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At least 703 records · Page 39Linked to original sources
PubMed2002

Morphine stimulates angiogenesis by activating proangiogenic and survival-promoting signaling and promotes breast tumor growth.

Morphine is used to treat pain in several medical conditions including cancer. Here we show that morphine, in a concentration typical of that observed in patients' blood, stimulates human microvascular endothelial cell proliferation and angiogenesis in vitro and in vivo. It does so by activating mitogen-activated protein kinase/extracellular signal-regulated kinase phosphorylation via Gi/Go-coupled G protein receptors and nitric oxide in these microvascular endothelial cells. Other contributing effects of morphine include activation of the survival signal PKB/Akt, inhibition of apoptosis, and promotion of cell cycle progression by increasing cyclin D1. Consistent with these effects, morphine in clinically relevant doses promotes tumor neovascularization in a human breast tumor xenograft model in mice leading to increased tumor progression. These results indicate that clinical use of morphine could potentially be harmful in patients with angiogenesis-dependent cancers.

Analgesics, Opioid↗
PubMed2002

Angiogenesis in health and disease: insights into basic mechanisms and therapeutic opportunities.

Angiogenesis, the process that leads to the formation of new blood vessels or neovascularization, continues to be a topic of major scientific and public interest. As knowledge of the molecular mechanisms that regulate neovascularization continues to emerge, there is increasing hope that new discoveries will lead to newer therapies that target angiogenesis as a reliable option for disease therapy. For example, it may be possible to develop strategies that, on the one hand, are designed to limit angiogenesis for the treatment of chronic diseases such as cancer or rheumatoid arthritis and, on the other, to promote angiogenesis in the ischemic heart or diabetic limb. With the emergence of tissue engineering as a discipline, it has become increasingly clear that long-term success in organ and tissue reconstruction will depend on the ability to develop a stable, renewable supply of blood vessels. In this review, I will provide a brief overview of this remarkably versatile biological response and discuss how recent discoveries in the field of angiogenesis have influenced the development of novel therapies, forced a reconsideration of conventional therapies, and revolutionized approaches to organ and tissue reconstruction.

Angiogenesis Inhibitors↗
PubMed2002

Domain swapping in a COOH-terminal fragment of platelet factor 4 generates potent angiogenesis inhibitors.

A few peptide residues in structurally important locations often determine biological functions of proteins implicated in the regulation of angiogenesis. We have shown recently that the short COOH-terminal segment PF-4(47-70) derived from platelet factor 4 (PF-4) is the smallest sequence that conserves potent antiangiogenic activity in vitro and in vivo. Here we show that modified COOH-terminal PF-4 peptides containing the sequence ELR (or related DLR), a critical domain present in proangiogenic chemokines, surprisingly elicit several times greater antiangiogenic potential than the original peptide. The modified peptides inhibit binding of iodinated vascular endothelial growth factor and fibroblast growth factor 2 to endothelial cell receptors, endothelial cell proliferation, migration, and microvessel assembly in the rat aortic ring model at lower doses than PF-4(47-70). On the differentiated chick chorioallantoic membrane, topical application of 40 micro g of modified peptides potently reduces capillary angiogenesis induced by vascular endothelial growth factor(165), a dose where peptide PF-4(47-70) was inactive. Established intracranial glioma in nude mice decreased significantly in size when treated locally with a total dose of 250 micro g of peptide PF-4(47-70)DLR (n = 10) compared with the same dose of the original PF-4(47-70) peptide (n = 10) or controls (n = 30). Tailored PF-4 peptides represent a new class of antiangiogenic agents with a defined mode of action and a strong in vivo activity.

Allantois↗
PubMedDate not supplied

The therapeutic efficacy of angiostatin against weakly- and highly-immunogenic 3LL tumors.

