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Endothelial Growth (endothelial + growth)
Kinds of Endothelial Growth Terms modified by Endothelial Growth Selected AbstractsChanges in skeletal muscle size, fibre-type composition and capillary supply after chronic venous occlusion in ratsACTA PHYSIOLOGICA, Issue 4 2008S. Kawada Abstract Aim:, We have previously shown that surgical occlusion of some veins from skeletal muscle results in muscle hypertrophy without mechanical overloading in the rat. The present study investigated the changes in muscle-fibre composition and capillary supply in hypertrophied muscles after venous occlusion in the rat hindlimb. Methods:, Sixteen male Wistar rats were randomly assigned into two groups: (i) sham operated (sham-operated group; n = 7); (ii) venous occluded for 2 weeks (2-week-occluded group; n = 9). At the end of the experimental period, specimens of the plantaris muscle were dissected from the hindlimbs and subjected to biochemical and histochemical analyses. Results:, Two weeks after the occlusion, both the wet weight of plantaris muscle relative to body weight and absolute muscle weight showed significant increases in the 2-week-occluded group (,15%) when compared with those in the sham-operated group. The concentrations of muscle glycogen and lactate were higher in the 2-week-occluded group, whereas staining intensity of muscle lipid droplets was lower in the 2-week-occluded group than those in the sham-operated group. The percentage of type I muscle fibre decreased, whereas that of type IIb fibre increased in the 2-week-occluded group when compared with the sham-operated group. Although the expression of vascular endothelial growth factor-188 mRNA increased, the number of capillaries around the muscle fibres tended to decrease (P = 0.07). Conclusion:, Chronic venous occlusion causes skeletal muscle hypertrophy with fibre-type transition towards faster types and changes in contents of muscle metabolites. [source] Vascular endothelial growth factor prevents G93A-SOD1-induced motor neuron degenerationDEVELOPMENTAL NEUROBIOLOGY, Issue 13 2009J. Simon Lunn Abstract Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disorder characterized by selective loss of motor neurons (MNs). Twenty percent of familial ALS cases are associated with mutations in Cu2+/Zn2+ superoxide dismutase (SOD1). To specifically understand the cellular mechanisms underlying mutant SOD1 toxicity, we have established an in vitro model of ALS using rat primary MN cultures transfected with an adenoviral vector encoding a mutant SOD1, G93A-SOD1. Transfected cells undergo axonal degeneration and alterations in biochemical responses characteristic of cell death such as activation of caspase-3. Vascular endothelial growth factor (VEGF) is an angiogenic and neuroprotective growth factor that can increase axonal outgrowth, block neuronal apoptosis, and promote neurogenesis. Decreased VEGF gene expression in mice results in a phenotype similar to that seen in patients with ALS, thus linking loss of VEGF to the pathogenesis of MN degeneration. Decreased neurotrophic signals prior to and during disease progression may increase MN susceptibility to mutant SOD1-induced toxicity. In this study, we demonstrate a decrease in VEGF and VEGFR2 levels in the spinal cord of G93A-SOD1 ALS mice. Furthermore, in isolated MN cultures, VEGF alleviates the effects of G93A-SOD1 toxicity and neuroprotection involves phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) signaling. Overall, these studies validate the usefulness of VEGF as a potential therapeutic factor for the treatment of ALS and give valuable insight into the responsible signaling pathways and mechanisms involved. © 2009 Wiley Periodicals, Inc. Develop Neurobiol, 2009 [source] CLINICAL STUDY: BRIEF REPORT: Serum levels of vascular endothelial growth factor A increase during alcohol withdrawalADDICTION BIOLOGY, Issue 3 2010Annemarie Heberlein ABSTRACT Vascular endothelial growth factor A (VEGF-A) is a key regulator of angiogenesis. This study investigated VEGF-A serum levels during alcohol withdrawal (days 1, 7 and 14, 