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Bais, Swarna, Elizabeth Wise, Eric M. Harris, Amy Meacham et Christopher R. Cogle. « AML Depends on VEGFR1 and Not VEGFR2 for Proliferation and Protection From Chemotherapy »,. Blood 118, no 21 (18 novembre 2011) : 3598. http://dx.doi.org/10.1182/blood.v118.21.3598.3598.
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Abstract Abstract 3598 Background: Vascular endothelial growth factor (VEGF) and its cognate receptors (VEGFRs) are known to serve important roles in normal hematopoiesis, but the importance of the VEGF/VEGFR axis in malignant hematopoiesis, namely acute myeloid leukemia (AML), is poorly defined. Methods: Bone marrow from AML patients were analyzed for VEGFRs on the malignant myeloblast populations. Human myeloid leukemia cell lines, KG-1, HL60 and K562, were also evaluated for VEGFR expression. Knockdown of VEGFR1 and VEGFR2 receptors in AML cells expressing these receptors were performed using lentivirus transfection of shRNA. Cell proliferation was quantified using XTT colorimetric assay and apoptosis was evaluated by Annexin V and PI staining. Results: Bone marrow from 12 consecutive AML patients showed that 33% of patients had malignant myeloblasts that expressed VEGFR1. Of the AML cell lines tested, only KG-1 cells expressed VEGFR1 and VEGFR2. Knockdown of VEGFR1 and VEGFR2 in KG-1 cells were confirmed by Western blot. When VEGFR1 was knocked down in KG-1 leukemia cells, cell proliferation was significant decreased (Figure 1). In addition, knocking down VEGFR1 resulted in enhanced sensitivity to cytarabine chemotherapy (Figure 1). In contrast, knockdown of VEGFR2 did not result in changes in leukemia cell proliferation or sensitivity to cytarabine chemotherapy (Figure 2). When KG-1 leukemia cells knocked down for VEGFR1 expression were transplanted into sublethally, irradiated NOD/scid/IL2R□−/− (NSG) mice (n=10), none of the mice showed engraftment of VEFR1 deficient cells. Conclusions: The VEGF/VEGFR axis is an important determinant in AML pathobiology. In specific, AML cells depend upon VEGFR1 and this receptor represents a promising target for future therapeutic intervention. Disclosures: No relevant conflicts of interest to declare.
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Zarkada, Georgia, Krista Heinolainen, Taija Makinen, Yoshiaki Kubota et Kari Alitalo. « VEGFR3 does not sustain retinal angiogenesis without VEGFR2 ». Proceedings of the National Academy of Sciences 112, no 3 (5 janvier 2015) : 761–66. http://dx.doi.org/10.1073/pnas.1423278112.
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Angiogenesis, the formation of new blood vessels, is regulated by vascular endothelial growth factors (VEGFs) and their receptors (VEGFRs). VEGFR2 is abundant in the tip cells of angiogenic sprouts, where VEGF/VEGFR2 functions upstream of the delta-like ligand 4 (DLL4)/Notch signal transduction pathway. VEGFR3 is expressed in all endothelia and is indispensable for angiogenesis during early embryonic development. In adults, VEGFR3 is expressed in angiogenic blood vessels and some fenestrated endothelia. VEGFR3 is abundant in endothelial tip cells, where it activates Notch signaling, facilitating the conversion of tip cells to stalk cells during the stabilization of vascular branches. Subsequently, Notch activation suppresses VEGFR3 expression in a negative feedback loop. Here we used conditional deletions and a Notch pathway inhibitor to investigate the cross-talk between VEGFR2, VEGFR3, and Notch in vivo. We show that postnatal angiogenesis requires VEGFR2 signaling also in the absence of Notch or VEGFR3, and that even small amounts of VEGFR2 are able to sustain angiogenesis to some extent. We found that VEGFR2 is required independently of VEGFR3 for endothelial DLL4 up-regulation and angiogenic sprouting, and for VEGFR3 functions in angiogenesis. In contrast, VEGFR2 deletion had no effect, whereas VEGFR3 was essential for postnatal lymphangiogenesis, and even for lymphatic vessel maintenance in adult skin. Knowledge of these interactions and the signaling functions of VEGFRs in blood vessels and lymphatic vessels is essential for the therapeutic manipulation of the vascular system, especially when considering multitargeted antiangiogenic treatments.
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Witmer, Antonella N., Jiapei Dai, Herbert A. Weich, Gijs F. J. M. Vrensen et Reinier O. Schlingemann. « Expression of Vascular Endothelial Growth Factor Receptors 1, 2, and 3 in Quiescent Endothelia ». Journal of Histochemistry & ; Cytochemistry 50, no 6 (juin 2002) : 767–77. http://dx.doi.org/10.1177/002215540205000603.
