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PubMed2003

Synergistic effect of TNF-alpha in soluble VCAM-1-induced angiogenesis through alpha 4 integrins.

In our present study we focused on soluble VCAM-1 (sVCAM-1)/alpha(4) integrin-induced angiogenesis and found that this type of angiogenesis was mediated through p38 mitogen-activated protein kinase and focal adhesion kinase (FAK). HUVEC expressed both alpha(4) and beta(1) integrins, and it was reported that expression of alpha(4) integrin and its counterreceptor, sVCAM-1/VCAM-1, was enhanced in response to an inflammatory cytokine, TNF-alpha. In endothelial cells phosphorylation of p38 and FAK, but not that of extracellular signal-regulated kinase 1/2 was induced by sVCAM-1. Migration of endothelial cells was stimulated in response to sVCAM-1 at similar levels as those induced by vascular endothelial growth factor, and sVCAM-1-induced migration was almost completely blocked by neutralizing Ab against alpha(4) integrin, by either an inhibitor of p38 (SB203580), or by adenovirus containing FAK-related nonkinase. sVCAM-1 also induced the formation of blood vessels in Matrigel plug assay in vivo, and this neovascularization was blocked by SB203580 or neutralizing Ab against alpha(4) integrin. Moreover, we also confirmed that both TNF-alpha and sVCAM-1 could synergistically induce angiogenesis in the corneas of mice when each factor at used dose could not induce. This angiogenesis by TNF-alpha and sVCAM-1 was almost completely blocked by coadministration of SB203580 and also by neutralizing Ab against alpha(4) integrin. These results suggest that sVCAM-1/alpha(4) integrin induces angiogenesis through p38 and FAK signaling pathways.

Adenoviridae↗
PubMedDate not supplied

Angiogenesis research: from laboratory to clinic.

Accumulating experimental evidence demonstrates that tumour growth and lethality are dependent on angiogenesis. When angiogenesis is inhibited by administering molecules which specifically suppress the growth of vascular endothelial cells, tumours in animals can be limited to a dormant microscopic size where they are essentially harmless. The most recent evidence that vascular endothelial cells exert potent growth control over tumour cells comes from the following studies, i. administration of an angiogenesis inhibitor specific for proliferating vascular endothelium in the tumour bed; ii. optimisation of the dose and schedule of conventional cytotoxic chemotherapy for the vascular endothelium; iii. targeting of low dose cytotoxic chemotherapy only to the vascular endothelium in the tumour bed; or iv. sensitisation of vascular endothelium in the tumour bed to radiotherapy by co-administration of an angiogenesis inhibitor. In the future, anti-angiogenic therapy may be added to conventional chemotherapy, radiotherapy, immunotherapy or other novel modalities such as gene therapy. Also, angiogenesis inhibitors may be administered together for increased efficacy. The overall goal of anti-angiogenic therapy is to reduce toxicity, reduce the risk of drug resistance and to increase anti-cancer efficacy.

Angiogenesis Inhibitors↗
PubMed2000

Schwann cell-conditioned medium inhibits angiogenesis.

Neuroblastomas are biologically heterogeneous tumors that consist of two main cell populations: neuroblastic/ganglionic cells and Schwann cells. The amount of Schwannian stroma strongly impacts prognosis, and favorable outcome is associated with tumors that are Schwannian stroma rich/stroma dominant. At the present time, there is controversy regarding the origin of Schwann cells in neuroblastoma tumors. However, recent studies have suggested that the Schwann cells in mature neuroblastoma tumors may be normal cells that produce soluble substances that enhance the survival and differentiation of neuroblastoma cell lines. Previously, we reported that in neuroblastoma, high vascular index correlated with clinically aggressive disease. In contrast, tumors with favorable histology and abundant Schwannian stroma had low tumor vascularity. As a first step toward investigating whether Schwann cells also play a role in inhibiting angiogenesis in neuroblastoma tumors, we examined the ability of conditioned medium collected from normal human Schwann cells to affect basic fibroblast growth factor- and vascular endothelial growth factor-induced endothelial cell proliferation and migration and in vivo angiogenesis. In vitro angiogenesis assays were also performed with conditioned medium collected from Schwann cells derived from a Schwannian stroma-dominant neuroblastoma tumor. Our results indicate that Schwann cells derived from either adult nerve or tumor tissue produce a potent inhibitor(s) of angiogenesis. Expression studies revealed tissue inhibitor of metalloproteinase (TIMP)-2 in conditioned medium collected from both normal and tumor-derived Schwann cells. In addition, TIMP-2 was detected in the cytoplasm of Schwann cells and ganglion cells in stroma-rich/stroma-dominant neuroblastoma tumors by immunohistochemistry studies. We postulate that the low level of vascularity and more benign clinical behavior of Schwannian stroma-rich/stroma-dominant neuroblastoma tumors result from the Schwann cell production of TIMP-2 and/or other inhibitors of angiogenesis.