76 male patients, 38 healthy controls). Patients showed significantly higher VEGF-A serum levels (t = 2.620, P = 0.010), which increased significantly during withdrawal (F = 4.484, P = 0.014, mean difference = ,36.835, P = 0.037). The increase of VEGF-A serum levels was significantly associated with initial breath alcohol concentration and the sumscore of the severity scale of alcohol dependence (SESA questionnaire, F = 5.252, P = 0.008). Increase of VEGF-A serum levels is closely associated to alcohol intoxication and severity of alcohol dependence. [source] Molecular characterization of the vascular features of focal nodular hyperplasia and hepatocellular adenoma: A role for angiopoietin-1,HEPATOLOGY, Issue 2 2010Annette S. H. Gouw Focal nodular hyperplasia (FNH) and hepatocellular adenoma (HCA) are two hepatic nodular lesions of different etiologies. FNH, a polyclonal lesion, is assumed to be a regenerative reaction following a vascular injury, whereas HCA is a monoclonal, benign neoplastic lesion. In addition to features that are predominantly found in either FNH or HCA (e.g., dystrophic vessels in FNH and single arteries in HCA), FNH and HCA share morphological vascular abnormalities such as dilated sinusoids. We hypothesized that these anomalous vascular features are associated with altered expression of growth factors involved in vascular remodeling. This was based on reports of morphologically abnormal hepatic vasculature and nodular lesions in transgenic models of hepatocytic overexpression of angiopoietin-1 (Ang-1), a member of the angiopoietin family, which is crucially involved in vascular morphogenesis and homeostasis. We investigated gene and protein expression of members of the angiopoietin system and vascular endothelial growth factor A (VEGF-A) and its receptors in 9 FNH samples, 13 HCA samples, and 9 histologically normal livers. In comparison with normal samples, a significant increase in Ang-1 was found in FNH (P < 0.01) and HCA (P < 0.05), whereas no significant changes in Ang-2, receptor tyrosine kinase with immunoglobulin-like and EGF-like domains 2, VEGF-A, or vascular endothelial growth factor receptor 2 (VEGFR-2) were observed. Conclusion: Because of the different etiological contexts of a preceding vascular injury in FNH and a neoplastic growth in HCA, Ang-1 might exert different effects on the vasculature in these lesions. In FNH, it could predominantly stimulate recruitment of myofibroblasts and result in dystrophic vessels, whereas in HCA, it may drive vascular remodeling that produces enlarged vessels and arterial sprouting that generates single arteries. Hepatology 2010 [source] Anti-VEGF-A therapy reduces lymphatic vessel density and expression of VEGFR-3 in an orthotopic breast tumor modelINTERNATIONAL JOURNAL OF CANCER, Issue 10 2007Brandt Whitehurst Abstract Because metastasis contributes significantly to cancer mortality, understanding its mechanisms is crucial to developing effective therapy. Metastasis is facilitated by lymphangiogenesis, the growth of new intratumoral or peritumoral lymphatic vessels from pre-existing vessels. Vascular endothelial growth factor A (VEGF-A) is a well-known angiogenic factor. Increasing evidence implicates VEGF-A in lymphangiogenesis, although the mechanism of its pro-lymphangiogenic effect is poorly understood. We examined the effect of the anti-VEGF-A neutralizing antibody 2C3 on tumor lymphangiogenesis and metastasis in an orthotopic breast carcinoma model using MDA-MB-231 cells and its luciferase-tagged derivative, 231-Luc+ cells. Anti-VEGF-A antibody therapy reduced blood and lymphatic vessel densities by 70% and 80%, respectively, compared with the control antibody. Treatment with 2C3 antibody also decreased incidence of lymphatic and pulmonary metastases by 3.2- and 4.5-fold, respectively. Macrophage infiltration was reduced in 2C3-treated tumors by 32%, but VEGF-C expression was unchanged. In contrast, neoplastic cells and blood vessels in tumors from 2C3-treated mice expressed significantly less angiopoietin-2 (Ang-2) than tumors from control mice. The reduction in Ang-2 was associated with