flt-1, VEGFR-2/Flk-1, alpha 5 integrin, VE-cadherin, VEGFA, ShcA, cytochrome P450 reductase, CD148/DEP-1, and EphrinB2) relate to this pathway. Furthermore, the findings highlight a potential network for regulating VEGF signaling involving integration of fibronectin, EphrinB2, Tie2, and connexin 45 signaling pathways via the ShcA/Ras/Raf/Mek/Erk cascade. In addition to retrospective application of AREVA as done herein, AREVA can be used prospectively to determine the relevancy to vasculogenesis of newly inactivated genes.
Anat Rec A Discov Mol Cell Evol Biol 2005 Oct
PMID:Genes critical to vasculogenesis as defined by systematic analysis of vascular defects in knockout mice. 1611 69

Tumor neovasculature is a potential but, until very recently, unexplored target for boron neutron capture therapy (BNCT) of cancer. In the present report, we describe the construction of a vascular endothelial growth factor (VEGF)-containing bioconjugate that potentially could be used to target up-regulated VEGF receptors (VEGFR), which are overexpressed on tumor neovasculature. A fifth-generation polyamidoamine dendrimer containing 128 reactive amino groups was reacted with 105 to 110 decaborate molecules to produce a macromolecule with 1,050 to 1,100 boron atoms per dendrimer. This was conjugated to thiol groups of VEGF at a 4:1 molar ratio using the heterobifunctional reagent sulfo-LC-SPDP. In addition, the boronated dendrimer was tagged with a near-IR Cy5 dye to allow for near-IR fluorescent imaging of the bioconjugate in vitro and in vivo. As would be predicted, the resulting VEGF-BD/Cy5 bioconjugate was not cytotoxic to HEK293 cells engineered to express 2.5 x 10(6) VEGFR-2 per cell. Furthermore, it showed binding and activation of VEGFR-2 comparable with that of native VEGF. Internalization of VEGF-BD/Cy5 by PAE cells expressing 2.5 x 10(5) VEGFR-2 per cell was inhibited by excess VEGF, indicating a VEGFR-2-mediated mechanism of uptake. Near-IR fluorescent imaging of 4T1 mouse breast carcinoma revealed selective accumulation of VEGF-BD/Cy5, but not BD/Cy5, particularly at the tumor periphery where angiogenesis was most active. Accumulation of VEGF-BD/Cy5 in 4T1 breast carcinoma was diminished in mice pretreated with a toxin-VEGF fusion protein that selectively killed VEGFR-2-overexpressing endothelial cells. Our data lay the groundwork for future studies using the VEGF-BD/Cy5 bioconjugate as a targeting agent for BNCT of tumor neovasculature.
Mol Cancer Ther 2005 Sep
PMID:Vascular endothelial growth factor selectively targets boronated dendrimers to tumor vasculature. 1617 35

Blockade of angiogenesis is a promising strategy to suppress tumor growth, invasion, and metastasis. Vascular endothelial growth factor (VEGF), which binds to tyrosine kinase receptors [VEGF receptors (VEGFR) 1 and 2], is the mediator of angiogenesis and mitogen for endothelial cells. Cyclooxygenase-2 (COX-2) plays an important role in the promoting action of nicotine on gastric cancer growth. However, the action of nicotine and the relationship between COX-2 and VEGF/VEGFR system in tumorigenesis remain undefined. In this study, the effects of nicotine in tumor angiogenesis, invasiveness, and metastasis were studied with sponge implantation and Matrigel membrane models. Nicotine (200 microg/mL) stimulated gastric cancer cell proliferation, which was blocked by SC-236 (a highly selective COX-2 inhibitor) and CBO-P11 (a VEGFR inhibitor). This was associated with decreased VEGF levels as well as VEGFR-2 but not VEGFR-1 expression. Topical injection of nicotine enhanced tumor-associated vascularization, with a concomitant increase in VEGF levels in sponge implants. Again, application of SC-236 (2 mg/kg) and CBO-P11 (0.4 mg/kg) partially attenuated vascularization by approximately 30%. Furthermore, nicotine enhanced tumor cell invasion through the Matrigel membrane by 4-fold and promoted migration of human umbilical vein endothelial cells in a cocultured system with gastric cancer cells. The activity of matrix metalloproteinases 2 and 9 and protein expressions of plasminogen activators (urokinase-type plasminogen activator and its receptor), which are the indicators of invasion and migration processes, were increased by nicotine but blocked by COX-2 and VEGFR inhibitors. Taken together, our results reveal that the promoting action of nicotine on angiogenesis, tumor invasion, and metastasis is COX-2/VEGF/VEGFR dependent.
Mol Cancer Res 2005 Nov
PMID:Nicotine induces cyclooxygenase-2 and vascular endothelial growth factor receptor-2 in association with tumor-associated invasion and angiogenesis in gastric cancer. 1631 86

