Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C1519670 (tumor angiogenesis)
 6,052 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Vascular endothelial growth factor receptor-2 (VEGFR-2/KDR/Flk-1) is a high-affinity receptor for vascular endothelial growth factor-A (VEGF-A), and mediates most of the endothelial growth and survival signals from VEGF-A. VEGFR-2 has a typical tyrosine kinase receptor structure with seven immunoglobulin (Ig)-like domains in the extracellular region, as well as a long kinase insert in the tyrosine kinase domain. It utilizes a unique signaling system for DNA synthesis in vascular endothelial cells, i.e. a phospholipase C gamma-protein kinase C-Raf-MAP kinase pathway. Although VEGF-A binds two receptors, VEGFR-1 and -2, a newly isolated ligand VEGF-E (Orf-virus-derived VEGF) binds and activates only VEGFR-2. Transgenic mice expressing VEGF-E(NZ-7) showed a dramatic increase in angiogenesis with very few side effects (such as edema and hemorrhagic spots), suggesting strong angiogenic signaling and a potential clinical utility of VEGF-E. VEGF family members bear three loops produced via three intramolecular disulfide bonds, and cooperation between loop-1 and loop-3 is necessary for the specific binding and activation of VEGFR-2 for angiogenesis. As it directly upregulates tumor angiogenesis, VEGFR-2 is an appropriate target for suppression of solid tumor growth using exogenous antibodies, small inhibitory molecules and in vivo stimulation of the immune system.
 ...
PMID:Vascular endothelial growth factor receptor-2: its unique signaling and specific ligand, VEGF-E. 1296 71

Angiogenesis or new vessel formation is an essential component in the growth and progression of neoplasms and there is growing evidence of its importance in hematological malignancies including multiple myeloma (MM). Vascular endothelial growth factor (VEGF) is believed to play a role in tumor angiogenesis. We studied the expression of VEGF and its receptors (VEGFR1 or Flt-1 and VEGFR2 or Flk-1/KDR) by myeloma cell lines and plasma cells isolated from patients, using different methods. VEGF expression by the plasma cells was demonstrated by immunohistochemistry in 18 of 20 patients with MM. Enzyme-linked immunosorbent assay demonstrated VEGF secretion in all six different myeloma cell lines studied. Five patient marrow samples and seven different myeloma cell lines were then studied for VEGF mRNA expression by reverse-transcriptase polymerase chain reaction (RT-PCR), which was positive in all. We further evaluated the expression of both VEGFR1 and VEGFR2 in different myeloma cell lines and five sorted myeloma bone marrow samples by RT-PCR. All the myeloma cell lines expressed VEGFR1 and three of the cell lines expressed VEGFR2. VEGFR1 expression was detected in all and VEGFR2 in all but one of the sorted marrow samples. Increased expression of VEGF by the myeloma cells taken in the context of the suspected prognostic value of marrow angiogenesis suggests a pathogenetic role for this cytokine and presence of its receptors on myeloma cells points toward an autocrine mechanism. Demonstration of the presence of VEGFR2 in our study provides a potential biological explanation for the preclinical activity observed with VEGFR2 inhibitors.
 ...
PMID:Expression of VEGF and its receptors by myeloma cells. 1451 53

The three human VEGF receptors 1-3 mediate biological signals important for new blood vessel formation and lymphangiogenesis. Soluble VEGF receptors contain all the information necessary for high affinity ligand binding and have been used as experimental tools and regulators in several angiogenic in vitro and in vivo models. Recombinant receptor molecules can be used for specific inhibition of VEGF mediated signal transduction and for blocking tumor angiogenesis by limiting the amount of VEGF secreted from tumor cells or stroma cells. A naturally occurring soluble VEGFR-1 has been discovered in the supernatant from endothelial cells and at present appears to be the key regulator for the availability of VEGF secreted from different cells and tissues. The exact physiological role has not yet been demonstrated.
 ...
PMID:Soluble VEGF receptors. 1451 42

Angiogenesis is deeply involved in the progression of major diseases such as cancer, diabetes, and rheumatoid arthritis. Molecular mechanism on angiogenesis was extensively studied, and several signaling systems including VEGF (VEGF-A), angiopoietin, PDGF, and ephrin were shown to be crucial for physiological angiogenesis. Interestingly, among these factors, VEGF appears to play key roles in most of the pathological angiogenesis, and other factors are considered to have additional effects on its development depending on the situation. VEGF binds and activates two tyrosine kinase receptors, VEGFR-1 (Flt-1) and VEGFR-2 (KDR/Flk-1), and stimulates endothelial cell growth, survival, and vascular permeability. VEGF induces not only tumor angiogenesis but also blood-vessel-dependent metastasis. Based on the importance of VEGF in diseases, many companies and institutes are now trying to generate appropriate small molecules as well as proteins that strongly antagonize the VEGF-VEGFR system. Several molecules quite effective for suppression of tumorigenesis and pathological angiogenesis in animal models are under clinical trials.
 ...
PMID:VEGF-receptor inhibitors for anti-angiogenesis. 1463 4

