Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Vascular targeting agents, which selectively destroy tumor blood vessels, are attractive agents for the treatment of solid tumors. They differ from anti-angiogenic agents in that they target the mature, blood-conducting vessels of the tumors. They are better suited for larger tumors where angiogenesis can occur less frequently. For application in man, target molecules are needed that are selectively expressed on the vascular endothelium of tumors. Such markers include the complexes that are formed when vascular endothelial growth factor (VEGF) binds to its receptors (VEGFR). VEGF production by tumor cells is induced by oncogenic gene mutations and by the hypoxic conditions within the tumor mass. The receptors, VEGFR1 (FLT-1) and VEGFR2 (KDR/Flk-1), are upregulated on vascular endothelial cells in tumors by hypoxia and by the increased local concentration of VEGF. Consequently, there is a high concentration of occupied receptors on tumor vascular endothelium. Here, we review the concept of vascular targeting and the development of monoclonal antibodies that bind to VEGF: VEGFR complexes and their use as tumor vascular targeting agents. A promising monoclonal antibody is 2C3, which blocks VEGF from binding to VEGFR2 but not VEGFR1. We conclude that 2C3 might have dual activity as an anti-angiogenic agent by inhibiting VEGFR2 activity and as a vascular targeting agent for selective drug delivery to tumor vessels.
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PMID:Vascular endothelial growth factor and vascular targeting of solid tumors. 1190 75

The angiogenic factor vascular endothelial growth factor-D (VEGF-D) isa ligand for VEGF receptor-3 (VEGFR-3/Flt-4) and receptor-2 (VEGFR-2/KDR)and is implicated in the development of lymphatic vessels and promotion of lymphatic metastases. We assessed the expression of VEGF-D and VEGFR-3 in relation to microvessel density (MVD) in colorectal carcinomas (CRC), adenomas, and adjacent normal tissue by immunohistochemistry on consecutive archival sections. VEGF-D was detected in malignant and benign epithelium and in some smooth muscle of the colorectum. High-grade VEGF-D expression was observed frequently (74%) in CRC compared with adenomas (0%) and adjacent normal mucosa (22%). High-grade VEGF-D expression was not correlated with MVD, Dukes' stage (A to C), or tumor differentiation, but was associated with lymphatic involvement and patient survival. By multivariate analysis, VEGF-D expression was found to be an independent prognostic factor for both disease-free and overall survival. VEGFR-3 expression was detected in a subset of vessels, typically thin-walled and devoid of RBCs, in 89% of CRC cases examined. VEGFR-3-positive vessel densities increased progressively from normal mucosa to adenomas and carcinomas and were correlated with MVD, but not with Dukes' stage (A to C), tumor differentiation, or VEGF-D expression. VEGFR-3 expression was spatially associated with macrophage-rich inflammatory infiltrates, which were significantly more frequent among VEGFR-3-positive cases. We conclude that VEGF-D expression, but not that of its receptor VEGFR-3, is an independent prognostic indicator in CRC. VEGF-D expression may be associated with disease outcome through the promotion of lymphatic involvement/metastases.
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PMID:Vascular endothelial growth factor-D expression is an independent prognostic marker for survival in colorectal carcinoma. 1191 38

We report a case of suprasellar papillary craniopharyngioma metastatic to the temporoparietal region 2 years after its initial resection. The literature documents examples of craniopharyngioma recurrences along the surgical tract, as well as remote ipsi- and contralateral metastases via cerebrospinal fluid seeding. Ours is the second report of a craniopharyngioma of papillary type to exhibit metastatic behavior. The tumor spread opposite the side of craniotomy. Although a rare occurrence, it confirms the limited capacity of histologically benign craniopharyngiomas to undergo meningeal seeding, likely the result of surgical manipulation. Immunohistochemical demonstration of increased microvascular density and vascular endothelial growth factor expression, as well as a high vascular endothelial growth receptor (VEGFR2) signal by in situ hybridization, suggests that tumor vascularity facilitated angiogenesis and may have been involved in the establishment and growth of the metastatic deposit.
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PMID:Metastatic papillary craniopharyngioma: case study and study of tumor angiogenesis. 1191 4

Co-expression of NRP1 and (VEGFR-2) KDR on the surface of endothelial cells (EC) enhances VEGF165 binding to KDR and EC chemotaxis in response to VEGF165. Overexpression of NRP1 by prostate tumor cells in vivo results in increased tumor angiogenesis and growth. We investigated the molecular mechanisms underlying NRP1-mediated angiogenesis by analyzing the association of NRP1 and KDR. An intracellular complex containing NRP1 and KDR was immunoprecipitated from EC by anti-NRP1 antibodies only in the presence of VEGF165. In contrast, VEGF121, which does not bind to NRP1, did not support complex formation. Complexes containing VEGF165, NRP1, and KDR were also formed in an intercellular fashion by co-culture of EC expressing KDR only, with cells expressing NRP1 only, for example, breast carcinoma cells. VEGF165 also mediated the binding of a soluble NRP1 dimer to cells expressing KDR only, confirming the formation of such complexes. Furthermore, the formation of complexes containing KDR and NRP1 markedly increased 125I-VEGF165 binding to KDR. Our results suggest that formation of a ternary complex of VEGF165, KDR, and NRP1 potentiates VEGF165 binding to KDR. These complexes are formed on the surface of EC and in a juxtacrine manner via association of tumor cell NRP1 and EC KDR.
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PMID:VEGF165 mediates formation of complexes containing VEGFR-2 and neuropilin-1 that enhance VEGF165-receptor binding. 1194 91

