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Query: UMLS:C1658953 (tumor vasculature)
 2,390 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Thromboembolism is one of the most common causes of death in cancer patients. Among the most frequent thrombotic complications in patients with cancer are disseminated intravascular coagulation, thrombotic thrombocytopenic purpura, and thrombocytosis. Clearly, these complications arise as tumor cells interact with almost all components of the hemostatic system including platelets. Platelets participate in tumor progression by contributing to the metastatic cascade, protecting tumor cells from immune surveillance, regulating tumor cell invasion, and angiogenesis. Platelets contain one of the largest stores of angiogenic and mitogenic factors and the tumor vasculature is leaky, which allows platelets to come in contact with the tumor and deposit multiple angiogenic factors including vascular endothelial growth factor (VEGF) and thrombin to tumor cells, which in turn contributes to tumor progression. This article reviews the recent literature on how platelets contribute to tumor growth, angiogenesis, and metastasis.
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PMID:Platelets and cancer: implications for antiangiogenic therapy. 1188 24

Angiogenesis is widely accepted to play a central role in tumor growth and spreading. Therefore, anti-angiogenic agents appear as promising tools in cancer therapy, and great efforts have been devoted to their identification in recent years. Despite fast progress in this area, a quantitative and objective system for rapid anti-angiogenic testing is not currently available. In this work, we describe a new platform for the large-scale screening of agents with potential anti-angiogenic activity. This involved the miniaturization of an in vitro two-dimensional assay model of vascular morphogenesis to run in a high-density format (384- or 1536-well microplates) and the development of a specific digital image-analysis system for the automated and quantitative evaluation of biological activity. To test the efficacy and reproducibility of the platform, we used a wide variety of well-characterized angiogenesis inhibitors, including antibodies against components of the extracellular matrix, peptides, and chemicals. The system proved to be a reproducible, polyvalent, and powerful tool for massive screening of agents with potential application in cancer therapy. Ongoing developmental work, directed toward optimizing this system for use with a fully automated high-throughput screening platform, should accelerate research into the mechanisms of tumor angiogenesis and the development of drugs that target the essential tumor vasculature.
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PMID:Development of a computer-assisted high-throughput screening platform for anti-angiogenic testing. 1196 10

Vascular endothelial-cadherin (VE-cadherin) is an endothelial cell-specific adhesion molecule that is localized exclusively at cell-cell contacts referred to as adherens junctions. VE-cadherin-mediated adhesion is crucial for proper assembly of vascular structures during angiogenesis as well as for maintenance of a normal vascular integrity. We have shown previously that a monoclonal antibody (BV13) to VE-cadherin not only inhibits the formation of vascular tubes during tumor angiogenesis but also disrupts adherens junctions of normal vasculature with a concomitant increase in vascular permeability. The goal of the current studies was to block VE-cadherin function during angiogenesis without disrupting existing junctions on normal endothelium. Using in vitro screening assays to test for functional blocking of adherens junction formation and in vivo assays to detect antibody effects on vascular permeability in normal tissues, we have identified a novel blocking antibody (E4G10) that inhibits VE-cadherin function during angiogenesis but does not disrupt existing adherens junctions on normal vasculature. E4G10 inhibited formation of vascular tubes in vivo in the Matrigel plug and corneal micropocket assays. E4G10 also inhibited tumor growth in three models of mouse and human tumors via an antiangiogenic mechanism. Examination of normal mouse and tumor tissues showed that E4G10 bound to endothelial cells in a subset of tumor vasculature but not to normal vasculature. Bromodeoxyuridine labeling experiments showed that E4G10 specifically targeted a subset of tumor endothelium that is undergoing active cell proliferation, which likely reflects the activated, angiogenic endothelium. These findings indicate that VE-cadherin can be selectively targeted during states of pathological angiogenesis, despite its ubiquitous distribution throughout the entire vasculature. Our data also suggest that antibody E4G10 recognizes VE-cadherin epitopes that are only accessible on endothelial cells forming new adherens junctions, such as in angiogenic tumor vasculature.
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PMID:Selective targeting of angiogenic tumor vasculature by vascular endothelial-cadherin antibody inhibits tumor growth without affecting vascular permeability. 1198 Jun 51

The demonstration that angiogenesis is required for the growth of solid tumors has fueled an intense interest in the development of new therapeutic strategies that target the tumor vasculature. Here we report the development of an immune-based antiangiogenic strategy that is based on the generation of T lymphocytes that possess a killing specificity for cells expressing vascular endothelial growth factor receptors (VEGFRs). To target VEGFR-expressing cells, recombinant retroviral vectors were generated that encoded a chimeric T cell receptor comprised of VEGF sequences linked to intracellular signaling sequences derived from the zeta chain of the T cell receptor. After transduction of primary murine CD8 lymphocytes by such vectors, the transduced cells were shown to possess an efficient killing specificity for cells expressing the VEGF receptor, Flk-1, as measured by in vitro cytotoxicity assays. After adoptive transfer into tumor-bearing mice, the genetically modified cytotoxic T lymphocytes strongly inhibited the growth of a variety of syngeneic murine tumors and human tumor xenografts. An increased effect on in vivo tumor growth inhibition was seen when this therapy was combined with the systemic administration of TNP-470, a conventional angiogenesis inhibitor. The utilization of the immune system to target angiogenic markers expressed on tumor vasculature may prove to be a powerful means for controlling tumor growth.
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PMID:Antitumor activity of cytotoxic T lymphocytes engineered to target vascular endothelial growth factor receptors. 1199 59