BACKGROUND: Antiagiogenesis represents a promising approach to cancer therapy. We have previously demonstrated that the antitumor effects of endostatin, one of the most potent angiostatic agents, could be enhanced when combined with immunotherapy. Our current study evaluated whether anti-tumor immune response could also potentiate the therapuetic efficacy of another antiangiogenic drug, angiostatin. METHODS AND RESULTS: Using Matrigel assay, we showed that our preparation of recombinant angiostatin possessed potent anti-angiogenic activity in vivo. The antitumor effects of recombinant angiostatin were tested against weakly-immunogenic 3LL Lewis lung carcinoma versus its highly immunogenic variant 3LL-C75. We showed that angiostatin inhibited the growth of 3LL-C75 more potently than that of 3LL tumor, suggesting that the host's immune response potentiates the antitumor effects of angiostatin. This conclusion was further supported by the finding that the antitumor activity of angiostatin against 3LL-C75 tumor was lower in immunodeficient nude mice in comparison with immunocompetent mice. Immunization of C57BL/6 mice with 3LL-C75 cells stimulated the antitumor immunity and inhibited the growth of parental 3LL tumor. Angiostatin treatment of immunized mice further enhanced the antitumor effect of tumor vaccination. CONCLUSION: Antitumor immune response could complement the therapeutic efficacy of angiostatin.

Angiogenesis Inhibitors↗
PubMed2002

Prediction of in vivo synergistic activity of antiangiogenic compounds by gene expression profiling.

Angiogenesis, an essential phenotype for tumor formation, requires the interaction of many cells within the tumor microenvironment. Therefore, successful antiangiogenic therapies must be able to block all of the different mechanisms tumors use to induce neovascularization. A major challenge for developing such protocols is determining which agents are likely to have the highest degree of synergistic activity in vivo. We treated human microvascular endothelial cells with six inhibitors of angiogenesis and used microarrays to seek divergent patterns of gene expression suggestive of potential synergies. The expression profiles of a thrombospondin-mimetic peptide (DI-TSPa) and TNP-470 (TNP) were very similar, whereas endostatin had a dramatically different profile. In vitro, endostatin was synergistically antiangiogenic with either TNP-470 or DI-TSPa. In vivo, mice bearing Lewis lung carcinoma cells treated with a combination of endostatin and either DI-TSPa or TNP-470, at doses that were ineffective when used alone, resulted in a marked inhibition of tumor growth and decreased tumor angiogenesis. Conversely, animals treated with both DI-TSPa and TNP-470 demonstrated a modest effect on both tumor growth and angiogenesis. These results suggest that even in the absence of a complete mechanistic understanding of how these inhibitors work, gene expression profiling may be used to predict synergistic antiangiogenic activity and thus maximize their antitumor efficacy.

Angiogenesis Inhibitors↗
PubMed2003

Angiogenesis: molecular mechanisms and functional interactions--2nd Kloster Seeon Meeting of the German Priority Research Grant "Angiogenesis".

The German Priority Research Program "Angiogenesis" (www.angiogenese.de) hosts a biannual meeting in the Kloster Seeon in Southern Germany. The 2nd Kloster Seeon Meeting "Angiogenesis: Molecular Mechanisms and Functional Interactions" was held in September 2002. It included sessions on hypoxia, the biology of endothelial precursor cells, angiogenic growth factors including VEGFs, the angiopoietins, ephrins, and FGFs, mechanisms of vascular sprouting and cell-cell contacts during angiogenesis, angiogenic signaling, lymphangiogenesis, angiogenesis during tumor invasion and metastasis, and on novel angiomanipulatory therapies. This report summarizes the key findings reported during the platform presentations of the meeting.

Animals↗
PubMed2003

Irradiation-induced angiogenesis through the up-regulation of the nitric oxide pathway: implications for tumor radiotherapy.

The combination of radiotherapy and antiangiogenic strategies has been shown to increase the tumor response in various experimental models. The rationale for this cotherapy was initially related to the expected gain in efficacy by acting on two different targets, e.g., tumor cells and endothelial cells (ECs). However, recent studies have documented more than additive effects due to apparent mutual potentiation of these approaches. In this study, we tested the hypothesis that these synergistic effects could stem from the stimulatory effects of ionizing radiations on angiogenesis, which would then need to be restrained to avoid tumor regrowth after irradiation. We found that irradiation dose-dependently induced the activation of the proangiogenic NO pathway in ECs through increases in endothelial nitric oxide synthase abundance and phosphorylation. Using 2- and 3-dimensional cultures of ECs and isolated mouse tumor arterioles, we documented that the irradiation-induced enhanced production of NO accounted for EC migration and sprouting. Irradiation was also shown to stimulate the colonization of Matrigel plugs implanted in mouse by ECs, where they formed capillary-like structures in a NO-dependent manner. These findings were confirmed by documenting the NO-mediated infiltration of CD31-positive ECs after local irradiation of Lewis lung carcinoma tumor-bearing mice. Finally, we measured a consistent increase in endothelial nitric oxide synthase mRNA by real-time PCR experiments in human biopsies of head and neck squamous cell carcinoma after low-dose irradiation. In conclusion, we have demonstrated that the potentiation of the NO signaling pathway after irradiation induces profound alterations in the EC phenotype leading to tumor angiogenesis. Moreover, our demonstration that the inhibition of NO production suppresses these provascular effects of irradiation highlights new potentials for the coordinated use of antiangiogenic strategies and radiotherapy in clinical practice.