inhibition of VEGFR-3 expression in intratumoral lymphatic endothelial cells. Both VEGF-A and Ang-2 upregulated the expression of VEGFR-3 in cultured lymphatic endothelial cells. VEGF-A induced proliferation of lymphatic endothelial cells was reduced by 50% by soluble Tie-2, suggesting that Ang-2 is an intermediary of the pro-lymphangiogenic VEGF-A effect. These results suggest a novel mechanism by which anti-VEGF-A therapy may suppress tumor lymphangiogenesis and subsequent metastasis supporting the use of anti-VEGF-A therapy to control metastasis clinically. © 2007 Wiley-Liss, Inc. [source] Liposome-based vascular endothelial growth factor-165 transfection with skeletal myoblast for treatment of ischaemic limb diseaseJOURNAL OF CELLULAR AND MOLECULAR MEDICINE, Issue 1-2 2010Lei Ye Abstract The study aims to use cholesterol (Chol) + DOTAP liposome (CD liposome) based human vascular endothelial growth factor-165 (VEGF165) gene transfer into skeletal myoblasts (SkMs) for treatment of acute hind limb ischaemia in a rabbit model. The feasibility and efficacy of CD liposome mediated gene transfer with rabbit SkMs were characterized using plasmid carrying enhanced green fluorescent protein (pEGFP) and assessed by flow cytometry. After optimization, SkMs were transfected with CD lipoplexes carrying plasmid-VEGF165 (CD-pVEGF165) and transplanted into rabbit ischaemic limb. Animals were randomized to receive intramuscular injection of Medium199 (M199; group 1), non-transfected SkM (group 2) or CD-pVEGF165 transfected SkM (group 3). Flow cytometry revealed that up to 16% rabbit SkMs were successfully transfected with pEGFP. Based on the optimized transfection condition, transfected rabbit SkM expressed VEGF165 up to day 18 with peak at day 2. SkMs were observed in all cell-transplanted groups, as visualized with 6-diamidino-2-phenylindole and bromodeoxyuridine. Angiographic blood vessel score revealed increased collateral vessel development in group 3 (39.7 ± 2.0) compared with group 2 (21.6 ± 1.1%, P < 0.001) and group 1 (16.9 ± 1.1%, P < 0.001). Immunostaining for CD31 showed significantly increased capillary density in group 3 (14.88 ± 0.9) compared with group 2 (8.5 ± 0.49, P < 0.001) and group 1 (5.69 ± 0.3, P < 0.001). Improved blood flow (ml/min./g) was achieved in animal group 3 (0.173 ± 0.04) as compared with animal group 2 (0.122 ± 0.016; P= 0.047) and group 1 (0.062 ± 0.012; P < 0.001). In conclusion, CD liposome mediated VEGF165 gene transfer with SkMs effectively induced neovascularization in the ischaemic hind limb and may serve as a safe and new therapeutic modality for the repair of acute ischaemic limb disease. [source] VEGF in biological controlJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 6 2007Ellen C. Breen Abstract Vascular endothelial growth factor A (VEGF-A) belongs to a family of heparin binding growth factors that include VEGF-B, VEGF-C, VEGF-D, and placental-like growth factor (PLGF). First discovered for its ability to regulate vascular endothelial cell permeability, VEGF is a well-known angiogenic factor that is important for vascular development and maintenance in all mammalian organs. The development of molecular tools and pharmacological agents to selectively inhibit VEGF function and block angiogenesis and/or vascular permeability has led to great promise in the treatment of various cancers, macular degeneration, and wound healing. However, VEGF is also important in animals for the regulation of angiogenesis, stem cell and monocyte/macrophage recruitment, maintenance of kidney and lung barrier functions and neuroprotection. In addition to its role in regulating endothelial cell proliferation, migration, and cell survival, VEGF receptors are also located on many non-endothelial cells and act through autrocrine pathways to regulate cell survival and function. The following review will discuss the role of VEGF in physiological angiogenesis as well as its role in non-angiogenic processes that take place in adult organs. J. Cell. Biochem. 