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Query: UMLS:C1519670 (tumor angiogenesis)
 6,052 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Vascular endothelial growth factor (VEGF) is a highly specific mitogen for vascular endothelial cells. Five VEGF isoforms are generated as a result of alternative splicing from a single VEGF gene. These isoforms differ in their molecular mass and in biological properties such as their ability to bind to cell-surface heparan-sulfate proteoglycans. The expression of VEGF is potentiated in response to hypoxia, by activated oncogenes, and by a variety of cytokines. VEGF induces endothelial cell proliferation, promotes cell migration, and inhibits apoptosis. In vivo VEGF induces angiogenesis as well as permeabilization of blood vessels, and plays a central role in the regulation of vasculogenesis. Deregulated VEGF expression contributes to the development of solid tumors by promoting tumor angiogenesis and to the etiology of several additional diseases that are characterized by abnormal angiogenesis. Consequently, inhibition of VEGF signaling abrogates the development of a wide variety of tumors. The various VEGF forms bind to two tyrosine-kinase receptors, VEGFR-1 (flt-1) and VEGFR-2 (KDR/flk-1), which are expressed almost exclusively in endothelial cells. Endothelial cells express in addition the neuropilin-1 and neuropilin-2 coreceptors, which bind selectively to the 165 amino acid form of VEGF (VEGF165). This review focuses on recent developments that have widened considerably our understanding of the mechanisms that control VEGF production and VEGF signal transduction and on recent studies that have shed light on the mechanisms by which VEGF regulates angiogenesis.
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PMID:Vascular endothelial growth factor (VEGF) and its receptors. 987 25

The vascular endothelial growth factor is produced by a large variety of human tumors, including melanoma, in which it appears to play an important role in the process of tumor-induced angiogenesis. Little information is available on the role of placenta growth factor, a member of the vascular endothelial growth factor family of cytokines, in tumor angiogenesis, even though placenta growth factor/vascular endothelial growth factor heterodimers have been recently isolated from tumor cells. To investigate the role of placenta growth factor and vascular endothelial growth factor homodimers and heterodimers in melanoma angiogenesis and growth, 19 human melanoma cell lines derived from primary or metastatic tumors were characterized for the expression of these cytokines and their receptors. Release of placenta growth factor and vascular endothelial growth factor polypeptides into the supernatant of human melanoma cells was demonstrated. Reverse transcriptase polymerase chain reaction analysis showed the presence of mRNAs encoding at least three different vascular endothelial growth factor isoforms (VEGF(121), VEGF(165), and VEGF(189)) and transcripts for two placenta growth factor isoforms (PlGF-1 and PlGF-2) in human melanoma cells. In addition, placenta growth factor expression in human melanoma in vivo was detected by immunohistochemical staining of tumor specimens. Both primary and metastatic melanoma cells were found to express the mRNAs encoding for vascular endothelial growth factor and placenta growth factor receptors (KDR, Flt-1, neuropilin-1, and neuropilin-2), and exposure of melanoma cells to these cytokines resulted in a specific proliferative response, supporting the hypothesis of a role of these angiogenic factors in melanoma growth. J Invest Dermatol 115:1000-1007 2000
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PMID:Human melanoma cells secrete and respond to placenta growth factor and vascular endothelial growth factor. 1112 Nov 33

Neuropilin is both a receptor for semaphorins, which are mediators of neuronal guidance, and for VEGF, an angiogenesis factor. While the function of neuropilin in the nervous system has been characterized, its role in angiogenesis is only beginning to be elucidated. This article reviews some of the structural and functional features of neuropilin and presents the experimental evidence showing that it is a mediator of angiogenesis. In particular, we show that neuropilin and its soluble isoforms regulate tumor angiogenesis and subsequent tumor growth.
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PMID:Neuropilin is a mediator of angiogenesis. 1119 Oct 60