Animals↗
PubMed2003

Hyperthermia inhibits angiogenesis by a plasminogen activator inhibitor 1-dependent mechanism.

Hyperthermia (HT) associated with radiotherapy or chemotherapy is a promising method for cancer treatment, although the molecular mechanisms of this process are not well understood. HT exhibits various antitumor effects, including damage of tumor vasculature. Here, we investigate the effect of HT on in vitro and in vivo angiogenesis. We show that heat treatment of endothelial cells (ECs) affect their differentiation into capillary-like structures in two models of in vitro angiogenesis. Furthermore, the formation of new vessels promoted by angiogenic inducers in the chick embryo chorioallantoic membrane assay is impaired after heat treatment. These effects cannot be explained by direct cytotoxicity but are dependent on modulation of angiogenesis-involved genes. Gene expression profile of ECs subjected to heat shock demonstrates that plasminogen activator inhibitor 1 (PAI-1), a protein involved in the control of extracellular matrix degradation, is specifically up-regulated. The use of anti-PAI-1-neutralizing antibodies reverts the effect of HT on the in vitro EC morphogenesis and in vivo vessel formation. Moreover, microvessel outgrowth from PAI-1(-/-) aortic rings was not affected by HT compared with aortic rings from PAI-1(+/+) mice. Heat treatment of murine mammary adenocarcinomas results in inhibition of tumor growth, associated with a reduction of microvessel number and an increase of PAI-1 expression. These results indicate that heat-mediated PAI-1 induction is an important pathway by which HT exerts its antitumor activity and may represent a rationale for a combined cancer therapy based on HT associated with antiangiogenic molecules.

Allantois↗
PubMed2003

[Severe vascular dysfunction shown in transplanted islets].

Despite recent advances in clinical islet transplantation, a surprisingly large number of islets (approximately 1 million) are still required to obtain insulin independence in type 1 diabetes. The reasons for this are obscure and likely multifactorial. One explanation may be disturbances in engraftment of the transplanted islets, i.e. the adaptation of the islet transplant to its new surroundings with regard to e.g. revascularization and blood perfusion. Endogenous islets have a dense glomerular-like angioarchitecture. Transplantation of isolated islets causes a disruption of their vascular connections, making the islets dependent on the formation of new blood vessels for optimal function. Evidence from experimental islet transplantation indicates an insufficient revascularization of transplanted islets with subsequent chronically decreased blood perfusion and oxygen tension, which has metabolic consequences within the tissue.

Animals↗
PubMed2003

Tissue-specific microvascular endothelial cell lines from H-2K(b)-tsA58 mice for studies of angiogenesis and metastasis.