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The vascular endothelial growth factor (VEGF) family is involved in angiogenesis, and therefore VEGFs are considered as targets for anti-angiogenic therapeutic strategies against cancer. However, the physiological functions of VEGFs in quiescent tissues are unclear and may interfere with such systemic therapies. In pathological conditions, increased levels of expression of the VEGF receptors VEGFR-1, VEGFR-2, and VEGFR-3 accompany VEGF activity. In this study we investigated normal human and monkey tissues for expression patterns of these receptors. Immunohistochemical staining methods at the light and electron microscopic level were applied to normal human and monkey tissue samples, using monoclonal antibodies (MAbs) against the three VEGFRs and anti-endothelial MAbs PAL-E and anti-CD31 to identify blood and lymph vessels. In human and monkey, similar distribution patterns of the three VEGFRs were found. Co-expression of VEGFR-1, −2, and −3 was observed in microvessels adjacent to epithelia in the eye, gastrointestinal mucosa, liver, kidney, and hair follicles, which is in line with the reported preferential expression of VEGF-A in some of these epithelia. VEGFR-1, −2, and −3 expression was also observed in blood vessels and sinusoids of lymphoid tissues. Furthermore, VEGFR-1, but not VEGFR-2 and −3, was present in microvessels in brain and retina. Electron microscopy showed that VEGFR-1 expression was restricted to pericytes and VEGFR-2 to endothelial cells in normal vasculature of tonsils. These findings indicate that VEGFRs have specific distribution patterns in normal tissues, suggesting physiological functions of VEGFs that may be disturbed by systemic anti-VEGF therapy. One of these functions may be involvement of VEGF in paracrine relations between epithelia and adjacent capillaries.
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Morimoto, Yukina, Masahiro Toda, Ryota Tamura, Kentarou Ohara, Yumiko Oishi et Kazunari Yoshida. « IMT-02 VEGF RECEPTORS EXPRESSION AND REPORT OF CLINICAL TRIAL OF PEPTIDE VACCINE IN SKULL BASE CHORDOMA ». Neuro-Oncology Advances 1, Supplement_2 (décembre 2019) : ii17. http://dx.doi.org/10.1093/noajnl/vdz039.077.
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Abstract Chordoma is a rare refractory neoplasm that arises from the embryological remnants of the notochord. Vascular endothelial growth factor (VEGF) is a potent activator of angiogenesis that is associated with the tumor-immune microenvironment. To evaluate the characteristics of vascular and tumor cells in chordoma, we first analyzed the expression of VEGF receptor (VEGFR) 1, VEGFR2, CD34, and Brachyury in a cell line and 54 tumor tissues. Patients with primary skull base chordomas were divided into the two groups as per the tumor growth rate. The expressions of VEGF-A, VEGFR1, and VEGFR2 on tumor cells; tumor infiltrative immune cells, including regulatory T cells (Tregs) and tumor-associated macrophages (TAMs); and immune-checkpoint molecules (PD-1/PD-L1) were analyzed with the clinical courses. Both VEGFR1 and VEGFR2 were strongly expressed not only on vascular endothelial cells, but also on tumor cells. The recurrent cases showed significantly higher VEGFR1 expressions on tumor cells than the primary cases. The expression of VEGF-A, and the numbers of CD163+ TAMs and Foxp3+ Tregs were significantly higher in the patients with rapid progressive course than the patients with slow progressive course. Based on the present results, VEGFRs-targeted therapy may show efficacy in regulating growth of chordomas.
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Feng, Yan, Ying Li, Xinling Yang, Limin Han, Luning Wang, Shan Gao, Ruixue Yin et al. « Direct evidence of VEGF-mediated neuroregulation and afferent explanation of blood pressure dysregulation during angiogenic therapy ». Frigid Zone Medicine 1, no 2 (1 décembre 2021) : 119–26. http://dx.doi.org/10.2478/fzm-2021-0015.
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Abstract Objective Oncocardiology is increasingly hot research field/topic in the clinical management of cancer with anti-angiogenic therapy of vascular endothelial growth factor (VEGF) that may cause cardiovascular toxicity, such as hypertension via vascular dysfunction and attenuation of eNOS/NO signaling in the baroreflex afferent pathway. The aim of the current study was to evaluate the potential roles of VEGF/VEGF receptors (VEGFRs) expressed in the baroreflex afferent pathway in autonomic control of blood pressure (BP) regulation. Methods The distribution and expression of VEGF/VEGFRs were detected in the nodose ganglia (NG) and nucleus of tractus solitary (NTS) using immunostaining and molecular approaches. The direct role of VEGF was tested by NG microinjection under physiological and hypertensive conditions. Results Immunostaining data showed that either VEGF or VEGFR2/VEGFR3 was clearly detected in the NG and NTS of adult male rats. Microinjection of VEGF directly into the NG reduced the mean blood pressure (MBP) dose-dependently, which was less dramatic in renovascular hypertension (RVH) rats, suggesting the VEGF-mediated depressor response by direct activation of the 1st-order baroreceptor neurons in the NG under both normal and disease conditions. Notably, this reduced depressor response in RVH rats was directly caused by the downregulation of VEGFR2, which compensated the up regulation of VEGF/VEGFR3 in the NG during the development of hypertension. Conclusion It demonstrated for the first time that the BP-lowering property of VEGF/VEGFRs signaling via the activation of baroreflex afferent function may be a common target/pathway leading to BP dysregulation in anti-angiogenic therapy.
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Coon, Brian G., Nicolas Baeyens, Jinah Han, Madhusudhan Budatha, Tyler D. Ross, Jennifer S. Fang, Sanguk Yun, Jeon-Leon Thomas et Martin A. Schwartz. « Intramembrane binding of VE-cadherin to VEGFR2 and VEGFR3 assembles the endothelial mechanosensory complex ». Journal of Cell Biology 208, no 7 (23 mars 2015) : 975–86. http://dx.doi.org/10.1083/jcb.201408103.