Although the systemic administration of a number of different gene products has been shown to result in the inhibition of angiogenesis and tumor growth in different animal tumor models, the relative potency of those gene products has not been studied rigorously. To address this issue, recombinant adenoviruses encoding angiostatin, endostatin, and the ligand-binding ectodomains of the vascular endothelial growth factor receptors Flk1, Flt1, and neuropilin were generated and used to systemically deliver the different gene products in several different preexisting murine tumor models. Single i.v. injections of viruses encoding soluble forms of Flk1 or Flt1 resulted in approximately 80% inhibition of preexisting tumor growth in murine models involving both murine (Lewis lung carcinoma, T241 fibrosarcoma) and human (BxPC3 pancreatic carcinoma) tumors. In contrast, adenoviruses encoding angiostatin, endostatin, or neuropilin were significantly less effective. A strong correlation was observed between the effects of the different viruses on tumor growth and the activity of the viruses in the inhibition of corneal micropocket angiogenesis. These data underscore the need for comparative analyses of different therapeutic approaches that target tumor angiogenesis and provide a rationale for the selection of specific antiangiogenic gene products as lead candidates for use in gene therapy approaches aimed at the treatment of malignant and ocular disorders.
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PMID:Comparative evaluation of the antitumor activity of antiangiogenic proteins delivered by gene transfer. 1127 74

Vascular endothelial growth factor A (VEGF-A), the founding member of the vascular permeability factor (VPF)/VEGF family of proteins, is an important angiogenic cytokine with critical roles in tumor angiogenesis. This article reviews the literature with regard to VEGF-A's multiple functions, the mechanisms by which it induces angiogenesis, and its current and projected roles in clinical oncology. VEGF-A is a multifunctional cytokine that is widely expressed by tumor cells and that acts through receptors (VEGFR-1, VEGFR-2, and neuropilin) that are expressed on vascular endothelium and on some other cells. It increases microvascular permeability, induces endothelial cell migration and division, reprograms gene expression, promotes endothelial cell survival, prevents senescence, and induces angiogenesis. Recently, VEGF-A has also been shown to induce lymphangiogenesis. Measurements of circulating levels of VEGF-A may have value in estimating prognosis, and VEGF-A and its receptors are potential targets for therapy. Recognized as the single most important angiogenic cytokine, VEGF-A has a central role in tumor biology and will likely have an important role in future approaches designed to evaluate patient prognosis. It may also become an important target for cancer therapy.
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PMID:Vascular permeability factor/vascular endothelial growth factor: a critical cytokine in tumor angiogenesis and a potential target for diagnosis and therapy. 1240 37

The neuropilin-1 (np1) and neuropilin-2 (np2) receptors form complexes with type-A plexins. These complexes serve as signaling receptors for specific class-3 semaphorins. Np1 and np2 function in addition as receptors for heparin-binding forms of vascular endothelial growth factor (VEGF), such as VEGF(165). Human umbilical vein endothelial cells (HUVEC) express tyrosine-kinase receptors for VEGF and basic fibroblast growth factor (bFGF), as well as np1, np2, and several type-A plexins. We have found that semaphorin-3F (s3f), a semaphorin which signals through the np2 receptor, was able to inhibit VEGF(165), as well as bFGF-induced proliferation of HUVECs. Furthermore, s3f inhibited VEGF as well as bFGF-induced phosphorylation of extracellular signal-regulated kinase-1/2. Our experiments indicate that bFGF does not bind to neuropilins, nor does s3f inhibit the binding of bFGF to FGF receptors. It is therefore possible that s3f inhibits the activity of bFGF by a mechanism that requires active s3f signal transduction rather than by inhibition of bFGF binding to FGF receptors. s3f also inhibited VEGF(165), as well as bFGF-induced in vivo angiogenesis as determined by the alginate micro-encapsulation and Matrigel plug assays. Overexpression of s3f in tumorigenic human HEK293 cells inhibited their tumor-forming ability but not their proliferation in cell culture. The tumors that did develop from s3f-expressing HEK293 cells developed at a much slower rate and had a significantly lower concentration of tumor-associated blood vessels, indicating that s3f is an inhibitor of tumor angiogenesis.
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PMID:Semaphorin-3F is an inhibitor of tumor angiogenesis. 1487 32