102: 1358,1367, 2007. © 2007 Wiley-Liss, Inc. [source] Review article: pharmacological therapy for hepatocellular carcinoma with sorafenib and other oral agentsALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 11-12 2008M. CHAPARRO Summary Background, Hepatocellular carcinoma (HCC) is the fifth most common malignancy worldwide. Unresectable disease patients have median survival of few months. There is a substantial need for novel treatments for patients with advanced HCC. Aim, To provide an update review of mechanism of hepatocarcinigenesis and systemic therapies for HCC and the relevant role of Sorafenib in patients with advanced disease. Methods, A Medline search was performed to identify pertinent original research and review articles. Selected references in these articles were also evaluated. Results, Systemic chemotherapy for HCC has been quite ineffective. Preclinical studies demonstrated that Raf/MAPK-ERK kinase (MEK)/Extracellular signal regulated kinase (ERK) pathway has a role in HCC. HCC tumours are highly vascularized and vascular endothelial growth factor (VEGF) augments HCC development and metastasis. Sorafenib blocks tumour cell proliferation by targeting Raf/MEK/ERK signalling and exerts an antiangiogenic effect by targeting VEGF receptors-2/3 and platelet derived growth factor receptor , tyrosine kinases. Conclusions, Currently available therapies are not effective for patients with advanced HCC. Sorafenib has demonstrated for the first time to prolong survival in patients with advanced HCC, and it is the new reference standard for systemic treatment in these patients. [source] Effects of long-term cyclo-oxygenase 2 selective and acid inhibition on Barrett's oesophagusALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 6 2007A. LANAS Summary Background There is an overexpression of cyclo-oxygenase 2 (COX-2) in Barrett's oesophagus (BO). Aim To determine the long-term effect of a COX-2 inhibitor on cellular mechanisms involved in BO. Methods A randomized controlled trial was conducted in BO patients allocated to continue the usual proton pump inhibitor (PPI) alone treatment, or PPI combined with rofecoxib (25 mg/day) for 6 months. Cell proliferation index and COX-2 expression in BO glands was determined in biopsy specimens at baseline and after treatment. Cell apoptosis, cyclin D1, p53 and vascular endothelial growth factor (VEGF) expression was also explored in a subset of patients. Student- t test and the U-Mann,Whitney test were used for quantitative and ordinal variables. Results Of 62 patients, 58 completed the study. A higher proportion of patients on rofecoxib + PPI exhibited a decrease in COX-2 expression compared to those treated with PPI alone, but cell proliferation index was not affected. Unlike PPI alone, rofecoxib + PPI was associated with an increase in the apoptotic cell index, a decrease in p53 cell staining and VEGF expression in mucosal vessels. No effect on low-grade dysplasia or cyclin D1 was observed. Conclusions The addition of rofecoxib to PPI therapy does not affect cell proliferation index in BO cells after 6 months of therapy, but does reduce COX-2 and VEGF expression and increases cell apoptosis. [source] Hypoxia-inducible factor-1 alpha and vascular endothelial growth factor expression in ischaemic colitis and ulcerative colitisALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 2006T. OKUDA Summary Background Hypoxia-inducible factor-1 alpha (HIF-1 alpha) is a transcriptional factor induced by ischaemic crisis in many tissues. Vascular endothelial growth factor (VEGF) is an important growth factor that plays a major role in angiogenesis. Aim We examined the aetiology and pathophysiology of human ischaemic colitis and ulcerative colitis from the viewpoint of the expression of these two ischaemic factors. Methods Thirty-two patients with ischaemic colitis, 16 with ulcerative colitis and 25 normal controls underwent colonoscopy. Biopsy samples were taken from a colitis lesion and a normal region in the same patient. In the normal controls, four biopsy samples were obtained from each subject. Biopsy samples were subjected to real-time polymerase chain reaction. Results Hypoxia-inducible factor and VEGF were overexpressed in ischaemic