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Endothelial responses to fluid shear stress are essential for vascular development and physiology, and determine the formation of atherosclerotic plaques at regions of disturbed flow. Previous work identified VE-cadherin as an essential component, along with PECAM-1 and VEGFR2, of a complex that mediates flow signaling. However, VE-cadherin’s precise role is poorly understood. We now show that the transmembrane domain of VE-cadherin mediates an essential adapter function by binding directly to the transmembrane domain of VEGFR2, as well as VEGFR3, which we now identify as another component of the junctional mechanosensory complex. VEGFR2 and VEGFR3 signal redundantly downstream of VE-cadherin. Furthermore, VEGFR3 expression is observed in the aortic endothelium, where it contributes to flow responses in vivo. In summary, this study identifies a novel adapter function for VE-cadherin mediated by transmembrane domain association with VEGFRs.
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Dewaele, B., G. Floris, R. Sciot, H. Prenen, A. Wozniak, L. Guillou, J. Coindre, C. Fletcher, P. Schöffski et M. Debiec-Rychter. « Tyrosine kinases as possible therapeutic targets in pulmonary artery intimal sarcoma ». Journal of Clinical Oncology 25, no 18_suppl (20 juin 2007) : 10055. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.10055.
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10055 Background: Pulmonary artery intimal sarcomas (PAIS) are very rare, highly malignant and clinically aggressive tumors, with yet elusive underlying pathogenic mechanisms and histogenesis. Our aim was to gain molecular insight in the oncogenic events leading to PAIS development, and to investigate the possibility of a pharmacological approach for the treatment of PAIS, specifically targeting the receptor tyrosine kinases (RTK) activated in these tumors. Methods: Fourteen cases of advanced high grade poorly differentiated PAIS were analyzed by immunohistochemistry and selectively by a variety of cytogenetic/molecular techniques, e.g. karyotyping, FISH, mRNA in situ hybridization, array-CGH, tyrosine kinases RT-PCR assay and Western blotting analysis. The study was supplemented by sequencing of PDGFRA, PDGFRB, KIT, VEGFR-1, VEGFR-2 and EGFR genes. Ex vivo functional assays were applied to test the sensitivity of PAIS primary tumor cells to different, clinically approved RTK inhibitors. Results: We demonstrate that (1) PAIS do not have mutations within the kinase domains of PDGFRs, KIT, VEGFRs or EGFR, (2) all cases show a similar cytogenetic molecular profile, characterized by amplification of PDGFRA/KIT/VEGFR2 and MDM2/CDK4 genes, while EGFR, PDGFRB and VEGFR1 are frequently polysomic but rarely highly amplified, (3) high level of expression of PDGFRA, VEGFR1/VEGFR2 and EGFR is uniformly present in the tested tumors, (4) PAIS demonstrate activation (phosphorylation) of PDGFRA and downstream PI3K-AKT and MAP-Kinase signaling pathways, (4) in ex vivo assays, a potent effect of BMS354825 on proliferation and survival of primary cells of PAIS is proven. Conclusions: PDGFRA is amplified and activated in PAIS, thus constituting one of many possible targets for the therapy. Tested inhibitors showed differential efficacy for inhibition of PAIS cells by ex vivo assays. No significant financial relationships to disclose.
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Tamura, Ryota, Yukina Morimoto, Mizuto Sato, Tetsuro Hikichi, Kazunari Yoshida et Masahiro Toda. « A Pilot Study of the Adverse Events Caused by the Combined Use of Bevacizumab and Vascular Endothelial Growth Factor Receptor-Targeted Vaccination for Patients with a Malignant Glioma ». Vaccines 8, no 3 (2 septembre 2020) : 498. http://dx.doi.org/10.3390/vaccines8030498.
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Anti-angiogenic therapy, targeting vascular endothelial growth factor (VEGF)-A/VEGF receptors (VEGFRs), is beneficial for tumor growth prevention in a malignant glioma. A simultaneous blockade using both bevacizumab (Bev), which targets circulating VEGF-A, and a multi-kinase inhibitor on VEGFRs was more effective for advanced solid cancers, including melanoma and renal cell carcinoma. However, previous clinical trials demonstrated a high adverse event rate. Additionally, no studies previously assessed treatment efficacy and safety using both VEGF-A and VEGFR-targeted agents for malignant gliomas. We had conducted clinical trials investigating VEGFRs peptide vaccination in patients with malignant gliomas, in which the treatment exhibited safety and yielded therapeutic effects in some patients. The combined use of Bev and VEGFRs vaccination may enhance the anti-tumor effect in malignant gliomas. In this pilot study, the adverse event profile in patients treated with Bev after the vaccination was investigated to establish this treatment strategy, in comparison to those treated with Bev collected from the published data or treated with the vaccination alone. In our previous clinical studies on patients with malignant gliomas, Bev was administered to 13 patients after VEGFRs vaccinations. One patient had a Grade 4 pulmonary embolism. Two patients had Grade 2 cerebral infarctions. There were no significant differences in the adverse event rates among patients treated with Bev, with the vaccination, or with Bev after the vaccination. Although careful observation is imperative for patients after this combination treatment strategy, VEGFRs-targeted vaccination may coexist with Bev for malignant gliomas.
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Zhang, Huanxiang, Laszlo Vutskits, Michael S. Pepper et Jozsef Z. Kiss. « VEGF is a chemoattractant for FGF-2–stimulated neural progenitors ». Journal of Cell Biology 163, no 6 (22 décembre 2003) : 1375–84. http://dx.doi.org/10.1083/jcb.200308040.
