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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

VEGF is a secreted growth factor that mediates its biological effects by binding to two transmembrane tyrosine kinase receptors, VEGFR-1 and VEGFR-2. The VEGF/receptor signaling system is involved in the regulation of two fundamental processes in vertebrates: the formation of blood vessels (angiogenesis) and of blood cells (hematopoiesis). Hematopoietic stem cells, capable of giving rise to all blood cell lineages, are often found in clusters with endothelial cells, the key cell type involved in the formation of blood vessels. Despite such proximity of VEGF-responsive cells, hematopoiesis occurs independently of neoangiogenesis in the adult bone marrow, suggesting that VEGF regulates the two processes by different mechanisms. In support of this hypothesis, the recently identified autocrine loop by which VEGF may control hematopoietic stem cell survival and repopulation, is fundamentally different from its paracrine effects regulating angiogenesis. Furthermore, coexpression of VEGF and its receptors, the prerequisite for autocrine loops, is frequently found in lymphomas and myelomas, suggesting that autocrine loops also play a role in hematological malignancies. Several therapeutic strategies blocking VEGF or VEGF-induced signaling are currently being investigated for the treatment of neoplastic diseases. They differ in their potential to interfere with the autocrine or paracrine effector functions of VEGF during angiogenesis, hematopoiesis, and tumor cell proliferation, properties which may ultimately determine their therapeutic potential.
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PMID:The role of VEGF in normal and neoplastic hematopoiesis. 1254 46

Vascular endothelial growth factor (VEGF) is a primary stimulant of tumor angiogenesis. We previously raised a neutralizing anti-VEGF monoclonal antibody 2C3 that blocks the interaction of VEGF with VEGFR2 (KDR/Flk-1) but not with VEGFRI (FLT-1/flt-1). Here, we describe the therapeutic effects of 2C3 on tumor growth in an orthotopic model of MDA-MB-231 human breast carcinoma implanted in the mammary fat pads (MFP) of nude mice. Administration of 2C3 to mice with 100-150 mm3 tumors inhibited tumor growth by 75%, as compared to recipients of the isotype-matched irrelevant control IgG, C44. Treatment with 2C3 also inhibited the establishment of tumor colonies and reduced tumor burden in the lungs of mice injected intravenously with MDA-MB-231 cells. No toxicity was observed in these studies. The mean microvascular density (MVD) of tumors in 2C3-treated mice was 55 +/- 5 per mm2, as compared to 188 +/- 5 per mm2 in the C44-treated control group. The decrease in MVD closely correlated with the degree of inhibition of tumor growth. Treated tumors mostly contained mid-size and large vessels. Microvessels were mainly confined to the peripheral layer of tumor that bordered on the normal MFP epithelium. Tumor vessels had decreased expression of VEGFR2, indicating that neutralization of tumor-derived VEGF by 2C3 down-regulates the expression of VEGFR2 on tumor vasculature. This, in turn, may limit reinitiation of angiogenesis by either tumor-derived or stromal VEGF. These findings suggest that 2C3 is a candidate for treating primary cancer and for preventing the outgrowth of tumor metastases in cancer patients.
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PMID:A monoclonal antibody that blocks VEGF binding to VEGFR2 (KDR/Flk-1) inhibits vascular expression of Flk-1 and tumor growth in an orthotopic human breast cancer model. 1254 58