Microvascular endothelial cells play a critical role in tumor progression and metastasis by forming capillary networks that encourage tumor growth and by promoting the attachment of circulating tumor cells to the vascular wall of distant tissues. Efforts to study the molecular mechanisms that mediate these complex processes in different anatomical compartments have been impeded by difficulties in the isolation and propagation of endothelial cells from different organs. To overcome these limitations, we used two-color flow cytometry to identify and select microvascular endothelial cells from primary cultures obtained from different organs of mice whose tissues harbor a temperature-sensitive SV40 large T antigen (H-2K(b)-tsA58 mice; ImmortoMice). The selection strategy targeted cell populations expressing the inducible endothelial cell adhesion molecules, E-selectin and VCAM-1, and proved successful in generating microvascular endothelial cell lines from a number of different organs. When cultured under permissive temperatures (33 degrees C), individual cell lines displayed doubling times consistent with endothelial cells possessing an angiogenic phenotype. The transfer of endothelial cells to nonpermissive temperatures (37 degrees C) resulted in cell differentiation and the induction of a quiescent state. Established cell lines exhibited several inherent endothelial properties, including the expression of constitutive and inducible levels of endothelial cell adhesion molecules E-selectin, intercellular adhesion molecule-1, and vascular cell adhesion molecule-1, internalization of acetylated low-density lipoprotein, and formation of loop structures on Matrigel surfaces. The immortalized endothelial cell lines established from H-2K(b)-tsA58 mice provide, for the first time, a cell culture system to examine factors regulating angiogenesis and tumor cell arrest in different organ systems.

Animals↗
PubMed2003

[Vasculogenesis and angiogenesis: molecular and cellular controls. II. The interactions between the cell and its environment].

Angiogenesis defined as a new blood vessel formation from a preexisting vessel is initiated by angiogenic growth factors and their receptors, that induce endothelial cells migration and proliferation. Extracellular proteolysis is essential for deassembly et reassembly of endothelial cells to their environmental matrix. The aim of this review is to update data upon the role of the coagulation and fibrinolysis system, metalloproteinases and adhesion molecules during this step of angiogenesis.

Blood Vessels↗
PubMed2003

Angiogenic and angiostatic factors in the molecular control of angiogenesis.

The vascular system that ensures an adequate blood flow is required to provide the cells with sufficient supply of nutrients and oxygen. Two different mechanisms of the formation of new vessels can be distinguished: vasculogenesis, the formation of the first primitive vascular plexus de novo and angiogenesis, the formation of new vessels from preexisting ones. Both processes are regulated by a delicate balance of pro- and anti-angiogenic factors. Physiologically, angiostatic mediators outweigh the angiogenic molecules and angiogenesis does not occur. Under certain conditions such as tumor formation or wound healing, the positive regulators of angiogenesis predominate and the endothelium becomes activated. Angiogenesis is initiated by vasodilatation and an increased permeability. After destabilization of the vessel wall, endothelial cells proliferate, migrate and form a tube, which is finally stabilized by pericytes and smooth muscle cells. Numerous soluble growth factors and inhibitors, cytokines and proteases as well as extracellular matrix proteins and adhesion molecules strictly control this multi-step process. The properties and interactions of angiogenic molecules such as VEGFs, FGFs, angiopoietins, PDGF, angiogenin, angiotropin, HGF, CXC chemokines with ELR motif, PECAM-1, integrins and VE-cadherin as well as angiostatic key players such as angiostatin, endostatin, thrombospondin, CXC chemokines without ELR motif, PEDF are discussed in this review with respect to their molecular impact on angiogenesis.

Angiopoietins↗
PubMed2003

Endostatin inhibits the vascular endothelial growth factor-induced mobilization of endothelial progenitor cells.

Circulating endothelial cells (CECs) are present in peripheral blood and have been shown to contribute to normal and pathological neovascularization. Antiangiogenic molecules can inhibit neovascularization in tumors and other sites, but their effect on CECs has not yet been determined. We hypothesize that angiogenic factors will increase the number of CECs, and conversely, antiangiogenic treatment will reduce these numbers. Mice treated with high levels of vascular endothelial growth factor (VEGF) showed increased numbers of Flk-1-positive cells in peripheral blood and endothelial cell colonies compared with vehicle-treated controls. These changes were accompanied by increased bone marrow neovascularization. In contrast, mice that received VEGF and endostatin had significantly lower numbers of CECs and reduced bone marrow vascularization. Endostatin-induced apoptosis was probably responsible for the decreased number of CECs. Systemic delivery of a VEGF antagonist, soluble Flt-1, also inhibited the VEGF-induced increase in CECs. These results were further confirmed in a Tie2/LacZ mouse model, in which endostatin reduced the number of beta-galactosidase-expressing peripheral blood mononuclear cells. We propose that endothelial progenitor cells are a novel target for endostatin and suggest that the relative numbers of CECs can serve as a surrogate marker for the biological activity of antiangiogenic treatment.

Animals↗