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

Like any growing healthy tissues, tumors build up their blood vessels by three mechanisms: angiogenesis, vasculogenesis, and intersucception. Vascular endothelial growth factor-A (VEGF-A) is one of the key factors responsible for stimulation and maintenance of the disorganized, leaky, and torturous tumor vasculature. In addition to VEGF-A, tumors produce multiple other factors to stimulate blood vessel growth. These include members in the platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), VEGF-C, insulin-like growth factor (IGF), angiopoietin (Ang), and hepatocyte growth factor (HGF) families. Recent studies show that these angiogenic factors can also promote lymphangiogenesis and potentially lymphatic metastasis. Understanding the roles of individual and combined angiogenic factors in promoting tumor angiogenesis is crucial for defining therapeutic targets and antiangiogenic drug development for the treatment of cancer.
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PMID:Therapeutic targets of multiple angiogenic factors for the treatment of cancer and metastasis. 1741 47

Most cancers are dependent on the growth of tumor blood vessels and inhibition of tumor angiogenesis may thus provide an efficient strategy to retard or block tumor growth. Recently, tumor vascular targeting has expanded to include not only endothelial cells (ECs) but also smooth muscle cells (SMCs), which contribute to a mature and functional vasculature. We have reported previously that delphinidin, a major biologically active constituent of berries, inhibits the vascular endothelial growth factor-induced phosphorylation of vascular endothelial growth factor receptor-2 and blocks angiogenesis in vitro and in vivo. In the present study, we show that delphinidin also inhibits activation of the platelet-derived growth factor (PDGF)-BB receptor-beta [platelet-derived growth factor receptor-beta (PDGFR-beta)] in SMC and that this inhibition may contribute to its antitumor effect. The inhibitory effect of delphinidin on PDGFR-beta was very rapid and led to the inhibition of PDGF-BB-induced activation of extracellular signal-regulated kinase (ERK)-1/2 signaling and of the chemotactic motility of SMC, as well as the differentiation and stabilization of EC and SMC into capillary-like tubular structures in a three-dimensional coculture system. Using an anthocyan-rich extract of berries, we show that berry extracts were able to suppress the synergistic induction of vessel formation by basic fibroblast growth factor-2 and PDGF-BB in the mouse Matrigel plug assay. Oral administration of the berry extract also significantly retarded tumor growth in a lung carcinoma xenograft model. Taken together, these results provide new insight into the molecular mechanisms underlying the antiangiogenic activity of delphinidin that will be helpful for the development of dietary-based chemopreventive strategies.
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PMID:Delphinidin, a dietary anthocyanidin, inhibits platelet-derived growth factor ligand/receptor (PDGF/PDGFR) signaling. 1833 83

Renal-cell carcinoma represents 95% of all renal tumours. The Von Hippel-Lindau (VHL) tumor-suppressor gene is mutated or silenced in most clear cell renal carcinomas. pVHL loss results in the stabilization of the heterodimeric transcription factor hypoxia-inducible factor (HIF) and enhanced transactivation of HIF target genes. HIF itself has been difficult to inhibit with drug-like molecules although a number of agents that indirectly inhibit HIF, including mTOR (mammalian target of rapamycin) inhibitors, have been identified. Moreover, a number of drugs have been developed that target HIF-responsive gene products, such as vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF), implicated in tumor angiogenesis. Many of these targeted therapies, especially sunitinib, have demonstrated significant activity in kidney cancer clinical trials and represent a substantive advance in the treatment of this disease.
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PMID:[Current strategies in the treatment of renal-cell cancer: targeted therapies]. 1838 Oct 31

In a fast-growing malignant tissue, tumor blood vessels are exposed to multiple growth factors and cytokines. Although the role of individual factors and their signaling pathways in regulation of tumor neovascularization is relatively well-studied, little is known about complex interactions between these factors and their cooperative effects in promoting tumor angiogenesis and metastasis. Our recent studies show that quiescent vascular endothelial cells usually remaining silence to platelet-derived growth factor (PDGF)-BB stimulation acquire their hyperresponsiveness after stimulation with fibroblast growth factor (FGF)-2, which transcriptionally switches on PDGF receptor expression in the activated endothelial cells. Interestingly, PDGF-BB also transduces positive feedback signals to the FGF-2 signaling system by amplifying its receptor expression in vascular mural cells. These uncoordinated reciprocal interactions in the tumor environment lead to the formation of disorganized and primitive vasculatures that facilitate tumor growth and metastasis in mice. These findings provide an example of complex interaction between tumor angiogenic factors. Thus, therapeutic development of antiangiogenic agents for the treatment of cancer should be aimed to block multiple angiogenic signaling pathways and their interactive loops.
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PMID:R Regulation of tumor angiogenesis and metastasis by FGF and PDGF signaling pathways. 1839 94