The presence of metastases in regional lymph nodes is a strong indicator of poor patient survival. A number of clinical and experimental studies suggest that tumor-induced lymphangiogenesis driven by vascular endothelial growth factor (VEGF)-C- and/or VEGF-D-induced activation of VEGF receptor (VEGFR)-3 may promote metastasis to regional lymph nodes. Here we show that constitutive VEGF-C and VEGF-D expression by tumor cells of diverse origin grown in tissue culture does not correlate with metastatic potential in vivo. However, tumors derived from cell lines that do not constitutively express VEGF-C or VEGF-D in tissue culture can nevertheless express one or both of these factors. We demonstrate that both tumor and stromal cells can contribute to this expression, suggesting that tumor cell-host interactions determine tumor expression of VEGF-C and VEGF-D. Using immunocompetent rat mammary tumor models, we show in two ways that this expression can promote metastasis via the lymphatics. Firstly, ectopic expression of a soluble VEGFR-3 receptor globulin protein in MT-450 tumor cells that are highly metastatic via the lymphatics blocked VEGF-C and VEGF-D activity and suppressed metastasis formation in both the regional lymph nodes and the lungs. Secondly, ectopic expression in the weakly metastatic NM-081 cell line of a mutant form of VEGF-C that is only able to activate VEGFR-3 strongly promoted metastasis of these cells to the regional lymph nodes and lung. These data show that expression of VEGF-C and VEGF-D in tissue culture does not reflect expression in vivo and that activation of VEGFR-3 in the absence of VEGFR-2 activation is sufficient to promote tumor-induced lymphangiogenesis and metastasis, and they support the notion that blockade of VEGFR-3 activation will be useful as a novel form of cancer therapy.
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PMID:Differential in vivo and in vitro expression of vascular endothelial growth factor (VEGF)-C and VEGF-D in tumors and its relationship to lymphatic metastasis in immunocompetent rats. 1256 18

Solitary fibrous tumor (SFT) is an uncommon tumor first reported in the pleura, but recently described in other tissues. CD34, which is expressed in hematopoietic stem cells, endothelial progenitor cells and vascular endothelial cells, is observed in most SFT and some investigators believe that its expression is a definitive marker of this tumor. In the present study, the expression of vascular endothelial cell markers, such as vascular endothelial growth factor receptor (VEGFR)-1 (flt-1), VEGFR-2 (flk-1/KDR), Tie-2 and c-Met, was examined in SFT to clarify the relationship between SFT and endothelial cells. By immunohistochemical staining of tumor cells from 26 patients, VEGFR-1 was detected in 24 (92%), VEGFR-2 in five (19%), Tie-2 in 14 (54%), and c-Met, a specific receptor of hepatocyte growth factor (HGF) in 23 patients (88%). Furthermore, VEGFR-3 (flt-4) immunoreactivity was detected in eight of 26 patients (31%). In contrast, VEGF, VEGF-C and HGF, which are ligands for the receptors, were not localized in the SFT cells. These findings indicate that most SFT may closely relate to vascular or lymphatic endothelial cells and the endothelial growth factors may contribute to the growth of SFT in a paracrine manner.
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PMID:Immunohistochemical localization of endothelial cell markers in solitary fibrous tumor. 1258 46

Malignant mesothelioma (MM) is a locally aggressive tumor that originates from the mesothelial cells of the pleural and sometimes peritoneal surface. Conventional treatments for MM, consisting of chemotherapy or surgery give little survival benefit to patients, who generally die within 1 year of diagnosis. Hence, there is an urgent need for the development of alternative therapies. Vascular endothelial growth factor (VEGF) is an autocrine growth factor for MM. The closely related molecule, VEGF-C, is also implicated in malignant mesothelioma growth. VEGF-C and its cognate receptor VEGFR-3 are co-expressed in mesothelioma cell lines. A functional VEGF-C autocrine growth loop was demonstrated in mesothelioma cells by targeting VEGF-C expression and binding to VEGFR-3. The ability of novel agents that reduce the levels of VEGF and VEGF-C to inhibit mesothelioma cell growth in vitro was assessed. Antisense oligonucleotide (ODN) complementary to VEGF that inhibited VEGF and VEGF-C expression simultaneously specifically inhibited mesothelioma cell growth. Similarly, antibodies to VEGF receptor (VEGFR-2) and VEGF-C receptor (VEGFR-3) were synergistic in inhibiting mesothelioma cell growth. In addition, a diphtheria toxin-VEGF fusion protein (DT-VEGF), which is toxic to cells that express VEGF receptors was very effective in inhibiting mesothelioma cell growth in vitro. These results indicate that targeting VEGF and VEGF-C simultaneously may be an effective therapeutic approach for malignant mesothelioma.
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PMID:Malignant mesothelioma growth inhibition by agents that target the VEGF and VEGF-C autocrine loops. 1259 15