The bladder transitional cell carcinoma cell line, BTT739 from the T739 mouse, was transfected with a plasmid that encoded an enhanced green fluorescence protein (GFP) and the cells stably expressing GFP were selected and subcloned. 1 x 10(3)-1 x 10(4) GFP-labeled BTT739 cells were injected under the skin of ear of T739 mice. On day 2-5 post injection, the most interesting manifestations observed were the chemotaxis-like movement of the tumor cells toward the pre-existing host vasculature, host vessel dilation and tortuosity and increased extravasation. On day 10 or later, the sprout from pre-existing host vasculature was observed. Once angiogenesis was triggered on, the tumor cells grew more rapidly and exhibited a specific growth pattern where tumor cells always associated with or surrounded the vessels. The newly formed microvessels always showed heavy extravasation. Immunohistochemistry staining revealed strong VEGF and VEGFR2 (Flk-1) expression in tumor cells. Angiography using Rhodamin-labeled dextran showed neovascularization with unprecedented clarity. However, the tumor mass, even bigger than 2 mm and being neovascularized, shrunk and then disappear in 3-5 days and left only delicated host vessels and recovered extravasation. The evidence from this observation indicated that angiogenesis induced by tumor cells after implantation into the host begins at very early stage. The micrometastases foci could not form or survive without vigorous and continuous angiogenesis. Furthermore, there was active VEGF paracrine and autocrine expression in tumor and high level VEGF secretion by tumor cells plays an important role in initiating angiogenesis and supporting micrometastases.
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PMID:[A novel model for visualization of tumor cell-induced angiogenesis in vivo]. 1195 29

Angiogenesis, or the formation of new blood vessels from preexisting vasculature, plays a major role in tumor growth and metastasis formation. Therefore, inhibiting tumor angiogenesis may be a promising therapeutic strategy. Paracrine stimuli from tumor cells are the main promoters of angiogenesis. They activate endothelial cells to proliferate and migrate, subsequently resulting in new tube formation and blood flow. This complex process involves numerous biological activities. Vascular endothelial growth factor (VEGF) is a potent and specific angiogenic factor. Originally identified for its ability to induce vascular permeability and stimulate endothelial cell growth, VEGF is now known to be a key requirement for tumor growth. Currently, three high-affinity tyrosine kinase receptors for VEGF have been identified, of which VEGF receptor (VEGFR)-Flk-1/KDR (VEGFR-2) is exclusively expressed in vascular endothelial cells. Because the VEGFR-2 system is a dominant signal-transduction pathway in regulating tumor angiogenesis, specific inhibitors of this pathway inhibit metastases, microvessel formation, and tumor-cell proliferation. Induction of apoptosis in tumor cells and endothelial cells has also been observed. The clinical importance of VEGF for tumor growth is supported by the fact that most tumors produce VEGF and that the inhibition of VEGF-induced angiogenesis significantly inhibits tumor growth in vivo. In this review, we discuss the biologic role of VEGF and the therapeutic options for inhibiting VEGF in cancer patients.
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PMID:The role of vascular endothelial growth factor (VEGF) in tumor angiogenesis and early clinical development of VEGF-receptor kinase inhibitors. 1197 Jul 55

Adult bone marrow (BM) is a rich reservoir for endothelial and hematopoietic stem and progenitor cells that contribute to revascularization of injured and tumor tissue. Physiological stress results in the release of specific chemo-cytokines that promote mobilization of stem cells to the circulation and direct their incorporation into the target tissues. In order to dissect the mechanism and identify the cellular mediators that regulate stem cell recruitment, we have developed an in vivo murine model, in which the plasma levels of chemokines are elevated by introducing adenoviral vectors (Advectors) expressing such chemokines. Among the known stem cell-active chemokines, the angiogenic factor VEGF through interaction with its receptors, VEGFR2 and VEGFR1 expressed on endothelial and hematopoietic stem cells, promotes mobilization and recruitment of these cells into the neo-angiogenic sites, thereby accelerating the revascularization process. Based on these studies, it has become apparent that mobilization of stem cells is a dynamic process and requires sequential release of chemocytokines, expression of adhesion molecules and activation of proteases that facilitate egress of cells from the BM to the circulation. Chemokine-activation of metalloproteinases is essential for the release of bio-active cytokines, thereby enhancing stem cell mobilization potential. Advectors are ideal for delivery of chemocytokines since they allow for long-term robust expression facilitating in vivo proliferation and mobilization of large numbers of an otherwise rare population of stem cells. VEGF-mobilized endothelial and hematopoietic stem cells provide for an enriched source of adult pluripotent cells that can be used for revascularization, tissue regeneration or gene therapy.
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PMID:Efficient mobilization and recruitment of marrow-derived endothelial and hematopoietic stem cells by adenoviral vectors expressing angiogenic factors. 1203 9