Adult↗
PubMed2000

HGF/NK4, a four-kringle antagonist of hepatocyte growth factor, is an angiogenesis inhibitor that suppresses tumor growth and metastasis in mice.

We reported that NK4, composed of the N-terminal hairpin and subsequent four kringle domains of hepatocyte growth factor (HGF), acts as the competitive antagonist for HGF. We now provide the first evidence that NK4 inhibits tumor growth and metastasis as an angiogenesis inhibitor as well as an HGF antagonist. Administration of NK4 suppressed primary tumor growth and lung metastasis of Lewis lung carcinoma and Jyg-MC(A) mammary carcinoma s.c. implanted into mice, although neither HGF nor NK4 affected proliferation and survival of these tumor cells in vitro. NK4 treatment resulted in a remarkable decrease in microvessel density and an increase of apoptotic tumor cells in primary tumors, which suggests that the inhibition of primary tumor growth by NK4 may be achieved by suppression of tumor angiogenesis. In vivo, NK4 inhibited angiogenesis in chick chorioallantoic membranes and in rabbit corneal neovascularization induced by basic fibroblast growth factor (bFGF). In vitro, NK4 inhibited growth and migration of human microvascular endothelial cells induced by bFGF and vascular endothelial growth factor (VEGF) as well as by HGF. HGF and VEGF activated the Met/HGF receptor and the KDR/VEGF receptor, respectively, whereas NK4 inhibited HGF-induced Met tyrosine phosphorylation but not VEGF-induced KDR phosphorylation. NK4 inhibited HGF-induced ERK1/2 (p44/42 mitogen-activated protein kinase) activation, but allowed for bFGF- and VEGF-induced ERK1/2 activation. These results indicate that NK4 is an angiogenesis inhibitor as well as an HGF antagonist, and that the antiangiogenic action of NK4 is independent of its activity as HGF antagonist. The bifunctional properties of NK4 to act as an angiogenesis inhibitor and as an HGF antagonist raises the possibility that NK4 may prove therapeutic for cancer patients.

Allantois↗
PubMed2000

[A fragment of collagen XVIII inhibits angiogenesis].

BACKGROUND: Malignant tumours may produce substances with both stimulatory and inhibitory effect on angiogenesis. MATERIAL AND METHODS: A protein fragment with angiogenesis-inhibiting potential was recently identified in conditioned media from a murine endothelial tumour cell line. RESULTS: The angiogenesis inhibitor, endostatin, is a 20 kDa C-terminal fragment of collagen XVIII, a proteoglycan/collagen found in vessel walls and basement membranes. The generation of endostatin or endostatin-like collagen XVIII fragments is catalyzed by proteolytic enzymes, including cathepsin L and matrix metalloproteases, that cleave peptide bonds within the protease-sensitive hinge region of the C-terminal domain. INTERPRETATION: The physiological processing of collagen XVIII to endostatin may represent a local control mechanism for the regulation of angiogenesis. The outcome of ongoing clinical trials will determine the role of endostatin as a possible angiogenesis-inhibiting drug in the future.

Angiogenesis Inhibitors↗
PubMed2001

Angiogenesis: a therapeutic target in arthritis.

A variety of pharmacological strategies are being subjected to clinical trial to inhibit neovascularization of solid tumors. Increased angiogenesis is also a key component of synovitis and bone modeling in arthritis. Molecular mechanisms and pathological consequences of blood vessel growth in arthritis are now being elucidated. Preclinical studies of angiogenesis inhibitors in animal models of inflammatory arthritis support the hypothesis that inhibition of neovascularization may reduce inflammation and joint damage. Clinical data are consistent with these models being predictive of efficacy in rheumatoid arthritis. However, controlled studies of specific anti-angiogenic agents in human arthritis remain limited. Further studies are required to demonstrate that pharmacological agents can effectively inhibit articular angiogenesis, and ameliorate inflammation and subsequent joint damage. Potential toxicity of angiogenesis inhibitors in reproduction, growth and development and wound repair may be circumvented by short-term or local application, or by targeting molecular mechanisms that are specific to pathological rather than physiological angiogenesis.

Angiogenesis Inhibitors↗
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↗
PubMedDate not supplied

Angiogenesis: basic and clinical aspects.