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Mmigration of undifferentiated neural progenitors is critical for the development and repair of the nervous system. However, the mechanisms and factors that regulate migration are not well understood. Here, we show that vascular endothelial growth factor (VEGF)-A, a major angiogenic factor, guides the directed migration of neural progenitors that do not display antigenic markers for neuron- or glia-restricted precursor cells. We demonstrate that progenitor cells express both VEGF receptor (VEGFR) 1 and VEGFR2, but signaling through VEGFR2 specifically mediates the chemotactic effect of VEGF. The expression of VEGFRs and the chemotaxis of progenitors in response to VEGF require the presence of fibroblast growth factor 2. These results demonstrate that VEGF is an attractive guidance cue for the migration of undifferentiated neural progenitors and offer a mechanistic link between neurogenesis and angiogenesis in the nervous system.
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Furuya, Mitsuko, Kentaro Kurasawa, Kiyotaka Nagahama, Kae Kawachi, Akinori Nozawa, Tsuneo Takahashi et Ichiro Aoki. « Disrupted Balance of Angiogenic and Antiangiogenic Signalings in Preeclampsia ». Journal of Pregnancy 2011 (2011) : 1–10. http://dx.doi.org/10.1155/2011/123717.
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The placenta plays a central role in governing local circulatory system that mediates maternal condition and fetal growth. In early gestational phases, the placenta exerts properties of invasion and neovascularization for successful placentation. Extravillous invasive trophoblasts replace uterine endometrial vasculature and establish local blood pathway to obtain oxygen and nutrients from the mother. In later phases, the placenta promotes villous angiogenesis and vascular maturation that are finely controlled by angiogenic and antiangiogenic molecules. Among various molecules involved in placental neovascularization, vascular endothelial growth factor receptors (VEGFRs) and angiotensin II receptor type 1 (AT1) mediate important signaling pathways for maternal circulatory system and fetal growth. VEGFR1 and VEGFR2 are functional receptors for placental growth factor (PlGF) and VEGF, respectively, and PlGF-VEGFR1 and VEGF-VEGFR2 interactions are disturbed in many preeclamptic patients by excess amount of soluble form of VEGFR1 (also named sFlt1), a natural PlGF/VEGF antagonist. Recent studies have disclosed that excessive sFlt1 production in the placenta and aberrant AT1 signaling in the mother are closely associated with the pathology of preeclampsia and intrauterine growth restriction (IUGR). In this paper, neovascularization of the placenta and pathological events associated with disrupted balance between angiogenic and antiangiogenic signaling in preeclampsia are discussed.
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Masood, Rizwan, Jie Cai, Tong Zheng, D. Lynne Smith, David R. Hinton et Parkash S. Gill. « Vascular endothelial growth factor (VEGF) is an autocrine growth factor for VEGF receptor–positive human tumors ». Blood 98, no 6 (15 septembre 2001) : 1904–13. http://dx.doi.org/10.1182/blood.v98.6.1904.
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Abstract Angiogenesis is required for the progression of tumors from a benign to a malignant phenotype and for metastasis. Malignant tumor cells secrete factors such as vascular endothelial growth factor (VEGF), which bind to their cognate receptors on endothelial cells to induce angiogenesis. Here it is shown that several tumor types express VEGF receptors (VEGFRs) and that inhibition of VEGF (VEGF antisense oligonucleotide AS-3) or VEGFRs (neutralizing antibodies) inhibited the proliferation of these cell lines in vitro. Furthermore, this effect was abrogated by exogenous VEGF. Thus, VEGF is an autocrine growth factor for tumor cell lines that express VEGFRs. A modified form of VEGF AS-3 (AS-3m), in which flanking 4 nucleotides were substituted with 2-O-methylnucleosides (mixed backbone oligonucleotides), retained specificity and was active when given orally or systemically in vitro and in murine tumor models. In VEGFR-2–expressing tumors, VEGF inhibition may have dual functions: direct inhibition of tumor cell growth and inhibition of angiogenesis.
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Inder, Marie K., Norihito Ueda, Andrew A. Mercer, Stephen B. Fleming et Lyn M. Wise. « Bovine papular stomatitis virus encodes a functionally distinct VEGF that binds both VEGFR-1 and VEGFR-2 ». Journal of General Virology 88, no 3 (1 mars 2007) : 781–91. http://dx.doi.org/10.1099/vir.0.82582-0.
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Bovine papular stomatitis virus (BPSV), a member of the genus Parapoxvirus, causes proliferative dermatitis in cattle and humans. Other species of the genus cause similar lesions, the nature of which has been attributed, at least in part, to a viral-encoded vascular endothelial growth factor (VEGF) that induces vascularization and dermal oedema through VEGF receptor-2 (VEGFR-2). The results of this study showed that BPSV strain V660 encodes a novel VEGF and that the predicted BPSV protein showed only 33–52 % amino acid identity to VEGFs encoded by the other species of the genus. BPSV VEGF showed higher identity to mammalian VEGF-A (51 %) than the other parapoxviral VEGFs (31–46 %). Assays of the purified BPSV VEGF (BPSVV660VEGF) demonstrated that it was also functionally more similar to VEGF-A, as it showed significant binding to VEGFR-1 and induced monocyte migration. Like VEGF-A and the other viral VEGFs, BPSVV660VEGF bound VEGFR-2 with high affinity. Sequence analysis and structural modelling of BPSVV660VEGF revealed specific residues, outside the known receptor-binding face, that are predicted either to influence VEGF structure or to mediate binding directly to the VEGFRs. These results indicate that BPSVV660VEGF is a biologically active member of the VEGF family and that, via its interaction with VEGFR-2, it is likely to contribute to the proliferative and highly vascularized nature of BPSV lesions. This is also the first example of a viral VEGF acting via VEGFR-1 and influencing haematopoietic cell function. These data suggest that BPSVV660VEGF is an evolutionary and functional intermediate between VEGF-A and the other parapoxviral VEGFs.