colitis lesions and quickly decreased to normal levels in the healing phase. In contrast, HIF but not VEGF was overexpressed in active ulcerative colitis lesions. In the remission phase of ulcerative colitis, VEGF decreased to low levels, although HIF was continuously overexpressed. Conclusions Overexpression of HIF and VEGF contribute to the tolerance of ischaemia in patients with active ischaemic colitis. The inconsistency in their expression might be associated with the chronic intestinal damage characteristic of ulcerative colitis. [source] A viral PAMP double-stranded RNA induces allergen-specific Th17 cell response in the airways which is dependent on VEGF and IL-6ALLERGY, Issue 10 2010J.-P. Choi To cite this article: Choi J-P, Kim Y-S, Tae Y-M, Choi E-J, Hong B-S, Jeon SG, Gho YS, Zhu Z, Kim Y-K. A viral PAMP double-stranded RNA induces allergen-specific Th17 cell response in the airways which is dependent on VEGF and IL-6. Allergy 2010; 65: 1322,1330. Abstract Background:, Innate immune response by a viral pathogen-associated molecular pattern dsRNA modulates the subsequent development of adaptive immune responses. Although virus-associated asthma is characterized by noneosinophilic inflammation, the role of Th17 cell response in the development of virus-associated asthma is still unknown. Objective:, To evaluate the role of the Th17 cell response and its underlying polarizing mechanisms in the development of an experimental virus-associated asthma. Methods:, An experimental virus-associated asthma was created via airway sensitization with ovalbumin (OVA, 75 ,g) and a low (0.1 ,g) or a high (10 ,g) doses of synthetic dsRNA [polyinosine,polycytidylic acid; poly(I:C)]. Transgenic (IL-17-, IL-6-deficient mice) and pharmacologic [a vascular endothelial growth factor receptor (VEGFR) inhibitor] approaches were used to evaluate the roles of Th17 cell responses. Results:, After cosensitization with OVA and low-dose poly(I:C), but not with high-dose poly(I:C), inflammation scores after allergen challenge were lower in IL-17-deficient mice than in wild-type (WT) mice. Moreover, inflammation enhanced by low-dose poly(I:C), but not by high-dose poly(I:C), was impaired in IL-6-deficient mice; this phenotype was accompanied by the down-regulation of IL-17 production from T cells from both lymph nodes and lung tissues. Airway exposure of low-dose poly(I:C) enhanced the production of VEGF and IL-6, and the production of IL-6 was blocked by treatment with a VEGFR inhibitor (SU5416). Moreover, the allergen-specific Th17 cell response and subsequent inflammation in the low-dose poly(I:C) model were impaired by the VEGFR inhibitor treatment during sensitization. Conclusions:, Airway exposure of low-level dsRNA induces an allergen-specific Th17 cell response, which is mainly dependent on VEGF and IL-6. [source] Plasma levels and skin-eosinophil-expression of vascular endothelial growth factor in patients with chronic urticariaALLERGY, Issue 11 2009A. Tedeschi Background:, Although chronic urticaria (CU) is often regarded as autoimmune in nature, only less than 50% of sera from CU patients contain histamine-releasing autoantibodies. This suggests that other factors may contribute to its pathogenesis. We evaluated the possible involvement of vascular endothelial growth factor (VEGF), one of the major mediators of vascular permeability, in CU. Methods:, Eighty consecutive adult patients with CU and 53 healthy subjects were studied. VEGF and prothrombin fragment F1+2 were measured by enzyme immunoassays. Autologous plasma skin test (APST) was performed in CU patients and, in six of them, skin biopsy specimens were taken from wheals to evaluate the immunohistochemical expression of VEGF and eosinophil cationic protein (ECP). Results:, Plasma VEGF concentrations were higher in CU patients (8.00 ± 0.90 pmol/l) than in controls (0.54 ± 0.08 pmol/l) (P = 0.0001) and tended to parallel both the severity of CU and to correlate with F1+2 levels. APST was positive in 85.1% of patients. VEGF concentration was significantly higher in APST-positive than in APST-negative patients (P = 