Angiogenesis, a process related to tumor growth and malignancy, is stimulated by several growth factors. Among these is vascular endothelial growth factor (VEGF), which acts on endothelial cells by binding with 2 specific receptors, VEGFR1 and VEGFR2. Recent studies have demonstrated that VEGF expression is correlated with microvessel density (MVD) and tumor progression. Digestive endocrine tumors are heterogeneous neoplasms exhibiting variable biological aggressiveness and behavior that often are not predictable on morphologic grounds alone. The aims of this study were to evaluate the expression of VEGF, VEGFR1, and VEGFR2 in digestive endocrine tumors and to examine its correlation with MVD and malignancy. A total of 84 specimens from endocrine neoplasms and normal gut and pancreatic tissue were immunohistochemically studied using specific antibodies directed against VEGF, VEGFR1, VEGFR2, endothelial antigens, and gastroenteropancreatic hormones. Ultrastructural immunocytochemistry was performed to identify the cellular localization of VEGF and the VEGFRs. In normal tissues, VEGF immunoreactivity was detected in G cells and PP cells. Ultrastructurally, VEGF was localized within secretory granules. The VEGFRs were not significantly expressed by normal endocrine cells. VEGF-immunoreactive (IR) cells were detected in 40 of 83 tumors, mainly G cell and enterochromaffin cell neoplasms. VEGFR1-IR cells were found in 44 of 82 tumors, and VEGFR2-IR cells were found in 55 of 82 tumors, with no predilection for any specific tumor type. The expression of VEGF and its receptors did not correlate with MVD or malignancy. These results suggest that in normal tissues, endothelial functions may be regulated by VEGF produced by some endocrine cells and that a VEGF/VEGFR binding mechanism may be involved in tumorigenesis, but not in tumor progression and aggressiveness.
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PMID:Localization of vascular endothelial growth factor and its receptors in digestive endocrine tumors: correlation with microvessel density and clinicopathologic features. 1260 62

Angiogenesis is increased in hematologic malignancies, including non-Hodgkin lymphoma (NHL). Elevated serum levels of two important angiogenic factors, vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF), are associated with a poor prognosis. Immunohistochemistry was used to evaluate 27 patients with NHL and bone marrow involvement (17 with low-grade B-cell NHL, including 7 with higher grade transformation; 6 with intermediate-grade B-cell NHL; and 4 with T-cell lymphoma). Among the 17 patients with low-grade B-cell NHL, results for 7 were positive for VEGF stain (41.2%), and results were negative for all other stains for VEGF receptors, bFGF, and bFGF receptors. In the 10 patients with intermediate-grade B-cell NHL and T-cell lymphoma, all VEGF staining was positive (100%), but bFGF staining was only weakly positive in 2. Staining results for seven patients who had low-grade B-cell NHL with higher grade transformation showed that VEGF staining was positive in large lymphoid cells of 5 patients and in small lymphoid cells of one patient. Staining for the receptors VEGFR-1 and VEGFR-2 was positive in large lymphoid cells in four and two cases, respectively. Staining for bFGF was positive in two cases of large lymphoid cells. We concluded that VEGF, but not bFGF, was associated with higher tumor grading of NHL and high-grade transformation of low-grade lymphoma.
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PMID:Immunohistochemical expression of basic fibroblast growth factor, vascular endothelial growth factor, and their receptors in stage IV non-Hodgkin lymphoma. 1260 99