Vascular endothelial growth factor (VEGF) and the high-affinity VEGF receptor Flk-1/KDR (VEGFR-2) are key regulators of tumor angiogenesis. Strategies to block VEGF/VEGFR-2 signaling were successfully used to inhibit experimental tumor growth and indicated that VEGFR-2 is the main signaling VEGF receptor in proliferating tumor endothelium. Here, we investigated the role of the VEGF receptor-1 (VEGFR-1/Flt-1) in the vascularization of 2 different experimental tumors in vivo. VEGFR-1 mutants were generated that lack the intracellular tyrosine kinase domain. Retrovirus-mediated gene transfer of the VEGFR-1 mutants led to a strong reduction of tumor growth and angiogenesis in xenografted C6 glioma and in syngeneic BFS-1 fibrosarcoma. Histological analysis of the inhibited fibrosarcoma revealed reduced vascular density, decreased tumor cell proliferation as well as increased tumor cell apoptosis and the formation of necrosis. The retroviral gene transfer of the full length VEGFR-1 also caused a significant reduction of tumor growth in both models. The inhibitory effects of the VEGFR-1 mutants and the full length VEGFR-1 in BFS-1 fibrosarcoma were mediated through host tumor endothelial cells because the BFS-1 fibrosarcoma cells were not infected by the retrovirus. The formation of heterodimers between VEGFR-2 and full length or truncated VEGFR-1 was observed in vitro and might contribute to the growth inhibitory effect by modulating distinct signal transduction pathways. The results of our study underline the central role of the VEGF/VEGFR-1 signaling system in tumor angiogenesis and demonstrate that VEGFR-1 can serve as a target for anti-angiogenic gene therapy.
 ...
PMID:Inhibition of solid tumor growth by gene transfer of VEGF receptor-1 mutants. 1522 61

We characterized the effect of potent vascular endothelial growth factor (VEGF) blockade on early-stage Wilms tumor xenograft growth, vasculature and metastasis. VEGF is a key mediator of both physiologic and tumor angiogenesis. We recently described that potent VEGF blockade induces regression of established Wilms tumor xenografts and vessels, also reducing the size but not the incidence of pre-existing metastases. In these studies, we examined the effects of potent VEGF blockade on earlier stages of experimental Wilms tumors, focusing on tumor growth, vasculature and metastasis. Athymic mice received intrarenal human Wilms tumor cell implants. Biweekly treatment with vehicle or the VEGF-Trap, a high-affinity soluble decoy receptor incorporating regions of VEGFR1 and VEGFR2, was begun 1 week later (100 or 500 micrograms/dose, n=20 in each group). Mice were euthanized at week 6 to examine tumor weight, incidence of lung metastases, vascularity and expression of angiogenic factors. A cohort of mice was examined 2 weeks after cessation of treatment. Compared to controls, VEGF-Trap treated tumors were significantly smaller (100 micrograms/dose: 92.7% smaller, p=0.0017; 500 micro g/dose: 99.0% smaller, p=0.0009). The incidence of lung metastasis also decreased significantly (p<0.0055). VEGF-Trap nearly eradicated tumor vasculature. Rare persisting vessels were characterized by large caliber, quiescence (lacking proliferation/apoptosis) and arterialization (both phenotypic and molecular). Potent VEGF blockade caused near-arrest of experimental Wilms tumor growth, resulted in nearly avascular tumors, and also decreased the incidence and size of metastases. Persistent vessels in tumors treated with VEGF-Trap displayed specific morphologic and molecular features, suggestive of arterialization. Future strategies that target these persisting vessels may enhance the efficacy of VEGF blockade therapy.
 ...
PMID:Effects of potent VEGF blockade on experimental Wilms tumor and its persisting vasculature. 1528 55

Angiopoietins (Ang1 and Ang2) modulate the activity of the endothelial cell (EC)-specific receptor tyrosine kinase Tie2, which together with vascular endothelial growth factor (VEGF-A) and its EC-specific receptors, VEGFR1 and VEGFR2, regulate normal physiological vessel development. The functional role of angiopoietins in tumor angiogenesis, in particular astrocytoma angiogenesis, remains unclear. In this study, we focus on the specific contribution of Ang1 to the vascular growth of glioblastoma multiforme (GBM) and its interactive role with VEGF-A. Subcutaneous and intracranial GBM xenografts were generated using 3 established astrocytoma cell lines (U87, U373, and U343) that were transfected to stably over-express Ang1. GBM xenografts were also generated to express low levels of VEGF-A and high Angl. We found that Ang1 increases the vascular growth of both subcutaneous and intracranial xenografts of GBM by approximately 3-fold. However, the increased vascular growth was only seen in xenografts with concurrent VEGF-A elevation, since decreasing VEGF-A expression resulted in a loss of the pro-angiogenic growth advantage seen with Ang1. Collectively, our data suggest that Ang1 regulates GBM vascularity in a VEGF-A dependent manner, synergizing the initial pro-angiogenic response that is triggered by VEGF-A and promoting the vascular growth of GBM.
 ...
PMID:Role of Ang1 and its interaction with VEGF-A in astrocytomas. 1545 96