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Assareh, Elham, Faramarz Mehrnejad, Kamran Mansouri, Ahmad Reza Esmaeili Rastaghi, Hossein Naderi-Manesh et S. Mohsen Asghari. « A cyclic peptide reproducing the α1 helix of VEGF-B binds to VEGFR-1 and VEGFR-2 and inhibits angiogenesis and tumor growth ». Biochemical Journal 476, no 4 (19 février 2019) : 645–63. http://dx.doi.org/10.1042/bcj20180823.
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Abstract Vascular endothelial growth factors (VEGFs) and their receptors (VEGFRs) are pivotal regulators of angiogenesis. The VEGF–VEGFR system is therefore an important target of anti-angiogenesis therapy. Based on the X-ray structure of VEGF-B/VEGFR-1 D2, we designed a cyclic peptide (known as VGB1) reproducing the α1 helix and its adjacent region to interfere with signaling through VEGFR-1. Unexpectedly, VGB1 bound VEGFR-2 in addition to VEGFR-1, leading to inhibition of VEGF-stimulated proliferation of human umbilical vein endothelial cells and 4T1 murine mammary carcinoma cells, which express VGEFR-1 and VEGFR-2, and U87 glioblastoma cells that mostly express VEGFR-2. VGB1 inhibited different aspects of angiogenesis, including proliferation, migration and tube formation of endothelial cells stimulated by VEGF-A through suppression of extracellular signal-regulated kinase 1/2 and AKT (Protein Kinase B) phosphorylation. In a murine 4T1 mammary carcinoma model, VGB1 caused regression of tumors without causing weight loss in association with impaired cell proliferation (decreased Ki67 expression) and angiogenesis (decreased CD31 and CD34 expression), and apoptosis induction (increased TUNEL staining and p53 expression, and decreased Bcl-2 expression). According to far-UV circular dichroism (CD) and molecular dynamic simulation data, VGB1 can adopt a helical structure. These results, for the first time, demonstrate that α1 helix region of VEGF-B recognizes both VEGFR-1 and VEGFR-2.
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Hiratsuka, Sachie, Yuki Kataoka, Kazuki Nakao, Kenji Nakamura, Shunichi Morikawa, Satoshi Tanaka, Motoya Katsuki, Yoshiro Maru et Masabumi Shibuya. « Vascular Endothelial Growth Factor A (VEGF-A) Is Involved in Guidance of VEGF Receptor-Positive Cells to the Anterior Portion of Early Embryos ». Molecular and Cellular Biology 25, no 1 (1 janvier 2005) : 355–63. http://dx.doi.org/10.1128/mcb.25.1.355-363.2005.
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ABSTRACT The hemangioblast in the mesoderm gives rise to both angioblasts and hematopoietic stem cells. The movement of hemangioblast precursor cells in the fetal trunk is a critical event in early embryogenesis. Vascular endothelial growth factor (VEGF) signaling is likely involved in this migration given the partial disturbance of VEGF receptor (VEGFR)-positive cell accumulation and migration in VEGFR2 null mice or mice with a truncated VEGFR1. However, it is not clear how the VEGF system regulates this migration or its direction. We show here that the expression of VEGF-A is dominant in the anterior portion of the embryo, whereas VEGFR1 and VEGFR2 are expressed in the posterior portion of the embryo. An inhibitor of VEGFR kinase blocked the migration of VEGFR-positive cells in a whole-embryo culture system. In addition, VEGFR-positive cells migrated toward a VEGFR1- or VEGFR2-specific ligand in vitro. Furthermore, VEGFR-positive cells derived from wild-type or VEGFR2+/− mice moved rapidly anteriorly, whereas cells derived from VEGFR2+/− mice carrying a truncated VEGFR1 [VEGFR1(TM-TK)−/−] migrated little when injected into wild-type mice. These results suggest that the VEGF-A protein concentrated in the anterior region plays an important role in the guidance of VEGFR-positive cells from the posterior portion to the head region by interacting with VEGFR in the mouse embryo.
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Schechter, Rebecca B., Madhavi Nagilla, Loren Joseph, Poluru L. Reddy, Arun Khattri, Sydeaka Watson, Laura D. Locati et al. « Genetic profiling of advanced RAI-resistant differentiated thyroid cancer and correlation with axitinib response. » Journal of Clinical Oncology 31, no 15_suppl (20 mai 2013) : 6066. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.6066.
