Vascular Endotelial Growth Factor Research Articles

Molecular modelling predicts that 2-methoxyestradiol disrupts HIF function by binding to the PAS-B domain

An estradiol metabolite, 2-methoxyestradiol (2ME), has emerged as an important regulator of ovarian physiology. 2ME is recognized as a potent anti-angiogenic agent in clinical trials and laboratory studies. However, little is known about its molecular actions and its endogenous targets. 2ME is produced by human ovarian cells during the normal menstrual cycle, being higher during regression of the corpus luteum, and is postulated to be involved in the anti-angiogenic process that plays out during luteolysis.We utilized cell biology techniques to understand the molecular mechanism of 2ME anti-angiogenic effects on human granulosa luteal cells. The principal effect of 2ME was to alter Hypoxia Inducible Factor 1A (HIF1A) sub-cellular localization. Molecular modelling and multiple bioinformatics tools indicated that 2ME impairs Hypoxia Inducible Factor complex (HIF) nuclear translocation by binding to a buried pocket in the HIF1A Per Arnt Sim (PAS)-B domain. Binding of 2ME to HIF1A protein is predicted to perturb HIF1A-Hypoxia Inducible Factor B (HIFB) interaction, a key step in HIF nuclear translocation, preventing the transcriptional actions of HIF, including Vascular Endotelial Growth Factor (VEGF) gene activation. To our knowledge, 2ME is the first putative HIF endogenous ligand characterized with anti-angiogenic activity. This postulate has important implications for reproduction, because angiogenic processes are critical for ovarian follicular development, ovulation and corpus luteum regression. The present research could contribute to the development of novel pharmacological approaches for controlling HIF activity in human reproductive diseases.

The Inorganic Perspective of VEGF: Interactions of Cu2 + with Peptides Encompassing a Recognition Domain of the VEGF Receptor

The vascular endothelial growth factor A (VEGF-A) is a potent angiogenic factor, its activity may be influenced by the presence of copper(II) ions. To mimic the interaction between copper(II) and VEGF (Vascular Endotelial Growth Factor), the N- and C-terminally blocked peptide fragments VEGF73-101 and VEGF84-101, owing to VEGF165 protein, have been synthesized. These protein domains represent a specific recognition site with the VEGF receptor (VEGFR). Copper(II) complexes with VEGF73-101 and VEGF84-101 were investigated by means of potentiometry and UV-Vis, ESI-MS, CD, EPR spectroscopic methods. Both peptides have three histidine residues and display a binding high affinity for copper(II) ions. The proliferative activity of the peptides in the absence and presence of copper(II) ions as well as of VEGF-165 protein was also tested on HUVEC cells (Human Umbilical Vein Endothelial Cells). The VEGF73-101 showed a dose-dependent anti-proliferative activity, while the shorter peptide VEGF84-101 did not affect HUVEC proliferation, both in the presence and in the absence of VEGF.

Ramucirumab Clinical Development: an Emerging Role in Gastrointestinal Tumors

Ramucirumab (IMC-1121B, LY3009806) is a fully human G1 monoclonal antibody that specifically targets vascular endotelial growth factor receptor 2 (VEGFR-2) with a substantially greater binding affinity than that of its natural ligands. Early clinical trials in patients with advanced solid tumors demonstrated that biologically relevant blood target concentrations are achievable with tolerable doses, and also showed some preliminary evidence of clinical activity. Several pivotal phase III trials have now been concluded and have led regulatory agencies to grant marketing authorization to ramucirumab for use as second line therapy in patients with advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma (as single agent or in combination with paclitaxel), in patients with advanced colorectal carcinoma (CRC) (in combination with infusional fluorouracil and irinotecan (FOLFIRI regimen)) and in patients with advanced non-small cell lung cancer (NSCLC) (in combination with docetaxel). In contrast, ramucirumab failed to significantly improve survival versus placebo as second line therapy in patients with advanced hepatocellular carcinoma (HCC). The aim of this review is to summarize the clinical development and emerging role of ramucirumab in gastrointestinal (GI) tumors, including relevant aspects of its mechanism of action, pharmacology, safety profile, and antitumor activity in gastric, HCC, and CRC carcinomas.