Inhibition of vascular endothelial growth factor (VEGF) signaling, a key regulator of tumor angiogenesis, through blockade of VEGF receptor (VEGFR)-2 by the monoclonal antibody DC101 inhibits angiogenesis, tumor growth, and invasion. In a surface xenotransplant assay on nude mice using a high-grade malignant squamous cell carcinoma cell line (A-5RT3), we show that DC101 causes vessel regression and normalization as well as stromal maturation resulting in a reversion to a noninvasive tumor phenotype. Vessel regression is followed by down-regulation of expression of both VEGFR-2 and VEGFR-1 on endothelial cells and increased association of alpha-smooth muscle actin-positive cells with small vessels indicating their normalization, which was further supported by a regular ultrastructure. The phenotypic regression of an invasive carcinoma to a well-demarcated dysplastic squamous epithelium is accentuated by the establishment of a clearly structured epithelial basement membrane and the accumulation of collagen bundles in the stabilized connective tissue. This normalization of the tumor-stroma border coincided with down-regulated expression of the stromal matrix metalloproteinases 9 and 13, which supposedly resulted in attenuated turnover of extracellular matrix components permitting their structural organization. Thus, in this mouse model of a human squamous cell carcinoma cell line, blockade of VEGF signaling resulted in the reversion of the epithelial tumor phenotype through stromal normalization, further substantiating the crucial role of stromal microenvironment in regulating the tumor phenotype.
 ...
PMID:Angiogenesis inhibition by vascular endothelial growth factor receptor-2 blockade reduces stromal matrix metalloproteinase expression, normalizes stromal tissue, and reverts epithelial tumor phenotype in surface heterotransplants. 1573 15

Vascular endothelial growth factor (VEGF) is associated with tumor angiogenesis and poor prognosis in human colorectal cancer (CRC). VEGF receptor-1 (VEGFR-1 or Flt-1) is a high-affinity receptor for VEGF and is typically considered specific to endothelial cells. Here we report the expression and function of VEGFR-1 in CRC cell lines. VEGFR-1 was expressed in all CRC cell lines studied as determined by RT-PCR, Western blot analysis, FACS, and ELISA. Treatment of the human CRC cell lines HT-29 and SW480 with VEGF-A (a ligand for both VEGFR-1 and -2) or VEGF-B (a ligand specific for VEGFR-1) led to activation of Erk-1/2, SAPK/JNK, and translocation of the p65 subunit of nuclear factor-kappaB into the nucleus. Both VEGF-A and -B led to significant induction of cell motility and invasiveness of CRC cells. Stimulation of cells with VEGF-A or -B also led to larger and more numerous colonies in soft agar. However, activation of VEGFR-1 did not increase CRC cell proliferation. In contrast to the previous paradigm that VEGFRs are not present on tumor cells of epithelial origin, we found that VEGFR-1 is present and functional on CRC cells, and activation by VEGF family ligands can activate processes involved in tumor progression and metastasis.
 ...
PMID:Expression and function of vascular endothelial growth factor receptor-1 on human colorectal cancer cells. 1573 59

PTEN is an important tumor suppressor gene. Hereditary mutation of PTEN causes tumor-susceptibility diseases such as Cowden disease. We used the Cre-loxP system to generate an endothelial cell-specific mutation of Pten (Tie2CrePten) in mice. Tie2CrePten(flox/+) mice displayed enhanced tumorigenesis due to an increase in angiogenesis driven by vascular growth factors. This effect was partially dependent on the PI3K subunits p85alpha and p110gamma. In vitro, Tie2CrePten(flox/+) endothelial cells showed enhanced proliferation/migration. Tie2CrePten(flox/flox) mice died before embryonic day 11.5 (E11.5) due to bleeding and cardiac failure caused by impaired recruitment of pericytes and vascular smooth muscle cells to blood vessels, and of cardiomyocytes to the endocardium. These phenotypes depend strongly on p110gamma rather than on p85alpha and were associated with decreased expression of Ang-1, VCAM-1, connexin 40, and ephrinB2 but increased expression of Ang-2, VEGF-A, VEGFR1, and VEGFR2. Pten is thus indispensable for normal cardiovascular morphogenesis and post-natal angiogenesis, including tumor angiogenesis.
 ...
PMID:The PTEN/PI3K pathway governs normal vascular development and tumor angiogenesis. 1610 12


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>