Colon carcinomas frequently express the epidermal growth factor receptor (EGFR), and this expression correlates with more aggressive disease and poor prognosis. Previous studies have shown that EGFR blockade by monoclonal antibody IMC-C225 can inhibit the growth of human colon carcinoma tumor cells in vitro and xenografts of these tumors in athymic mice. In this report, we have studied the in vivo activity of IMC-C225 combined with the topoisomerase I inhibitor irinotecan (CPT-11) using two models of human colorectal carcinoma in nude mice. IMC-C225 was tested at a dose of 1 or 0.5 mg administered q3d. CPT-11 was administered at a dose of 100 mg/kg/week or a maximum tolerated dose of 150 mg/kg/week. Treatment with the combination of IMC-C225 (1 and 0.5 mg) and CPT-11 (100 mg/kg) significantly inhibited the growth of established DLD-1 and HT-29 tumors compared with either CPT-11 or IMC-C225 monotherapy (P < 0.05). Combination therapy with IMC-C225 (1 mg) and the MTD of CPT-11 (150 mg/kg) resulted in a regression rate of 100 and 60% of established DLD-1 and HT-29 tumors, respectively. In a refractory tumor model, combined treatment with IMC-C225 and CPT-11 significantly inhibited the growth of CPT-11 refractory DLD-1 and HT-29 tumors, whereas either agent alone did not control tumor growth. Histological examination of treated tumors showed extensive tumor necrosis, decreased tumor cell proliferation, increased tumor cell apoptosis, and a marked decrease in tumor vasculature. These results suggest that EGFR blockade by IMC-C225 combined with topoisomerase I inhibitors may be an effective therapy against chemorefractory colorectal carcinoma tumors.
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PMID:Enhanced antitumor activity of anti-epidermal growth factor receptor monoclonal antibody IMC-C225 in combination with irinotecan (CPT-11) against human colorectal tumor xenografts. 1200 11

Tumor growth depends upon an adequate supply of oxygen and nutrients achieved through angiogenesis and maintenance of an intact tumor vasculature. Therapy with individual agents that target new vessel formation or existing vessels has suppressed experimental tumor growth, but rarely resulted in the eradication of tumors. We therefore tested the combined anti-tumor activity of vasostatin and interferon-inducible protein-10 (IP-10), agents that differently target the tumor vasculature. Vasostatin, a selective and direct inhibitor of endothelial cell proliferation, significantly reduced Burkitt tumor growth and tumor vessel density. IP-10, an "angiotoxic" chemokine, caused vascular damage and focal necrosis in Burkitt tumors. When combined, vasostatin plus IP-10 reduced tumor growth more effectively than each agent alone, but complete tumor regression was not observed. Microscopically, these tumors displayed focal necrosis and reduction in vessel density. Combination therapy with the inhibitors of angiogenesis vasostatin and IP-10 is effective in reducing the rate of tumor growth but fails to induce tumor regression, suggesting that curative treatment may require supplemental drugs targeting directly the tumor cells.
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PMID:Anti-tumor activities of the angiogenesis inhibitors interferon-inducible protein-10 and the calreticulin fragment vasostatin. 1219 35

Tumor angiogenesis is an essential step in tumor progression and metastasis formation. Suppression of tumor angiogenesis results in the inhibition of tumor growth. Recent evidence indicates that vascular integrins, in particular alpha V beta 3, are important regulators of angiogenesis, including tumor angiogenesis. Integrin alpha V beta 3 antagonists, such as blocking antibodies or peptides, suppress tumor angiogenesis and tumor progression in many preclinical tumor models. The potential therapeutic efficacy of extracellular integrin antagonists in human cancer is currently being tested in clinical trials. Selective disruption of the tumor vasculature by high doses of tumor necrosis factor (TNF) and interferon gamma (IFN-gamma), and the antiangiogenic activity of nonsteroidal anti-inflammatory drugs are associated with the suppression of integrin alpha V beta 3 function and signaling in endothelial cells. Furthermore, expression of isolated integrin cytoplasmic domains disrupts integrin-dependent adhesion, resulting in endothelial cell detachment and apoptosis. These results confirm the critical role of vascular integrins in promoting endothelial cell survival and angiogenesis and suggest that intracellular targeting of integrin function and signaling may be an alternative strategy to extracellular integrin antagonists for the therapeutic inhibition of tumor angiogenesis.
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PMID:Suppression of tumor angiogenesis through the inhibition of integrin function and signaling in endothelial cells: which side to target? 1238 Jun 40