VEGF is fundamental in the development and maintenance of the vasculature. VEGF(165) signaling through VEGF receptor (VEGFR)-2/kinase insert domain receptor (KDR) is a highly regulated process involving the formation of a tertiary complex with glypican (GYP)-1 and neuropilin (NRP)-1. Both VEGF and VEGFR-2 expression are reduced in emphysematous lungs; however, the mechanism of regulation of VEGF(165) signaling through the VEGFR-2 complex in response to cigarette smoke exposure in vivo, and in smokers with and without chronic obstructive pulmonary disease (COPD), is still unknown. We hypothesized that cigarette smoke exposure disrupts the VEGF(165)-VEGFR-2 complex, a potential mechanism in the pathogenesis of emphysema. We show that cigarette smoke exposure reduces NRP-1 and GYP-1 as well as VEGF and VEGFR-2 levels in rat lungs and that VEGF, VEGFR-2, GYP-1, and NRP-1 expression in the lungs of both smokers and patients with COPD are also reduced compared with nonsmokers. Moreover, our data suggest that specific inhibition of VEGFR-2 alone with NVP-AAD777 would appear not to result in emphysema in the adult rat lung. As both VEGF(165) and VEGFR-2 expression are reduced in emphysematous lungs, decreased GYP-1 and NRP-1 expression may yet further disrupt VEGF(165)-VEGFR-2 signaling. Whether or not this by itself is critical for inducing endothelial cell apoptosis and decreased vascularization of the lung seen in emphysema patients is still unclear at present. However, targeted therapies to restore VEGF(165)-VEGFR-2 complex may promote endothelial cell survival and help to ameliorate emphysema.
Am J Physiol Lung Cell Mol Physiol 2006 May
PMID:Cigarette smoke disrupts VEGF165-VEGFR-2 receptor signaling complex in rat lungs and patients with COPD: morphological impact of VEGFR-2 inhibition. 1636 60

Recent studies suggest the possibility of a direct antiangiogenic effect of anti-epidermal growth factor receptor (EGFR) drugs due to the presence of EGFR on endothelial cells. The aim of this study was to analyze the direct effect on endothelial cells of associating EGFR targeting, vascular endothelial growth factor receptor (VEGFR)-2 targeting, and irradiation. We examined both the cytotoxic effects and the effect on molecular markers resulting from the combined action of gefitinib (Iressa; anti-EGFR), ZM317450 [VEGFR tyrosine kinase inhibitor (VTKI); anti-VEGFR-2], and irradiation (radiation therapy) on HMME7 cells, an immortalized microvascular endothelial cell of human origin. The presence of a functional EGFR pathway sensitive to gefitinib was shown in HMME7 cells (gefitinib-induced decrease in phospho-EGFR, phospho-p42/p44, and phospho-Akt). The stimulation of VEGFR-2 pathway led to an increase in Akt phosphorylation that was inhibited by VTKI. Of note, a post-radiation therapy induction of phospho-p42/p44 was observed on HMME7 cells, and this effect was inhibited by a pretreatment with gefitinib. Based on combination indexes (Chou and Talalay analyses), the associations gefitinib-radiation therapy, VTKI-radiation therapy, VTKI-gefitinib, and gefitinib-VTKI-radiation therapy were found to be additive, slightly synergistic, and markedly synergistic, respectively, for the cytotoxicity on HMME7 cells. Among molecular explanatory factors that were examined, the combination gefitinib-radiation therapy totally abolishes DNA-dependent protein kinase expression, and gefitinib attenuates the radiation therapy-induced enhancement of ERCC1 and augments the VTKI-induced CD95 enhancement. The existence of a radiation therapy-dependent neoangiogenesis may be related to the induction of EGFR pathway in endothelial cells, a phenomenon that can be attenuated by anti-EGFR drugs like gefitinib. In complement to the direct antitumor effects of radiation therapy and anti-EGFR drugs, a strong antiangiogenic effect may be obtained with therapeutic strategies combining radiation therapy with EGFR and VEGFR-2 targeting agents.
Mol Cancer Ther 2005 Dec
PMID:Response of endothelial cells to a dual tyrosine kinase receptor inhibition combined with irradiation. 1637 11


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