The cardiovascular system is the first functional organ system to develop in the vertebrate embryo. A widely accepted view is that blood vessels arise through two mechanisms during development, vasculogenesis and angiogenesis. New vessels in the adult arise mainly through angiogenesis, although vasculogenesis also may occur. The existence of a postnatal vasculogenesis is also supported by the evidence that both endothelial cells and endothelial precursor cells co-exist in the circulation. Angiogenesis is a biological process by which new capillaries are formed and it occurs in many physiological and pathological conditions. It is controlled by the net balance between molecules that have positive and negative regulatory activity and this concept had led to the notion of the "angiogenic switch", depending on an increased production of one or more of the positive regulators of angiogenesis. Considerable benefit can be derived in the clinical setting from manipulating angiogenesis, either positively or negatively. There is a variety of important clinical situations in which it would be desiderable to promote angiogenic processes, such as situations in which it would be desiderable to promote angiogenic processes, such as for the induction of collateral vascularization in an ischemic heart or limb. Conversely, there are pathologic conditions in which preventing angiogenic processes could be useful in the treatment of a growing tumor or a chronic inflammatory process.

Angiogenesis Inhibitors↗
PubMed1992

[Angiogenesis induced by rat glioma cells in vitro].

Angiogenesis induced by rat glioma cells was examined in vitro using a double chamber co-culture system. Cultured microvascular endothelial cells from Fisher 344 rat brain, rat C6 glioma cells and rat T9 gliosarcoma cells were used for this study. Endothelial cells, cultured on type I collagen, formed capillary-like structures. In the co-culture system, C6 glioma cells promoted this formation. On the other hand T9 gliosarcoma cells had no effect on it. The supernatants of C6 glioma cells and T9 gliosarcoma cells suppressed the proliferation of the endothelial cells. C6 glioma cells probably produce and release soluble factors promoting angiogenesis. The proliferation of endothelial cells is thus suppressed while angiogenesis is made more intense. This in-vitro model is useful to elucidate the mechanism of tumor angiogenesis and to evaluate the promoting and inhibiting factors of angiogenesis.

Angiogenesis Inducing Agents↗
PubMed2003

Angiogenesis inhibitors target the endothelial cell cytoskeleton through altered regulation of heat shock protein 27 and cofilin.

Inhibition of angiogenesis has emerged as a key focus for the treatment of cancer, necessitating a better understanding of the downstream molecular targets of angiogenesis inhibitors. Endostatin, thrombospondin-1, fumagillin, and its synthetic derivative, TNP-470, are potent inhibitors of endothelial cell proliferation and migration in culture and of angiogenesis in vivo. To identify targets that mediate the effects of these inhibitors, we compared two-dimensional gel electrophoresis patterns from lysates of treated and untreated human endothelial cells. Among the proteins identified were cofilin and hsp27, two proteins involved in actin dynamics. Western blotting and immunofluorescence experiments confirmed that the phosphorylation states and subcellular localization of these two proteins were affected by all of the inhibitors tested and that treated cells had a more extensive network of actin stress fibers and more numerous focal adhesion plaques compared with untreated cells. Endothelial monocyte activating polypeptide II, another angiogenesis inhibitor, elicited the same response in the actin cytoskeleton and focal adhesions of endothelial cells. This more adherent phenotype may explain the shared ability of these inhibitors to block endothelial migratory signals. Starting with a proteomics approach, we have identified common effector molecules used by a panel of angiogenesis inhibitors that perturb the cytoskeleton to prevent endothelial migration.

Actin Cytoskeleton↗
PubMed2003

[Angiogenesis and hematological malignancies].

BACKGROUND: It is fairly well documented that the growth and metastasis of solid tumours is accompanied by increased formation of new blood vessels emanating from a pre-existing vascular bed. Recent findings suggest that angiogenesis also takes place in haematological malignancies. These findings suggest that angiogenesis might be a potential target for therapy. MATERIALS AND METHODS: A short review is presented on the basis of literature identified on PubMed and Medline as well as our own data. RESULTS: When surrogate markers are used, such as the plasma concentration of angiogenic growth factors or the density of blood vessels within the bone marrow, angiogenesis is associated with poor prognosis and treatment outcome in haematopoietic malignancy. While human treatment data are scarce, findings in animal experiments suggest that anti-angiogenesis might retard leukemogenesis. INTERPRETATION: The proliferation and dissemination of malignant blood cells seems to be related to increased angiogenesis in the bone marrow. Targeting components of the angiogenic process might offer adjunct treatment modalities in haematopoietic malignancy.

Angiogenesis Inhibitors↗
PubMed2004

In vitro cultured rat islets express genes that both prevent and promote angiogenesis.