Determination of serum levels of interleukin 6 (IL6), vascular endotelial growth factor (VEGF), and soluble receptor of interleukin 2 (srIL2) as a markers of tumor activity: A preliminary study.

e22198 Background: Previous studies have postulated the role of IL6, VEGF and srIL2 as indicators of disease activity in different morbid conditions including cancer. Methods: Serum samples from pa...

Colorectal cancer patients show decrease in cellular immunity and enhanced plasma level of transforming growth factor – beta and vascular endothelial growth factor (VEGF)

Background Colorectal cancer is the second leading cause of cancer death in the world. The cause of high mortality is that almost half the cancers are detected at an advanced stage of disease. In addition to surgical and chemotherapy treatment in recent years, applied monoclonal antibody therapy may target against growth factors, and particularly against the receptors for growth factors. In clinical practice, an antibody against vascular endotelial growth factor (VEGF) - bevacizumab-is already used. VEGF is the factor responsible for neoangiogenesis and it was considered as a possible prognostic marker of disease progression. The correlation of higher levels of VEGF with the response to applied therapy, disease progress levels and a poor prognosis in patients with solid tumors is recently discussed. Transforming growth factor - beta (Transforming growth factor - beta, TGF-beta) is also neoangiogenetic and highly immunosuppressive factor. TGF-beta suppresses natural immunity against tumors. The TGF is considered as another possible prognostic marker of disease progression. The purpose of the study was to monitor immune responses in patients with colorectal cancer, particularly the examination of cellular as well as humoral immunity. TGF beta, and VEGF production was monitored. Methods

Abstract 5382: Vascular endotelial growth factor and transforming growth factor-beta are enhanced in plasma of breast cancer patients resistant to endocrine therapy

Abstract Although more than 2/3 of treated patients respond to the endocrine therapy, most patients with metastatic breast cancer will develop resistance. Estrogen modulate angiogenesis, in part, through the effects on VEGF. It appears that other factor contributing to the resistance may be a transforming factor-beta (TGF-beta). It is highly immunosuppressive factor that inhibits the natural and specific immunity against tumors and stimulates production of vascular endotelial growth factor /VEGF. Defects in the immune response correlated with poor prognosis and therefore in recent years, research focused on a precise description of the status and function of the immune system and its possible effect in cancer patients. The purpose of the study was to monitor immune responses in patients with hormone receptor positive breast cancer resistant to hormone therapy, particularly the examination of cellular (CD4, CD8, HLA-DR) as well as humoral immunity. TGF beta, and VEGF production was monitored and we analyzed the changes during hormonal treatment. Methods: 60 patients included in the research project were implemented routine cancer teratment with hormonal therapy. Basic parameters (histological type and grade, the degree of expression of ER and PR, HER2, and the proliferative marker) were established. Patients were evaluated by a cancer clinical immunologist to exclude immune disorders, allergic or autoimmune origin. TGF beta, VEGF were mesured by ELISA and anti-tumor cellular immunity (CD4, CD8, antigen presenting cells) will be measured by flow cytometry. Results In patients with resistance to hormone therapy mainly depression in cellular immunity was found.Immunglobulin plasma level was dicreased as well (mainly IgG4 subtype). Most patients have shown clinical symptoms of immunodeficiency (frequent infections of respiratory or urinary tract, herpetic infections) TGF beta as well as VEGF plasma level were increased. Significant increase of autoantibodies production was found, particulary in those, involved into blood coagulacion process/anti phospholipide and anti cardiolipin autoantibodies. Conclusion Correlation of these factors with resistance to hormonal therapy, and the state of anticancer immunity could help in the future with the the prediction of resistance to hotmonal therapy and contribute to the selection of targeted immune therapy in cancer patients. Dedication: This project was supported by grant IGA NT11168-3/2010 Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5382. doi:1538-7445.AM2012-5382