Cediranib (AZD2171; Recentin, AstraZeneca, Wilmington, Delaware) is a once-daily oral tyrosine kinase inhibitor that targets vascular endothelial growth factor receptors 1, 2, and 3, c-KIT, and platelet-derived growth factor receptors. In preclinical testing it inhibits tumor angiogenesis and inhibits tumor growth in a wide range of tumor models. Phase 1 studies show cediranib to be generally well tolerated as monotherapy at doses of 45 mg/d or less, with a pharmacokinetic profile that supports once-daily oral administration and toxic effects consistent with those seen in other agents that target the vascular endothelial growth factor pathway. Encouraging results from phase 1 studies as monotherapy or in combination with chemotherapy have prompted further investigation in several thoracic malignancies, including ongoing trials in malignant mesothelioma, small cell lung cancer, and an ongoing phase 2/3 trial in non-small cell lung cancer (NSCLC) in combination with chemotherapy. The NSCLC trials include patients with squamous cell histologic features and treated brain metastases, populations for which bevacizumab is currently not indicated. These trials will determine whether cediranib will join the growing armamentarium of therapeutic options for thoracic malignancies and broaden the number of patients with NSCLC who could potentially benefit from antiangiogenic therapy.
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PMID:The tyrosine kinase inhibitor cediranib for non-small cell lung cancer and other thoracic malignancies. 1852 Feb 96

Inhibition of tumor angiogenesis through blockade of the vascular endothelial growth factor (VEGF) signaling pathway is a novel treatment modality in oncology. Preclinical findings suggest that long-term clinical outcomes may improve with blockade of additional proangiogenic receptor tyrosine kinases: platelet-derived growth factor receptors (PDGFR) and fibroblast growth factor receptors (FGFR). BIBF 1120 is an indolinone derivative potently blocking VEGF receptor (VEGFR), PDGFR and FGFR kinase activity in enzymatic assays (IC(50), 20-100 nmol/L). BIBF 1120 inhibits mitogen-activated protein kinase and Akt signaling pathways in three cell types contributing to angiogenesis, endothelial cells, pericytes, and smooth muscle cells, resulting in inhibition of cell proliferation (EC(50), 10-80 nmol/L) and apoptosis. In all tumor models tested thus far, including human tumor xenografts growing in nude mice and a syngeneic rat tumor model, BIBF 1120 is highly active at well-tolerated doses (25-100 mg/kg daily p.o.), as measured by magnetic resonance imaging of tumor perfusion after 3 days, reducing vessel density and vessel integrity after 5 days, and inducing profound growth inhibition. A distinct pharmacodynamic feature of BIBF 1120 in cell culture is sustained pathway inhibition (up to 32 hours after 1-hour treatment), suggesting slow receptor off-kinetics. Although BIBF 1120 is rapidly metabolized in vivo by methylester cleavage, resulting in a short mean residence time, once daily oral dosing is fully efficacious in xenograft models. These distinctive pharmacokinetic and pharmacodynamic properties may help explain clinical observations with BIBF 1120, currently entering phase III clinical development.
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PMID:BIBF 1120: triple angiokinase inhibitor with sustained receptor blockade and good antitumor efficacy. 1855 24

Melanoma growth, angiogenesis and metastatic progression are strongly promoted by the inflammatory tumor microenvironment due to high levels of cytokine and chemokine secretion by the recruited inflammatory and stromal cells. In addition, platelets and molecular components of procoagulant pathways have been recently emerging as critical players of tumor growth and metastasis. In particular, thrombin, through the activity of its receptor protease-activated receptor-1 (PAR-1), regulates tumor cell adhesion to platelets and endothelial cells, stimulates tumor angiogenesis, and promotes tumor growth and metastasis. Notably, in many tumor types including melanoma, PAR-1 expression directly correlates with their metastatic phenotype and is directly responsible for the expression of interleukin-8, matrix metalloproteinase-2 (MMP-2), vascular endothelial growth factor, platelet-derived growth factor, and integrins. Another proinflammatory receptor-ligand pair, platelet-activating factor (PAF) and its receptor (PAFR), have been shown to act as important modulators of tumor cell adhesion to endothelial cells, angiogenesis, tumor growth and metastasis. PAF is a bioactive lipid produced by a variety of cells from membrane glycerophospholipids in the same reaction that releases arachidonic acid, and can be secreted by platelets, inflammatory cells, keratinocytes and endothelial cells. We have demonstrated that in metastatic melanoma cells, PAF stimulates the phosphorylation of cyclic adenosine monophosphate response element-binding protein (CREB) and activating transcription factor 1 (ATF-1), which results in overexpression of MMP-2 and membrane type 1-MMP (membrane type 1-MMP). Since only metastatic melanoma cells overexpress CREB/ATF-1, we propose that metastatic melanoma cells are better equipped than their non-metastatic counterparts to respond to PAF within the tumor microenvironment. The evidence supporting the hypothesis that the two G-protein coupled receptors, PAR-1 and PAFR, contribute to the acquisition of the metastatic phenotype of melanoma is presented and discussed.
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PMID:Emerging roles of PAR-1 and PAFR in melanoma metastasis. 1930 89