Vascular endothelial growth factor (VEGF) plays a key role in the growth and metastasis of solid tumors. We generated a fusion protein containing VEGF(121) linked by a flexible G(4)S tether to the toxin gelonin (rGel) and expressed this as a soluble protein in bacteria. Purified VEGF(121)/rGel migrated as an 84-kDa homodimer under nonreducing conditions. VEGF(121)/rGel bound to purified, immobilized Flk-1, and the binding was competed by VEGF(121). Both VEGF(121)/rGel and VEGF(121) stimulated cellular kinase insert domain receptor (KDR) phosphorylation. The VEGF(121)/rGel fusion construct was highly cytotoxic to endothelial cells overexpressing the KDR/Flk-1 receptor. The IC(50) of the construct on dividing endothelial cells expressing 10(5) or more KDR/Flk-1 receptors per cell was 0.5-1 nM, as compared with 300 nM for rGel itself. Dividing endothelial cells overexpressing KDR were approximately 60-fold more sensitive to VEGF(121)/rGel than were nondividing cells. Endothelial cells overexpressing FLT-1 were not sensitive to the fusion protein. Human melanoma (A-375) or human prostate (PC-3) xenografts treated with the fusion construct demonstrated a reduction in tumor volume to 16% of untreated controls. The fusion construct localized selectively to PC-3 tumor vessels and caused thrombotic damage to tumor vessels with extravasation of red blood cells into the tumor bed. These studies demonstrate the successful use of VEGF(121)/rGel fusion construct for the targeted destruction of tumor vasculature in vivo.
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PMID:In vitro and in vivo studies of a VEGF121/rGelonin chimeric fusion toxin targeting the neovasculature of solid tumors. 1206 Jul 33

The vascular endothelial growth factor (VEGF) receptor fetal liver kinase 1 (flk1; VEGFR-2, KDR) is an endothelial cell-specific receptor tyrosine kinase that mediates physiological and pathological angiogenesis. We hypothesized that an active immunotherapy approach targeting flk1 may inhibit tumor angiogenesis and metastasis. To test this hypothesis, we first evaluated whether immune responses to flk1 could be elicited in mice by immunization with dendritic cells pulsed with a soluble flk1 protein (DC-flk1). This immunization generated flk1-specific neutralizing antibody and CD8+ cytotoxic T cell responses, breaking tolerance to self-flk1 antigen. Tumor-induced angiogenesis was suppressed in immunized mice as measured in an alginate bead assay. Development of pulmonary metastases was strongly inhibited in DC-flk1-immunized mice challenged with B16 melanoma or Lewis lung carcinoma cells. DC-flk1 immunization also significantly prolonged the survival of mice challenged with Lewis lung tumors. Thus, an active immunization strategy that targets an angiogenesis-related antigen on endothelium can inhibit angiogenesis and may be a useful approach for treating angiogenesis-related diseases.
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PMID:Active immunization against the vascular endothelial growth factor receptor flk1 inhibits tumor angiogenesis and metastasis. 1207 Feb 85

Tumor growth and metastasis require concomitant growth of new blood vessels, which are stimulated by angiogenic factors, including vascular endothelial growth factor (VEGF), secreted by most tumors. Whereas the angiogenic property and molecular mechanisms of VEGF have been well studied, the biological function of its related homolog, placenta growth factor (PlGF), is poorly understood. Here we demonstrate that PlGF-1, an alternatively spliced isoform of the PlGF gene, antagonizes VEGF-induced angiogenesis when both factors are coexpressed in murine fibrosarcoma cells. Overexpression of PlGF-1 in VEGF-producing tumor cells results in the formation of PlGF-1/VEGF heterodimers and depletion of the majority of mouse VEGF homodimers. The heterodimeric form of PlGF-1/VEGF lacks the ability to induce angiogenesis in vitro and in vivo. Similarly, PlGF-1/VEGF fails to activate the VEGFR-2-mediated signaling pathways. Further, PlGF-1 inhibits the growth of a murine fibrosarcoma by approximately 90% when PlGF-1-expressing tumor cells are implanted in syngeneic mice. In contrast, overexpression of human VEGF in murine tumor cells causes accelerated and exponential growth of primary fibrosarcomas and early hepatic metastases. Our data demonstrate that PlGF-1, a member of the VEGF family, acts as a natural antagonist of VEGF when both factors are synthesized in the same population of cells. The underlying mechanism is due to the formation of functionally inactive heterodimers.
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PMID:Placenta growth factor-1 antagonizes VEGF-induced angiogenesis and tumor growth by the formation of functionally inactive PlGF-1/VEGF heterodimers. 1208 92


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