Melanoma is the most lethal skin cancer. Most deaths from melanoma result from metastases. Semaphorins have been shown to inhibit neuronal and endothelial cell migration, but the effects of semaphorins on tumor metastasis have not been documented. We found that semaphorin 3F (SEMA3F) was markedly downregulated in highly metastatic human cell lines in vitro and in vivo, which suggested that it may be a metastasis inhibitor. Metastatic human melanoma cells were transfected with SEMA3F and implanted into mice; the resultant tumors did not metastasize. Rather, the primary tumors resembled benign nevi characterized by large areas of apoptosis, diminished vascularity, inhibition of hyperplasia in overlying epidermal cells, and encapsulated tumor borders delineated by thick layers of fibroblasts and collagen matrix. This phenotype is in stark contrast to highly invasive, vascular mock-transfected tumors. In vitro, tumor cells expressing SEMA3F had a diminished capacity to adhere and migrate on fibronectin. Consistent with semaphorin-mediated chemorepulsion of neurons, tumor cells expressing SEMA3F were chemorepulsive for vascular and lymphatic endothelial cells expressing neuropilin-2 (NRP2), a novel mechanism for a tumor angiogenesis inhibitor. The repulsive activity was abrogated by NRP2 RNA interference. Together these results indicate that SEMA3F is a potent metastasis inhibitor that targets both tumor and stromal cells and raise the possibility of SEMA3F having therapeutic potential.
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PMID:Semaphorin 3F, a chemorepulsant for endothelial cells, induces a poorly vascularized, encapsulated, nonmetastatic tumor phenotype. 1552 Aug 58

Nerves and blood vessels resemble each other in their ability to form branching networks. They are in close proximity suggesting possible molecular interactions. The patterning of nerves and blood vessels are not random but are regulated by attractive and repulsive cues. Four major neuronal guidance factors that are sensed by growth cones have been identified, Semaphorin, Ephrin, Slit and Netrin, and their cognate receptors, neuropilin, Eph, roundabouts (Robo) and uncoordinated-5 (UNC5). Unexpectedly, these ligand/receptor pairs also regulate developmental and tumor angiogenesis. Together, there is strong evidence that development of the nervous and vascular systems are regulated by common cues.
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PMID:A role for axon guidance receptors and ligands in blood vessel development and tumor angiogenesis. 1597 25

The neuropilins were originally described as receptors for the six axon guidance factors belonging to the class-3 semaphorins. They were subsequently found to function in addition as receptors for specific splice forms of angiogenic factors belonging to the VEGF family. The neuropilins are expressed in many types of cancer cells, in endothelial cells and in additional many types of normal diploid cell types. Recent findings indicate that the neuropilins and their associated plexin and tyrosine-kinase VEGF receptors play a regulatory role in developmental angiogenesis as well as in tumor angiogenesis. The neuropilin ligands belonging to the semaphorin family as well as the various VEGF's function as modulators of angiogenesis and tumor angiogenesis. Furthermore, since many types of cancer cells express neuropilins and neuropilin associated receptors, it is not surprising that various neuropilin ligands can modulate the behavior of cancer cells directly leading to the potentiation or inhibition of tumor progression.
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PMID:The neuropilins and their role in tumorigenesis and tumor progression. 1635 25

Neuropilins (NRP) are membranous receptors capable of binding two disparate ligands, class 3 semaphorins (SEMA) and vascular endothelial growth factors (VEGF), and regulating two diverse systems, neuronal guidance and angiogenesis. The neuropilin genes, NRP1 and NRP2, share similar protein structure, but differ in their expression patterns, regulation, and ligand-binding specificities. NRPs vary in their expression patterns; for example, endothelial cells express both NRP1 and NRP2, lymphatic endothelial cells predominantly express NRP2, and epidermal cells predominantly express NRP1. NRP expression can be differentially regulated by transcription factors, e.g. prox-1 induces NRP2 while suppressing NRP1, or by growth factors, e.g. epidermal growth factor (EGF) induces NRP1 but not NRP2. Nearly all tumor cells express NRP1, NRP2, or both. Carcinomas express NRP1, whereas neuronal tumors and melanomas predominantly express NRP2. SEMAs play a role in neoplasms as angiogenesis inhibitors. For example, SEMA3F, which binds specifically to NRP2, inhibits tumor angiogenesis and metastasis. Metastatic tumor cells lose SEMA3F expression during progression. Therefore, SEMA3F may have therapeutic potential. This article focuses on the role of NRPs and SEMAs in tumor progression and angiogenesis.
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PMID:Neuropilins in neoplasms: expression, regulation, and function. 1644 11


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