Antiangiogenesis therapy has become a potentially promising tool to inhibit tumor growth by targeting an essential yet untransformed tissue component. Identifying the factors involved and understanding the mechanisms required for tumor angiogenesis will facilitate efficient and specific targeting. In neurofibromas, tumor growth is facilitated by a genetically and cytologically diverse mixture of cell types, including Schwann cells, fibroblast, mast cells, and neurons where nf-/- Schwann cells are most likely the tumorigenic cell type. The matrix forming nf+/- cells may provide a permissive environment, facilitating tumor development, perhaps by providing landscaping factors such as the angiogenic molecules fibroblast growth factor-2, platelet-derived growth factor, endothelial growth factor, vascular endothelial growth factor, and midkine, which have been detected in neurofibromas. Systemic overexpression of specific factors such as midkine owing to loss of one nf allele might further lower the overall threshold for tumorigenesis and development of a tumor vasculature. Targeting these heparin-binding growth factors might inhibit not only angiogenesis but also proliferation of tumor cells because most of these factors also stimulate proliferation of neurofibroma-derived Schwann cells. We discuss the role of specific secreted molecules for angiogenesis in tumors of neurofibromatosis 1 and possible Approaches for their targeting. Furthermore, results are discussed that demonstrate the efficacy of antiangiogenesis targeting to inhibit growth of neurofibrosarcomas in experimental animal models.
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PMID:Antiangiogenesis in neurofibromatosis 1. 1240 56

Photodynamic therapy (PDT) with hypericin has been shown to inhibit tumor growth in different tumor models, and tumor vascular damage was suggested to be mainly responsible for the antitumoral effect. Here, we demonstrate tumor vascular damage and its consequence on local tumor control after hypericin-mediated PDT by using both short and long drug-light intervals. Radiation-induced fibrosarcoma-1 tumors were exposed to laser light at either 0.5 or 6 h after a 5 mg/kg dose of hypericin. Tumor perfusion was monitored by fluorescein dye-exclusion assay and by Hoechst 33342 staining of functional blood vessels. Significant reduction in tumor perfusion was found immediately after both PDT treatments. A complete arrest of vascular perfusion was detected by 15 h after the 0.5 h-interval PDT, whereas well-perfused areas could still be found at this time in tumors after the 6 h-interval PDT. A histological study confirmed that primary vascular damage was involved in both PDT treatments. Tumor cells appeared intact shortly after light treatment, degenerated at later hours and became extensively pycnotic at 24 h after the 0.5 h-interval PDT. PDT under this condition led to complete tumor cure. In contrast, significant numbers of viable tumor cells, especially at the tumor periphery, were found histologically at 24 h after the 6 h-interval PDT. No tumor cure was obtained when PDT was performed at this time. Our results strongly suggest that targeting the tumor vasculature by applying short drug-light interval PDT with hypericin might be a promising way to eradicate solid tumors.
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PMID:Antivascular tumor eradication by hypericin-mediated photodynamic therapy. 1246 45

By implanting nondisrupted pieces of human lung tumor biopsy tissues into SCID mice, it has been possible to establish viable grafts of the tumor, as well as the tumor-associated microenvironment, including inflammatory cells, fibroblasts, tumor vasculature, and the extracellular matrix. Using this xenograft model, we have evaluated and characterized the effects of a local and sustained release of human rIL-12 (rhIL-12) from biodegradable microspheres. In response to rhIL-12, the human CD45+ inflammatory cells present within the xenograft mediate the suppression or the complete arrest of tumor growth in SCID mice. Analysis of the cellular events reveals that human CD4+ and CD8+ T cells are induced by rhIL-12 to produce and secrete IFN-gamma. Serum levels of human IFN-gamma in mice bearing rhIL-12-treated tumor xenografts correlate directly with the degree of tumor suppression, while neutralizing Abs to human IFN-gamma abrogate the IL-12-mediated tumor suppression. Gene expression profiling of tumors responding to intratumoral rhIL-12 demonstrates an up-regulation of IFN-gamma and IFN-gamma-dependent genes not observed in control-treated tumors. Genes encoding a number of proinflammatory cytokines, chemokines (and their receptors), adhesion molecules, activation markers, and the inducible NO synthase are up-regulated following the introduction of rhIL-12, while genes associated with tumor growth, angiogenesis, and metastasis are decreased in expression. NO contributes to the tumor killing because an inhibitor of inducible NO synthase prevents IL-12-induced tumor suppression. Cell depletion studies reveal that the IL-12-induced tumor suppression, IFN-gamma production, and the associated changes in gene expression are all dependent upon CD4+ T cells.
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PMID:Human CD4+ T cells present within the microenvironment of human lung tumors are mobilized by the local and sustained release of IL-12 to kill tumors in situ by indirect effects of IFN-gamma. 1249 25


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