341 Prediction of Non Sentinel Nodal Metastases After Positive Sentinel Lymph Node Biopsy for Early Breast Cancer – Burney Breast Unit Experience

Background: Endocrine therapy is an essential modality in patients with hormone receptor positive breast cancer. Even with high therapeutic efficacy of first-line hormonal treatment, most patients with metastatic breast cancer will develop resistance. It appears that a factor contributing to the resistance may be a transforming factor-beta (TGF-beta). It is highly immunosuppressive factor that inhibits the natural and specific immunity against tumors and stimulates vascular endotelial growth factor (VEGF). The purpose of the study was to monitor immune responses in patients with hormone receptor positive breast cancer, particularly the examination of cellular (CD4, CD8) as well as humoral immunity, TGF beta and VEGF production. Materials and Methods: Patients included in the research project were implemented routine cancer teratment with hormonal therapy. Basic parameters (histological type and grade, the degree of expression of ER and PR, HER2, and the proliferative marker) were established. Patients were evaluated by a cancer clinical immunologist to exclude immune disorders, allergic or autoimmune origin. TGF beta, VEGF were mesured by ELISA and anti-tumor cellular immunity (CD4, CD8, antigen presenting cells) was measured by flow cytometry. Results: In patients with resistance to endocrine therapy mainly depression in cellular immunity was found, mainly CD 8, cytotoxic T lymphocytes were significantly [p < 0.05] decreased. Immunglobuline plasma level was decreased as well (mainly IgG4 subtype[p < 0.05]). Most patients have shown clinical symptoms of immunodeficiency (frequent infections of respiratory or urinary tract, herpetic infections). TGF beta as well as VEGF plasma level were significantly increased. Conclusions: Correlation of these factors with resistance to endocrine therapy could help in the future with the the prediction of therapy response and contribute to the selection of targeted therapy in breast cancer cancer patients. Dedication: This project was supported by govermental grant IGA NT11168−3/2010

Anti-Angiogenic Approaches to Malignant Gliomas

Despite advances in multidisciplinary approaches, the prognosis for most patients with malignant gliomas is poor. Malignant gliomas are highly vascularized tumors with elevated expression of vascular endothelial growth factor (VEGF), an important mediator of angiogenesis. Recent studies of bevacizumab, an anti-VEGF monoclonal antibody, alone or associated with chemotherapy, have demonstrated high response rates and prolongation of median and 6-month progression-free survival. Clinical evaluation of several multitarget small molecule tyrosine kinase inhibitors is ongoing. Other promising antiangiogenic compounds are cilengitide and continuous temozolomide. Toxicity is acceptable. Open issues are represented by patterns of tumor progression, resistance mechanisms and biomarkers.

Abstract C68: Transforming growth factor-beta and vascular endothelial growth factor are enhanced in plasma of breast cancer patients resistent to hormone therapy

Abstract Even with high therapeutic efficacy of first-line hormonal treatment, most patients with metastatic breast cancer will develop resistance. It appears that a factor contributing to the resistance may be a transforming growth factor-beta (TGF-beta). It is highly immunosuppressive factor that inhibits the natural and specific immunity against tumors and stimulates production of vascular endotelial growth factor (VEGF). Defects in the immune response correlated with poor prognosis and therefore in recent years, research focused on a precise description of the status and function of the immune system and its possible effect in cancer patients. The purpose of the study was to monitor immune responses in patients with hormone receptor-positive breast cancer resistant to hormone therapy, particularly the examination of cellular (CD4, CD8, HLA-DR) as well as humoral immunity. TGF-beta and VEGF production was monitored and we analyzed the changes during hormonal treatment. Methods: Patients included in the research project were implemented routine cancer treatment with hormonal therapy. Basic parameters (histological type and grade, the degree of expression of ER and PR, HER2, and the proliferative marker) were established. Patients were evaluated by a cancer clinical immunologist to exclude immune disorders, allergic or autoimmune origin. TGF-beta and VEGF were mesured by ELISA and antitumor cellular immunity (CD4, CD8, antigen presenting cells) will be measured by flow cytometry. Results: In patients with resistance to hormone therapy mainly depression in cellular immunity was found. Immunglobulin plasma level was decreased as well (mainly IgG4 subtype). Most patients have shown clinical symptoms of immunodeficiency (frequent infections of respiratory or urinary tract, herpetic infections) TGF-beta as well as VEGF plasma level were increased. Significant increase of autoantibodies production was found, particulary in those, involved into blood coagulacion process/antiphospholipide and anticardiolipin autoantibodies. Conclusion: Correlation of these factors with resistance to hormonal therapy, and the state of anticancer immunity could help in the future with the the prediction of resistance to hormonal therapy and contribute to the selection of targeted immune therapy in cancer patients. Acknowledgement: This project was supported by grant IGA NT11168-3/2010. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr C68.