CONTEXT: Endogenous pancreatic islets are supported by a dense sinusoidal capillary system which is disrupted following isolation and culture in vitro. A rapid and accurate revascularization is therefore crucial for the survival and functioning of the transplanted islet. Although a blood flow is established in islet grafts within 1-2 weeks, these islets show poor development of intra-islet capillaries. To improve the revascularization process and the arrangement of the new blood vessels, islet production of the factors governing these processes needs to be further characterized. OBJECTIVE: To study the expression of factors which regulate angiogenesis in cultured rat islets. DESIGN AND MAIN OUTCOME MEASURES: Rat islets were isolated and cultured for one week. After 6 hours of exposure to normoxic (21% O2) or hypoxic (1% O2) conditions, mRNA expression was evaluated by the GEArray Angiogenesis 1 and 2 systems. The expression of the vascular endothelial growth factor (VEGF), the tyrosine kinase with immunoglobulin and epidermal growth factor homology domains 1 (Tie1) and acidic fibroblast growth factor (aFGF), was further evaluated by semi-quantitative RT-PCR. RESULTS: We found the expression of 19 genes that code for factors either promoting or preventing angiogenesis. Only VEGF and Tie1 were upregulated in response to hypoxia. CONCLUSION: Hypoxia-induced islet vascularization may involve VEGF and Tie-induced signaling events. The results also show that cultured islets express genes which prevent angiogenesis concurrently with genes coding for factors stimulating angiogenesis. The balance between these factors is probably of vital importance for the revascularization process in transplanted islets. Thus, pharmacologic or genetic attenuation of islet-derived angiostatic factors may prove beneficial in promoting islet revascularization in future transplantation trials.

Angiogenesis Inhibitors↗
PubMed2004

[Inhibitory effects of artesunate on angiogenesis].

AIM: To investigate the inhibitory effects of artesunate on angiogenesis. METHODS: The in vitro anti-angiogenic effect of artesunate was tested on models of angiogenesis: proliferation, migration and tube formation of human umbilical vein endothelial (HUVE) cells; The anti-angiogenic effect in vivo was evaluated in nude mice by means of human ovarian cancer HO-8910 implantation and immunohistochemical stainings for microvessel (CD31), vascular endothelial growth factor (VEGF) and VEGF receptor KDR/flk-1. RESULTS: Artesunate significantly inhibited angiogenesis in a concentration-dependent form in range of 0.5-50 mumol.L-1. The IC50 of artesunate for HUVE cells was (21 +/- 3) mumol.L-1. Growth of xenograft tumor was decreased and microvessel density was reduced following drug-treatment with no apparent toxicity to the animals. Artesunate also remarkably lowered VEGF expression on tumor cells and KDR/flk-1 expression on endothelial cells as well as tumor cells. CONCLUSION: Artesunate was shown to inhibit angiogenesis in vitro and in vivo. These findings together with the known low toxicity of artesunate are clues that artesunate may be a promising angiogenesis inhibitor.

Angiogenesis Inhibitors↗
PubMed2004

[Angiogenesis and antiangiogenic cancer therapy].

Physiologic angiogenesis takes place during tissue growth and repair, during the female reproductive cycle, and during fetal development. Angiogenesis is also required for tumor growth and metastasis and, therefore, represents an exciting target for cancer treatment. Angiogenesis is a complex process that is tightly regulated by pro- and antiangiogenic growth factors. Pathologic angiogenesis is characterized by either excessive (eg. cancer) or inadequate (eg. coronary artery disease) neovascularization. Avascular tumors are severely restricted in their growth potential because of the lack of a blood supply. For tumors to develop in size and metastatic potential they must make an "angiogenic switch" through perturbing the local balance of proangiogenic and antiangiogenic factors. Frequently, tumors overexpress proangiogenic factors, such as vascular endothelial growth factor, allowing them to make this angiogenic switch. Two strategies used in the development of antiangiogenic agents involve the inhibition of proangiogenic factors (eg. anti-vascular endothelial growth factor monoclonal antibodies) as well as therapy with endogenous inhibitors of angiogenesis. Emerging antiangiogenic agents currently in clinical studies are discussed in this review.

Angiogenesis Inhibitors↗
PubMedDate not supplied

Roxithromycin inhibits angiogenesis of human hepatoma cells in vivo by suppressing VEGF production.