0.0003). Immunohistochemically, all specimens from patients with CU showed a strong expression of VEGF (P = 0.002) that colocalized with ECP, a classic eosinophil marker. Conclusions:, VEGF plasma levels are elevated in CU and parallel the disease severity. This supports a possible role of this molecule in CU pathophysiology. Eosinophils are the main cellular source of VEGF in CU lesional skin. [source] Cytokines, matrix metalloproteases, angiogenic and growth factors in tears of normal subjects and vernal keratoconjunctivitis patientsALLERGY, Issue 5 2009A. Leonardi Background:, To detect the presence of multiple mediators and growth factors in tears of vernal keratoconjunctivitis (VKC) patients with active disease using stationary phase antibody arrays. Methods:, Tears were collected from 12 normal subjects (CT) and 24 active VKC patients. Tears were centrifuged and successively probed using three microwell plate arrays specific for: (i) cytokines: interleukin (IL)-2, IL-4, IL-5, IL-8, IL-10, IL-12, IL-13, interferon-, and tumour necrosis factor-,; (ii) growth factors: basic fibroblast growth factor (bFGF), platelet-derived growth factor, thrombopoietin, angiopoietin-2, vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF), keratocyte growth factor, tissue inhibitor of metalloprotease (TIMP)-1 and heparin-binding epithelial growth factor (HB-EGF) and (iii) matrix metalloprotease (MMP)-1, MMP-2, MMP-3, MMP-8, MMP-9, MMP-10, MMP-13, TIMP-1 and TIMP-2. Results:, Interleukin-8 signals were detected in all CT and highly detected in all VKC samples. The Th2-type cytokines, IL-4, IL-5 and IL-10 were detected only in tears of VKC patients. Signals for bFGF, HB-EGF, VEGF and HGF were detected in 41,87% of VKC samples and in few CT samples. Only TIMP-1 and TIMP-2 were found in all normal and patient tear samples, whereas MMP-1, MMP-2, MMP-3, MMP-9 and MMP-10 were highly present in all VKC samples. Conclusions:, Stationary phase antibody array methodology was useful for the screening of various cytokines, growth factors and MMPs in tears. These analyses identified in tears of VKC patients previously unreported factors including MMP-3 and MMP-10 and multiple proteases, growth factors and cytokines, which may all play an important role in the pathogenesis of conjunctival inflammation. [source] Pathological significance of vascular endothelial growth factor A isoform expression in human cancerPATHOLOGY INTERNATIONAL, Issue 5-6 2002Masato Nakamura Vascular endothelial growth factor (VEGF) is a highly specific factor for vascular endothelial cells. Five VEGF-A isoforms (splice variants 121, 145, 165, 189 and 206) are generated as a result of alternative splicing from a single VEGF-A gene. These differ in their molecular weights and in biological properties such as their ability to bind to cell-surface heparan sulfate proteoglycans. Deregulated VEGF-A expression contributes to the development of solid tumors by promoting tumor angiogenesis. More specifically, VEGF-A189 expression is related to angiogenesis and prognosis in certain human solid tumors. VEGF-A189 expression is also related to the xenotransplantability of human cancers into immunodeficient mice in vivo. Consequently, inhibition of VEGF-A or VEGF-A189 signaling regulates the development and metastasis of a variety of tumors. This review focuses on recent studies of the mechanisms by which VEGF-A regulates angiogenesis in the cancer stroma and on our recent findings concerning the potential mechanisms of VEGF-A189 expression on tumor growth and metastasis. [source] Continuous occurrence of both insufficient neovascularization and elevated vascular permeability in rabbit proximal femur during inadequate repair of steroid-associated osteonecrotic lesionsARTHRITIS & RHEUMATISM, Issue 10 2009Ge Zhang Objective To examine the features of the intraosseous vasculature, the size of the marrow stem cell pool (MSCP), and expression of vascular endothelial growth factor A (VEGF) during inadequate repair of steroid-associated osteonecrotic lesions in rabbits. Methods Steroid-associated osteonecrosis was induced in male rabbits. At 0, 1, 2, 4, and 6 weeks