731: Specific gene expression in the placenta of a mouse model lacking endothelial nitric oxide synthase

We have previously shown that the abnormal intrauterine environment in mice lacking the endothelial nitric oxide synthase (NOS3) leads to hypertension and abnormal vascular function in the adult offspring. NOS3, vascular endotelial growth factor receptor-1(VEGF-R1) and tumor necrosis factor-á (TNFá) are known to play a role in utero-placental perfusion, angiogenesis and inflammation. Our objective was to evaluate their involvement in the altered fetal programming of adult vascular function in this transgenic model of utero-placental insufficiency.

Prognostic value of MGMT promoter status and EGFRvIII expression in glioblastoma patients.

e12518 Background: Methylation of MGMT promoter, an enzyme involved in DNA repair, has been associated with longer survival and efficacy of alkylating agents in patients with glioblastoma (GBM). The prognostic value of GBM-associated alterations of signal transduction pathways, such as the epidermal growth factor receptor (EGFR)/phosphoinisitide-3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway, that is inhibited by the negative regulator phosphatase and tensin homology (PTEN), has not yet been established. Methods: We prospectively evaluated 34 adult patients with GBM who underwent gross total resection followed by standard radiotherapy and temozolomide. Clinical variables included age, sex, and KPS. Tumor samples from these patients were analyzed for MGMT promoter status and expression of EGFRvIII (the mutant variant III of the EGFR) by RT-PCR, and for expression of PTEN and vascular endotelial growth factor (VEGF) by immunohistochemistry. Overall survival curves were estimated by the Kaplan-Meier method and compared with use of the two-sided logrank test. Results: Preoperative KPS more than 70 and expression of EGFRvIII were significantly associated with longer overall survival of patients (p = 0.0014 and p = 0.0336, respectively). Patients with GBM harboring methylation of the MGMT promoter and expression of EGFRvIII showed a trend toward a better survival, albeit it did not reach the statistical significance (p = 0.0763). Conclusions: Our study suggests a prognostic role for the EGFRvIII expression. The evaluation of this factor may be useful in adjunct of the determination of MGMT promoter status for the stratification of patients with GBM into distinct prognostic and therapeutic subgroups. No significant financial relationships to disclose.

Mecanismos de ação dos corticosteróides na polipose rinossinusal

Os glicocorticóides (GC) são drogas de escolha no tratamento clínico da polipose nasossinusal conforme recomendação da literatura. Entretanto, seus mecanismos de ação nas regressões dos sintomas clínicos e dos pólipos não são totalmente compreendidos. Sabe-se que a administração tópica e ou sistêmica dos glicocorticóides leva a variações na expressão de citocinas, quimiocinas e linfocinas, além das alterações celulares. Assim, os GC suprimem a expressão de citocinas pró-inflamatórias, de quimiocinas, de moléculas de adesão, além de estimular a transcrição de citocinas antiinflamatórias. Citocinas pró-fibróticas como a IL-11, fator básico de crescimento do fibroblasto (b-FGF) e fator de crescimento endotelial vascular (VEGF), relacionados com o crescimento do pólipo, também são suprimidos pela ação do GC. Tal ação depende fundamentalmente da interação com os seus receptores (GR), pois alguns indivíduos apresentam algum grau de resistência celular ao seu efeito, que parece estar relacionada com a presença da isoforma &lt;FONT FACE=Symbol&gt;b&lt;/font&gt; do GR. Genes envolvidos nas fases de produção de imunoglobulinas, apresentação e processamento do antígeno também sofrem ação dos GC de forma variada. OBJETIVOS: Fazer uma revisão da literatura sobre os mecanismos de ação do GC na PNS. CONCLUSÃO: A compreensão desses mecanismos implicará no desenvolvimento de drogas mais eficazes na sua terapêutica.