BACKGROUND: Recently, 14-member macrolide antibiotics such as Clarithromycin and Roxithromycin (RXM) have been shown to have anti-cancer and anti-angiogeneic effects. However, it is not fully understood whether and how RXM suppresses angiogenesis in human hepatoma, which is a well-known hypervascular tumor. MATERIALS AND METHODS: In the present study, we examined the effects of RXM on tumor angiogenesis in the human hepatoma cell line, HepG2. In vivo, angiogenesis was examined using a mouse dorsal air sac model. RESULTS: The inhibitory effect of RXM was dose-dependent and the angiogenesis index of 100mg/kg/day of RXM administered intraperitoneally twice a day was significantly lower than the control. Next, we examined the effect of RXM on vascular endothelial growth factor (VEGF) mRNA expression and its protein level in HepG2 cells. When 100 microM of RXM were added, VEGF mRNA expression in HepG cells was inhibited and its protein level reduced. CONCLUSION: These results suggest that RXM inhibits tumor angiogenesis in human hepatoma, and that VEGF alteration may be involved in the mechanism of this inhibitory effect. Because RXM is widely used in clinical practice, it may represent an effective new strategy for human hepatoma therapy.

Air Sacs↗
PubMed2006

Embryonic stem cells: a novel tool for the study of antiangiogenesis and tumor-induced angiogenesis.

Major research initiatives in antiangiogenesis research have been undertaken to control angiogenic diseases such as polyarthritis, psoriasis, endometriosis, and diabetic retinopathy, and inhibition of tumor-induced angiogenesis has emerged as one of the most promising anti-cancer therapies currently available. Although several quantitative in vivo (i.e., animal models) as well as in vitro (i.e., pure endothelial cell cultures) angiogenesis assays have been described, the development of novel angiogenesis assays with organotypic culture systems that take into account oxygen and nutrient gradients, depth-dependent changes in intracellular pH and a redox state similar to that found in a natural tissue microenvironment are necessary to investigate blood vessel growth. Embryonic stem cells of mouse and human origin have the capacity to develop into three-dimensional tissues with functional capillaries, and this model system represents an excellent in vitro model for antiangiogenesis research. Upon confrontation of stem cells by co-culture with multicellular tumor spheroids, tumor-induced angiogenesis, i.e., the invasion of endothelial host-derived cells into a tumor tissue, can also be monitored. The current review provides an overview of embryonic stem cells as novel tools for antiangiogenesis research and outlines the use of confrontation cultures for the study of tumor-induced angiogenesis.

Angiogenesis Inhibitors↗
PubMedDate not supplied

Angiogenesis under normal and pathological conditions.

Angiogenesis, i.e. the generation of new blood capillaries, occurs in utero (during embryonal and fetal development) and in both physiological and pathological situations during extrauterine life. Several angiogenic factors have now been isolated, including angiogenin, acidic and basic fibroblast growth factors, and alpha and beta transforming growth factors. Their amino acid sequences have been determined and their genes cloned. Other factors await complete characterisation. An account is given of techniques used in the investigation of angiogenesis, both in vivo (transparent chambers; corneal micropockets; implantation on chick chorioallantoic membrane; employment of polymers for the sustained release of angiogenesis factors) and in vitro (cloning and long-term culture of capillary endothelial cells). The angiogenesis induced by solid tumours differs from other forms in that it is not self-limited and continues indefinitely until eradication of the tumour or death of the host. Anti-angiogenic factors have also been identified, particularly a new class of nonglucocorticoid steroids. Their employment in tumour therapy is a possibility, since neoplastic expansion is essentially dependent on angiogenesis.

Angiogenesis Inducing Agents↗
PubMed1984

Characterization of a chemoattractant for endothelium induced by angiogenesis effectors.

The mechanism of neovascularization was further explored by the use of chemically defined angiogenesis effectors. The vascularization of the rabbit cornea was selected as an experimental approach that permits comparison of one cornea treated by the angiogenesis effector with the contralateral cornea of the same subject treated by the same molecule deprived of angiogenic capacity. Under these conditions, we observed that neovascularization was initiated by the appearance of a chemoattractant for the bovine capillary endothelium only in the cornea treated by the angiogenesis effector. The chemoattractant was purified about 150-fold by a single-step procedure, using gelatin:Sepharose affinity chromatography. Chemoattraction resulted from the combined effect of a chemotactic factor(s) and an activating factor(s). The association of the two enhanced 5- to 8-fold the motility of the capillary endothelium in a concentration-dependent manner with optimum at 0.2 mg/ml. The activating factor(s) does not have chemotactic capacity, but without it, chemotaxis is reduced to about one half. The chemotactic complex was present in the cornea regardless of the nature of the angiogenesis effector used as the triggering device. Heat and proteases eliminated chemotaxis and destroyed the chemotactic complex. Thus, neovascularization may be triggered by effectors able to induce in the cornea proteins, normally not present, that influence angiogenesis via mobilization of capillary endothelium.

Angiogenesis Inducing Agents↗