postinduction, vascularization and permeability indices were quantified by dynamic magnetic resonance imaging (MRI). In addition, the size of the MSCP in the hematopoietic and mesenchymal compartments was determined, and marrow mononuclear cells expressing specific surface markers for endothelial progenitor cells or periendothelial mural precursor cells were counted. At various time points after the rabbits were killed, the proximal femora were dissected to examine the intraosseous vasculature by angiography, histomorphometry, and ultramorphology. In addition, osteonecrotic lesion repair and marrow VEGF expression were evaluated. Results Lesion formation without repair was observed at 2 weeks after induction of steroid-associated osteonecrosis. Rabbits displaying destructive repair (DR+) and those displaying reparative osteogenesis (DR,) from 4 weeks to 6 weeks postinduction were identified. From week 2 to week 6, the vascularization index was significantly lower in DR+ rabbits compared with DR, rabbits, whereas the permeability index was significantly higher in DR+ rabbits compared with DR, rabbits. The features of the intraosseous vasculature determined by angiography, histomorphometry, and ultramorphology were consistent with those determined by dynamic MRI. The MSCP size and number of marrow mononuclear cells expressing specific surface markers were all significantly lower in DR+ rabbits than in DR, rabbits from week 1 to week 6. The increased VEGF expression at 2 weeks was maintained through week 6 in DR+ rabbits, whereas VEGF expression decreased in DR, rabbits from week 2 to week 6. Conclusion Continuous occurrence of both insufficient neovascularization and elevated vascular permeability is accompanied by a continuously low- level MSCP and uncontrolled VEGF expression during inadequate repair of steroid-associated osteonecrotic lesions. [source] Carbonic anhydrase IX and pathological features as predictors of outcome in patients with metastatic clear-cell renal cell carcinoma receiving vascular endothelial growth factor-targeted therapyBJU INTERNATIONAL, Issue 6 2010Toni K. Choueiri Study Type , Prognosis (retrospective cohort) Level of Evidence 2b OBJECTIVE To investigate the utility of tumour carbonic anhydrase IX (CAIX) expression and histological features for predicting the outcome in patients with metastatic clear-cell renal cell carcinoma (mRCC) treated with vascular endothelial growth factor (VEGF)-targeted therapy. PATIENTS AND METHODS We identified 118 patients with mRCC initiating first-line VEGF-targeted therapy, including 94 with clinical and histological data, and available tissue. The primary endpoint was to detect an interaction between sorafenib vs sunitinib treatment and CAIX status on tumour shrinkage. Other treatment outcomes were also assessed. RESULTS There was heterogeneity in tumour responsiveness to sunitinib or sorafenib according to CAIX status; the mean shrinkage was ,17% vs ,25% for sunitinib-treated patients with high vs low tumour CAIX expression, compared to ,13% vs +9% for sorafenib-treated patients (P interaction, 0.05). A higher tumour clear-cell component was independently associated with greater tumour shrinkage (P= 0.02), response (P= 0.02) and treatment duration (P= 0.02). CONCLUSIONS Although CAIX expression had no prognostic value in patients with clear-cell mRCC treated with VEGF-targeted therapy, it might be a predictive biomarker for response to sorafenib treatment. Patients with a higher clear-cell component in their tumours are likely to have a superior clinical benefit from VEGF-targeted therapy. [source] Inhibitory effects of epigallocatechin-3 gallate, a polyphenol in green tea, on tumor-associated endothelial cells and endothelial progenitor cellsCANCER SCIENCE, Issue 10 2009Noritaka Ohga The polyphenol epigallocatechin-3 gallate (EGCG) in green tea suppresses tumor growth by direct action on tumor cells and by inhibition of angiogenesis, but it is not known whether it specifically inhibits tumor angiogenesis. We examined the anti-angiogenic effect of EGCG on tumor-associated endothelial cells (TEC), endothelial