Mechanism of action of glucocorticoids in nasal polyposis

SummaryGlucocorticoids (GC) are the drugs of choice for the clinical treatment of nasal polyposis, according to the medical literature. Its mechanism of action in the regression of clinical symptoms and polyps, however, is not fully understood. The topical and/or systemic use of glucocorticoids lead to variable expression of cytokines, chemokines and lymphokines, as well as changes in cells. It is known that GC suppresses the expression of pro-inflammatory cytokines, chemokines and adhesion molecules such as ICAM-1 and E-selectin; GC also stimulate the transcription of anti-inflammatory cytokines such as TGF-β. GC suppress pro-fibrotic cytokines related to polyp growth, such as IL-11, the basic fibroblast growth factor (b-FGF), and the vascular endotelial growth factor (VEGF). The action of GC depends fundamentally on their interaction with receptors (GR); certain subjects have a degree of resistance to its effect, which appears to be related with the presence of a β isoform of GR. GC also act variably on the genes involved in immunoglobulin production, presentation, and antigen processing.AimWe present a review of the literature on the mechanisms of GC action in nasal polyosis.ConclusionUnderstanding the mechanism of action of GC in nasal polyposis will aid in the development of new, more efficient, drugs.

Nuevos factores pronósticos y predictivos en el cáncer colorrectal avanzado

Cancer patients often show a clinical tendency to thromboembolic events. This tendency is due to tumor cell-related factors together with the damage of the vascular endothelial exerted by chemotherapy treatment. Gastrointestinal tumors especially contribute to these types of events. More recently, the implication of tumor angiogenesis in clotting/fibrynolisys and plasminogen systems activation has been addressed in cancer patients. Finally, some hemostasis and angiogenesis-related factors such as platelets, von Willebrand factor, fibrinogen, plasminogen activator inhibitor type-1, D dimer, and vascular endotelial growth factor have been highlighted as new potential response and survival predictors in colorectal cancer patients. In this review article, the current evidence supporting the use of these proteins in assessing prognosis in colorectal cancer patients is critically exposed and discussed.

Prognostic significance of cyclooxigenase-2 (COX-2), vascular endotelial growth factor (VEGF) in patients with rectal cancer treated with preoperative radiotherapy

Identifying a biological marker of aggressive disease would help not only to select high-risk patients, but also to develop novel strategies in the management of advanced rectal cancer. The aim of this study was to determine the prognostic value of the expression of cyclooxigenase 2 (COX-2) and vascular endotelial growth factor (VEGF) detected by immunohistochimestry in a group of patients with locally advanced rectal cancer treated with preoperative radiotherapy with/without chemotherapy and radical surgery.

Prognostic significance of cyclooxigenase-2 (COX-2), vascular endotelial growth factor (VEGF) in patients with rectal cancer treated with preoperative radiotherapy

Identifying a biological marker of aggressive disease would help not only to select high-risk patients, but also to develop novel strategies in the management of advanced rectal cancer. The aim of this study was to determine the prognostic value of the expression of cyclooxigenase 2 (COX-2) and vascular endotelial growth factor (VEGF) detected by immunohistochimestry in a group of patients with locally advanced rectal cancer treated with preoperative radiotherapy with/without chemotherapy and radical surgery.