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6066 Background: The VEGFR inhibitor axitinib has demonstrated compelling antitumor activity in advanced RAI-resistant differentiated thyroid cancer (DTC). Biomarkers predicting which patients may benefit from axitinib are unavailable. We aimed to describe molecular markers in DTC that correlate with clinical outcome to axitinib. Methods: Pretreatment FFPE thyroid cancer blocks from patients treated with axitinib were collected and genomic DNA was isolated. The OncoCarta Mutation Panel was used to test for 238 mutations. Copy number of VEGFR1-3 and PIK3CA was determined using qPCR. Genomic DNA was analyzed for coding regions of VEGFR1-3 with custom primers. Clinical response to axitinib, including best response (BR) (RECIST) and progression free survival (PFS), was ascertained from corresponding patients. Fisher’s exact test and logistic regression models were used to correlate BR with molecular findings. Cox proportional hazards regression was used to correlate PFS with molecular defects. Results: A total of 22 pathology samples (11 primary, 11 metastatic) were identified. In patients with 2 samples (n = 4), results were concordant and only included once for analysis. Of 18 specimens, 4 tumors (22%) harbored BRAF V600E mutations, 2 (11%) had KRAS mutations (G12A, G13D) and 2 (11%) had HRAS mutations (Q61R, Q61K). One sample with mutated KRAS also had a PIK3CA (H1047R) mutation. qPCR showed increased copy numbers of PIK3CA in 6 (33%) tumors, VEGFR1 in 0 (0%) tumors, VEGFR2 in 4 (22%) tumors, and VEGFR3 in 6 (33%) tumors. VEGFR sequencing showed a possibly damaging non-synonymous SNP in VEGFR2 (G539GR) in 2 samples (11%), a possibly damaging SNP in VEGFR3 (E350VE) in 1 sample (6%), and a potentially novel mutation in VEGFR2 (T439IT) in 2 samples (11%). No significant relationship was seen between BR or PFS and the presence of molecular defects. Conclusions: While DTC is genetically heterogenous, primary and metastatic lesions showed identical alterations. Molecular evaluation of DTC specimens did not predict clinical response to axitinib but data were limited by small sample size. We did identify molecular changes in VEGFR that should be further explored. This study was supported by Pfizer, Inc.
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Shibuya, M. « Vascular Endothelial Growth Factor Receptor Family Genes : When Did the Three Genes Phylogenetically Segregate ? » Biological Chemistry 383, no 10 (6 octobre 2002) : 1573–79. http://dx.doi.org/10.1515/bc.2002.177.
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AbstractThe vascular endothelial growth factor (VEGF) receptor family in mammals contains three members, VEGFR1(Flt-1), VEGFR2(KDR/Flk-1) and VEGFR3 (Flt-4), which directly regulate the formation of blood vessels and lymphatic vessels. These two circular systems are essential for the supply of O2 and nutrients to all tissues of the body as well as the drainage of excess fluids with waste metabolites from peripheral tissues. VEGF receptors have a characteristic structure with 7 Iglike domains in the extracellular domain and a cytoplasmic tyrosine kinase domain with a long kinase insert region. Recently, some novel findings on the phylogenetical conservation of VEGF receptor genes in animals were reported: the conservation of the VEGFR1/solubleVEGFR1 gene in birds, and the conservation of the VEGFRPDGFRlike receptor gene in nonvertebrates. Based on this new information as well as established observations, here the possibility is discussed that the three VEGFR genes phylogenetically segregated not at once when the vertebrates established, but in a stepwise manner: two genes first (the VEGFR1/R2 progenitor and the VEGFR3 gene), and subsequently the three genes VEGFR1, R2 and R3.
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Macy, Margaret E., Deborah DeRyckere et Lia Gore. « In Vitro Evaluation of the Antitumor Activity of Vandetanib in Pediatric Acute Leukemias. » Blood 110, no 11 (16 novembre 2007) : 857. http://dx.doi.org/10.1182/blood.v110.11.857.857.
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Abstract Acute leukemia is the most common childhood cancer, accounting for approximately 3500 new cases per year in the United States. While a majority of these patients are cured with modern therapy, a proportion will do poorly and have little chance for a cure; the development of novel therapeutic agents is critical for these patients. Vascular endothelial growth factor (VEGF) is known to be a strong promoter of angiogenesis (Shweiki et al., Nature1992. 359:843–5) and elevated levels of VEGF are correlated with poorer prognosis in patients with leukemia (Aguayo et al., Blood.1999. 94:3717–21; Avramis et al., Clin Cancer Res.2006. 12:6978–84). Vandetanib (ZACTIMA™; ZD6474) is an orally active small molecule tyrosine kinase inhibitor with activity against VEGF receptor 2 (VEGFR2), VEGF receptor 1 (VEGFR1), VEGF receptor 3 (VEGFR3), epidermal growth factor receptor (EGFR), platelet derived growth factorβ (PDGFRβ), and Rearranged during transfection (RET). We have used a panel of 18 acute leukemia cell lines derived from patients with acute lymphoid leukemias (ALL) or acute myeloid leukemias (AML) of different lineages and developmental stages, to investigate the potential anti-leukemic effects of vandetanib. Proliferation and/or survival of 4 of the cell lines are inhibited at clinically achievable concentrations of vandetanib, with IC50 values ranging from 85nM to 2.3μM. This anti-tumor activity is dose dependent and results in accumulation of cells in G1 phase. At higher concentrations, treatment with vandetanib induces apoptosis. The vandetanib-sensitive cell lines express VEGFR1 and/or VEGFR3 and do not express VEGFR2 or EGFR. Stimulation of a vandetanib-sensitive AML cell line (Molm-13) with VEGF-C or a mutant form of VEGF-C that specifically stimulates VEGFR-3 results in increased proliferation and/or survival. In this cell line, this effect is specific to VEGFR-3 signaling, as stimulation of VEGFR-1 with VEGF-B does not affect proliferation or survival. Thus, our data suggest that vandetanib-mediated anti-leukemia activity is due to inhibition of VEGFR3 and/or VEGFR1. However, vandetanib-resistant cell lines also express VEGFR1 and/or VEGFR3 and thus, expression of VEGFR1 and/or VEGFR3 does not predict vandetanib sensitivity. In order to determine whether VEGFR signaling may play a role in promoting survival in other contexts, we investigated the interactions between vandetanib and standard pediatric re-induction chemotherapy agents. For these studies, a vandetanib-resistant B-lineage ALL cell line was treated concurrently with vandetanib and either adriamycin, aramycin-C (cytarabine), etoposide, or methotrexate. Anti-tumor activity was measured and Bliss independence was evaluated. Vandetanib exhibits synergistic anti-tumor activity in combination with all 4 of the chemotherapy agents investigated. Thus, vandetanib can mediate direct anti-tumor effects against specific acute leukemia cell lines and can also augment the effects of chemotherapy. Taken together, our data suggest that vandetanib may be an effective agent for treatment of pediatric acute leukemias.