Vascular endothelial growth factor (VEGF) and its receptors (VEGFR) have been implicated in promoting solid tumor growth and metastasis via stimulating tumor-associated angiogenesis. We recently showed that certain 'liquid' tumors such as leukemia not only produce VEGF, but also express functional VEGFR, resulting in an autocrine loop for tumor growth and propagation. A chimeric anti-VEGFR2 (or kinase insert domain-containing receptor, KDR) antibody, IMC-1C11, was shown to be able to inhibit VEGF-induced proliferation of human leukemia cells in vitro, and to prolong survival of nonobese diabetic-severe combined immune deficient (NOD-SCID) mice inoculated with human leukemia cells. Here we produced two fully human anti-KDR antibodies (IgG1), IMC-2C6 and IMC-1121, from Fab fragments originally isolated from a large antibody phage display library. These antibodies bind specifically to KDR with high affinities: 50 and 200 pM for IMC-1121 and IMC-2C6, respectively, as compared to 270 pM for IMC-1C11. Like IMC-1C11, both human antibodies block VEGF/KDR interaction with an IC(50) of approximately 1 nM, but IMC-1121 is a more potent inhibitor to VEGF-stimulated proliferation of human endothelial cells. These anti-KDR antibodies strongly inhibited VEGF-induced migration of human leukemia cells in vitro, and when administered in vivo, significantly prolonged survival of NOD-SCID mice inoculated with human leukemia cells. It is noteworthy that the mice treated with antibody of the highest affinity, IMC-1121, survived the longest period of time, followed by mice treated with IMC-2C6 and IMC-1C11. Taken together, our data suggest that anti-KDR antibodies may have broad applications in the treatment of both solid tumors and leukemia. It further underscores the efforts to identify antibodies of high affinity for enhanced antiangiogenic and antitumor activities.
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PMID:Inhibition of human leukemia in an animal model with human antibodies directed against vascular endothelial growth factor receptor 2. Correlation between antibody affinity and biological activity. 1264 50

The vascular endothelial growth factor (VEGF) and its interaction with the vascular endothelial growth factor receptor 2 [VEGFR2/murine fetal liver kinase 1 (Flk-1), human kinase domain receptor] are an important angiogenic pathway leading to tumor vascularization. A plasmid DNA encoding the complete extracellular domain (ECD) of murine Flk-1 including the endogenous signal sequence was designed as a possible competitor of the receptor to sequester VEGF. The plasmid DNA was used to treat B16F10 cell-induced subcutaneous melanomas in syngeneic mice. The Flk-1 ECD-encoding plasmid DNA injected intramuscularly did not lead to tumor reduction. However, intratumoral injection caused a dose-dependent reduction and significant retardation of tumor growth. Blood vessels analyzed by immunohistochemistry with anti-CD31 antibodies as indicators of vascularization appeared smaller in diameter after treatment. A combination of Flk-1 ECD and DNA encoding murine interleukin-12 or murine interferon-gamma inducible protein-10 improved the effect, leading to tumor regression and long-term survival of the mice.
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PMID:A combination of plasmid DNAs encoding murine fetal liver kinase 1 extracellular domain, murine interleukin-12, and murine interferon-gamma inducible protein-10 leads to tumor regression and survival in melanoma-bearing mice. 1268 54

Knowledge on the functional properties of tumor-derived endothelial cells (TEC) can be relevant for the development of antiangiogenic therapeutic strategies. In the present study, we obtained and characterized endothelial cell lines from human renal carcinomas. TEC did not undergo senescence and showed constant expression of markers of endothelial activation and angiogenesis. In vitro, TEC, in contrast to normal endothelial cells, were resistant to apoptosis, proadhesive for renal carcinoma cells, and able to grow and organize in the absence of serum in persistent capillary-like structures. In vivo, TEC were able to grow in immunodeficient mice and to form vascular structures connected with the circulation. At a molecular level, gene array analysis showed an increased expression of genes involved in survival and cell adhesion compared with expression in normal microvascular endothelial cells. Moreover, expression of angiopoietin-1 and vascular endothelial growth factor (VEGF)-D and the Akt survival pathway were up-regulated. Inhibition of interaction of VEGFR-2 or VEGFR-3 with VEGF-D but not of Tie-2-angiopoietin-1 interaction with soluble receptors abrogated Akt activation and survival of TEC. These results indicate that at least some of the TEC within a tumor display abnormal characteristics in terms of survival and angiogenic properties and also indicate the presence of a functional autocrine pathway related to VEGF-D.
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PMID:Altered angiogenesis and survival in human tumor-derived endothelial cells. 1270 14


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