progenitor cells (EPC), and normal endothelial cells (NEC). EGCG suppressed the migration of TEC and EPC but not NEC. EGCG also inhibited the phosphorylation of Akt in TEC but not in NEC. Furthermore, vascular endothelial growth factor-induced mobilization of EPC into circulation was inhibited by EGCG. MMP-9 in the bone marrow plasma plays key roles in EPC mobilization into circulation. We observed that expression of MMP-9 mRNA was downregulated by EGCG in mouse bone marrow stromal cells. In an in vivo model, EGCG suppressed growth of melanoma and reduced microvessel density. Our study showed that EGCG has selective anti-angiogenic effects on TEC and EPC. It is suggested that EGCG could be a promising angiogenesis inhibitor for cancer therapy. (Cancer Sci 2009; 100: 1963,1970) [source] Vascular endothelial growth factor receptor-2: Its unique signaling and specific ligand, VEGF-ECANCER SCIENCE, Issue 9 2003Masabumi Shibuya Vascular endothelial growth factor receptor-2 (VEGFR-2/KDR/Flk-1) is a high-affinity receptor for vascular endothelial growth factor-A (VEGF-A), and mediates most of the endothelial growth and survival signals from VEGF-A. VEGFR-2 has a typical tyrosine kinase receptor structure with seven immunoglobulin (Ig)-like domains in the extracellular region, as well as a long kinase insert in the tyrosine kinase domain. It utilizes a unique signaling system for DNA synthesis in vascular endothelial cells, i.e. a phospholipase C,-protein kinaseC-Raf-MAP kinase pathway. Although VEGF-A binds two receptors, VEGFR-1 and -2, a newly isolated ligand VEGF-E (Orf-virus-derived VEGF) binds and activates only VEGFR-2. Transgenic mice expressing VEGF-ENZ-7 showed a dramatic increase in angiogenesis with very few side effects (such as edema and hemorrhagic spots), suggesting strong angiogenic signaling and a potential clinical utility of VEGF-E. VEGF family members bear three loops produced via three intramolecular disulfide bonds, and cooperation between loop-1 and loop-3 is necessary for the specific binding and activation of VEGFR-2 for angiogenesis. As it directly upregulates tumor angiogenesis, VEGFR-2 is an appropriate target for suppression of solid tumor growth using exogenous antibodies, small inhibitory molecules and in vivo stimulation of the immune system. [source] Thalidomide for the Treatment of Refractory Multiple Myeloma: Association of Plasma Concentrations of Thalidomide and Angiogenic Growth Factors with Clinical OutcomeCANCER SCIENCE, Issue 9 2002Tsunayuki Kakimoto Recent reports showed that thalidomide has anti-angiogenic activity and is effective for the treatment of refractory multiple myeloma (MM). We examined the relationship between the clinical efficacy and adverse effects of thalidomide and the plasma concentrations of this drug as well as angiogenic growth factors in refractory MM. Ten out of twenty-four evaluable patients (42%) showed more than 25% reduction of M-protein, and eight (33%) achieved more than 50% reduction. These changes were associated with restoration of anemia and recovery of normal immunoglobulin level. Somnolence and headache, constipation, peripheral neuropathy and skin rash were frequently observed, but were well tolerated. However, grade 2,4 severe neutropenia was also observed in nine cases. These adverse effects other than neutropenia occurred more frequently in the patients with higher plasma concentrations of thalidomide (,2.0 ,g/ml at 12 h after the last administration) and were readily alleviated by dose reduction. In contrast, neutropenia developed regardless of the plasma concentration. Plasma concentrations of angiogenic growth factors were frequently elevated before treatment. After thalidomide treatment, these growth factor levels tend to decrease to near-normal ranges in responders but were still high in most non-responders. After thalidomide treatment, plasma vascular endothelial growth factor (VEGF) level was significantly reduced in responders (P=0.025), but not in non-responders (P=0.37). Reduction of plasma VEGF level might be an important indicator for anti-myeloma effect of thalidomide. [source] | |||||||||||||