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Hamada, Koichi, Yuichi Oike, Nobuyuki Takakura, Yasuhiro Ito, Lotta Jussila, Daniel J. Dumont, Kari Alitalo et Toshio Suda. « VEGF-C signaling pathways through VEGFR-2 and VEGFR-3 in vasculoangiogenesis and hematopoiesis ». Blood 96, no 12 (1 décembre 2000) : 3793–800. http://dx.doi.org/10.1182/blood.v96.12.3793.h8003793_3793_3800.
Texte intégralRésumé :
Signaling by vascular endothelial growth factors (VEGFs) through VEGF receptors (VEGFRs) plays important roles in vascular development and hematopoiesis. The authors analyzed the function of VEGF-C signaling through both VEGFR-2 and VEGFR-3 in vasculoangiogenesis and hematopoiesis using a coculture of para-aortic splanchnopleural mesoderm (P-Sp) explants from mouse embryos with stromal cells (OP9). Vasculogenesis and angiogenesis were evaluated by the extent of vascular bed and network formation, respectively. Addition of VEGF-C to the P-Sp culture enhanced vascular bed formation and suppressed definitive hematopoiesis. Both vascular bed and network formations were completely suppressed by addition of soluble VEGFR-1–Fc competitor protein. Formation of vascular beds but not networks could be rescued by VEGF-C in the presence of the competitor, while both were rescued by VEGF-A. VEGFR-3–deficient embryos show the abnormal vasculature and severe anemia. Consistent with these in vivo findings, vascular bed formation in the P-Sp from the VEGFR-3–deficient embryos was enhanced to that in wild-type or heterozygous embryos, and hematopoiesis was severely suppressed. When VEGFR-3–Fc chimeric protein was added to trap endogenous VEGF-C in the P-Sp culture of the VEGFR-3–deficient embryos, vascular bed formation was suppressed and hematopoiesis was partially rescued. These results demonstrate that because VEGF-C signaling through VEGFR-2 works synergistically with VEGF-A, the binding of VEGF-C to VEGFR-3 consequently regulates VEGFR-2 signaling. In VEGFR-3–deficient embryos, an excess of VEGF-C signals through VEGFR-2 induced the disturbance of vasculogenesis and hematopoiesis during embryogenesis. This indicates that elaborated control through VEGFR-3 signaling is critical in vasculoangiogenesis and hematopoiesis.
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Gao, Minna, Bo Zeng, Xiong Zhang et Li Yu. « Molecular Mechanism on Inhibition of MB Angiogenesis by Curcumin Blocking the Wnt/β-Catenin and NF-κB Signaling Pathway and Inhibiting the Expression of VEGFs/VEGFRs ». Advanced Materials Research 1120-1121 (juillet 2015) : 798–802. http://dx.doi.org/10.4028/www.scientific.net/amr.1120-1121.798.
Texte intégralRésumé :
Medulloblastoma (MB) is one of the most common malignant tumors in pediatric brain. The genesis and development of MB are related to abnormal and persistent activation of the Wnt/β-catenin abnormal and NF-κB signaling pathway. The VEGF, as the main target gene regulated by the crosstalk between the two signaling pathways, is closely related to MB. In previous studies, We found that the genesis of MB is associated with the abnormal expression of key molecular GSK-3β,β-catenin and downstream target gene PPAR-gamma in Wnt /β-catenin signaling pathway.It also found that, there have abnormal expression of VEGF-A, C and its receptor VEGFR-2 in MB, and positively correlate with β-catenin. curcumin has anti-angiogenic function, but the exact mechanism is unclear. Combining with the early research findings and the latest literatures, we hypothesized that curcumin can inhibit the expression of VEGFs/VEGFRs by blocking the Wnt/β-catenin and NF-κB signaling pathway.
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Secker, Genevieve A., et Natasha L. Harvey. « Regulation of VEGFR Signalling in Lymphatic Vascular Development and Disease : An Update ». International Journal of Molecular Sciences 22, no 14 (20 juillet 2021) : 7760. http://dx.doi.org/10.3390/ijms22147760.
Texte intégralRésumé :
The importance of lymphatic vessels in a myriad of human diseases is rapidly gaining recognition; lymphatic vessel dysfunction is a feature of disorders including congenital lymphatic anomalies, primary lymphoedema and obesity, while improved lymphatic vessel function increases the efficacy of immunotherapy for cancer and neurological disease and promotes cardiac repair following myocardial infarction. Understanding how the growth and function of lymphatic vessels is precisely regulated therefore stands to inform the development of novel therapeutics applicable to a wide range of human diseases. Lymphatic vascular development is initiated during embryogenesis following establishment of the major blood vessels and the onset of blood flow. Lymphatic endothelial progenitor cells arise from a combination of venous and non-venous sources to generate the initial lymphatic vascular structures in the vertebrate embryo, which are then further ramified and remodelled to elaborate an extensive lymphatic vascular network. Signalling mediated via vascular endothelial growth factor (VEGF) family members and vascular endothelial growth factor receptor (VEGFR) tyrosine kinases is crucial for development of both the blood and lymphatic vascular networks, though distinct components are utilised to different degrees in each vascular compartment. Although much is known about the regulation of VEGFA/VEGFR2 signalling in the blood vasculature, less is understood regarding the mechanisms by which VEGFC/VEGFD/VEGFR3 signalling is regulated during lymphatic vascular development. This review will focus on recent advances in our understanding of the cellular and molecular mechanisms regulating VEGFA-, VEGFC- and VEGFD-mediated signalling via VEGFRs which are important for driving the construction of lymphatic vessels during development and disease.