Inhibition of tumor angiogenesis through blockade of the vascular endothelial growth factor (VEGF) signaling pathway is a new treatment modality in oncology. Preclinical findings suggest that blockade of additional pro-angiogenic kinases, such as fibroblast and platelet-derived growth factor receptors (FGFR and PDGFR), may improve the efficacy of pharmacological cancer treatment. Indolinones substituted in position 6 were identified as selective inhibitors of VEGF-, PDGF-, and FGF-receptor kinases. In particular, 6-methoxycarbonyl-substituted indolinones showed a highly favorable selectivity profile. Optimization identified potent inhibitors of VEGF-related endothelial cell proliferation with additional efficacy on pericyctes and smooth muscle cells. In contrast, no direct inhibition of tumor cell proliferation was observed. Compounds 2 (BIBF 1000) and 3 (BIBF 1120) are orally available and display encouraging efficacy in in vivo tumor models while being well tolerated. The triple angiokinase inhibitor 3 is currently in phase III clinical trials for the treatment of nonsmall cell lung cancer.
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PMID:Design, synthesis, and evaluation of indolinones as triple angiokinase inhibitors and the discovery of a highly specific 6-methoxycarbonyl-substituted indolinone (BIBF 1120). 1952 65

Cutaneous melanoma is the most aggressive skin cancer; it is highly metastatic and responds poorly to current therapies. The expression of platelet-derived growth factor receptors (PDGF-Rs) is reported to be reduced in metastatic melanoma compared with benign nevi or normal skin; we then hypothesized that PDGF-Ralpha may control growth of melanoma cells. We show here that melanoma cells overexpressing PDGF-Ralpha respond to serum with a significantly lower proliferation compared with that of controls. Apoptosis, cell cycle arrest, pRb dephosphorylation, and DNA synthesis inhibition were also observed in cells overexpressing PDGF-Ralpha. Proliferation was rescued by PDGF-Ralpha inhibitors, allowing to exclude nonspecific toxic effects and indicating that PDGF-Ralpha mediates autocrine antiproliferation signals in melanoma cells. Accordingly, PDGF-Ralpha was found to mediate staurosporine cytotoxicity. A protein array-based analysis of the mitogen-activated protein kinase pathway revealed that melanoma cells overexpressing PDGF-Ralpha show a strong reduction of c-Jun phosphorylated in serine 63 and of protein phosphatase 2A/Balpha and a marked increase of p38gamma, mitogen-activated protein kinase kinase 3, and signal regulatory protein alpha1 protein expression. In a mouse model of primary melanoma growth, infection with the Ad-vector overexpressing PDGF-Ralpha reached a significant 70% inhibition of primary melanoma growth (P < .001) and a similar inhibition of tumor angiogenesis. All together, these data demonstrate that PDGF-Ralpha strongly impairs melanoma growth likely through autocrine mechanisms and indicate a novel endogenous mechanism involved in melanoma control.
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PMID:Platelet-derived growth factor-receptor alpha strongly inhibits melanoma growth in vitro and in vivo. 1964 3

The authors review the antineoplastic effect of mammalian target of rapamycin (mTOR) inhibitors and their biological basis. mTOR is an intracellular serine/threonine kinase that is a central controller of cell growth and proliferation. mTOR integrates signals from sources such as nutrients and growth factors. mTOR regulation can affect angiogenesis, cell growth, nutrient uptake and utilization, and metabolism. Growth factors such as insulin growth factor, epidermal growth factor, platelet-derived growth factor and vascular endothelial growth factor bind to and activate receptors located on the cell surface. Receptors activate intracellular signaling cascades phosphatidylinositol 3 kinase-serine-threonine kinase-mTOR (PI3K-AKT-mTOR) leading to protein synthesis. Activation of the mTOR pathway is linked to increased protein synthesis by modulating elements that are important in cellular processes, including growth, proliferation, angiogenesis and nutrient uptake. Many growth factor receptors and signaling pathway components are deregulated in cancer. Deregulations in mTOR-linked pathways increase the risk of developing cancer or have been identified in many human cancers. Deregulations include overexpression of growth factors, overexpression or mutations of growth factor receptors, loss of tumor suppressor genes, and gain-of-function mutations in mTOR-linked pathways. These deregulations permit the survival, growth, proliferation and migration of cancer cells and promote tumor angiogenesis. Targeting them has been a successful anticancer strategy. Targeting mTOR as well as these deregulated pathways could provide enhanced anticancer activity. The efficacy of mTOR inhibitors in preventing several types of cancers in transplanted patients or in recovering cancers developed in transplant patients has been documented in both trials and single reports.
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PMID:Antineoplastic effect of proliferation signal inhibitors: from biology to clinical application. 1966


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