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Ji, James W., Feilim Mac Gabhann et Aleksander S. Popel. « Skeletal muscle VEGF gradients in peripheral arterial disease : simulations of rest and exercise ». American Journal of Physiology-Heart and Circulatory Physiology 293, no 6 (décembre 2007) : H3740—H3749. http://dx.doi.org/10.1152/ajpheart.00009.2007.
Texte intégralRésumé :
VEGF is a key promoter of angiogenesis and a major target of proangiogenic therapy for peripheral arterial disease (PAD). Greater understanding of VEGF angiogenic signaling and guidance by gradients for new capillaries will aid in developing new proangiogenic therapies and improving existing treatments. However, in vivo measurements of VEGF concentration gradients at the cell scale are currently impossible. We have developed a computational model to quantify VEGF distribution in extensor digitorum longus skeletal muscle using measurements of VEGF, VEGF receptor (VEGFR), and neuropilin-1 (NRP1) expression in an experimental model of rat PAD. VEGF is secreted by myocytes, diffuses through and interacts with extracellular matrix and basement membranes, and binds VEGFRs and NRP1 on endothelial cell surfaces of blood vessels. We simulate the effects of increased NRP1 expression and of therapeutic exercise training on VEGF gradients, receptor signaling, and angiogenesis. Our study predicts that angiogenic therapy for PAD may be achieved not only through VEGF upregulation but also through modulation of VEGFRs and NRP1. We predict that expression of 104 NRP1/cell can increase VEGF binding to receptors by 1.7-fold (vs. no NRP1); in nonexercise-trained muscle with PAD, angiogenesis is hindered due to limited VEGF upregulation, signaling, and gradients; in exercise-trained muscle, VEGF signaling is enhanced by upregulation of VEGFRs and NRP1, and VEGF signaling is strongest within the first week of exercise therapy; and hypoxia-induced VEGF release is important to direct angiogenesis towards unperfused tissue.
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Verbiest, Annelies, Benoit Beuselinck, Gabrielle Couchy, Sylvie Job, Aurelien De Reynies, Clément Meiller, Maarten Albersen et al. « Metastatic clear cell renal cell carcinoma : Proangiogenic gene expression and outcome on sunitinib. » Journal of Clinical Oncology 35, no 15_suppl (20 mai 2017) : e16085-e16085. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.e16085.
Texte intégralRésumé :
e16085 Background: Clear cell renal cell carcinomas (ccRCC) are hypervascular tumors that respond to vascular endothelial growth factor receptor (VEGFR) inhibitors such as sunitinib. They can be divided into 4 mRNA-expression based subgroups (ccrcc 1-4) with different outcomes on sunitinib. We hypothesized that the expression of proangiogenic genes is predictive for response to sunitinib. Methods: Retrospective series of metastatic ccRCC-patients treated with sunitinib as first line targeted therapy (n = 104). We studied expression of genes involved in angiogenesis and the immune-suppressive microenvironment (qRT-PCR) and mutational status of Von Hippel Lindau and Polybromo (PBRM) 1 (sequencing) on primary tumor samples. Outcome parameters were response rate (Response Evaluation Criteria in Solid Tumors), progression free survival (PFS) and overall survival (OS). Gene expression levels were tested in multivariate analysis (MV) against the IMDC risk criteria, presence of bone metastases and sarcomatoid dedifferentiation ≥25%. Results: Expression of Hypoxia Inducible Factor (HIF) 2A, Platelet Derived Growth Factor Receptor B, VEGFC, VEGFR1 and VEGFR2 was significantly correlated with PFS on MV and expression of HIF1A, HIF2A and VEGFR2 with OS. VEGFR2-expression was also correlated with partial response (p = 0.03) and anti-correlated with early progressive disease (p = 0.008). HIF2A, VEGFA, VEGFR1, VEGFR2 and VEGFR3-expression was higher in ccrcc2-tumors compared to others. Expression of genes involved in angiogenesis and in the immune-suppressive microenvironment was not directly correlated nor anti-correlated. In tumors with a bi-allelic PBRM1-inactivation, HIF2A, VEGFA, VEGFR1 and VEGFR2-expression were higher compared to tumors with 1 or 2 functional PBRM1-alleles. This did not translate in different outcome on sunitinib. Conclusions: Tumoral expression of genes involved in the HIF-VEGF-VEGFR proangiogenic pathway, especially VEGFR2, is associated with favorable outcome on sunitinib in metastatic ccRCC. Expression of these genes was high in the molecular ccrcc2-subgroup, known to be sensitive to sunitinib. These findings could be used for patient selection in future clinical trials.
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Hamada, Koichi, Yuichi Oike, Nobuyuki Takakura, Yasuhiro Ito, Lotta Jussila, Daniel J. Dumont, Kari Alitalo et Toshio Suda. « VEGF-C signaling pathways through VEGFR-2 and VEGFR-3 in vasculoangiogenesis and hematopoiesis ». Blood 96, no 12 (1 décembre 2000) : 3793–800. http://dx.doi.org/10.1182/blood.v96.12.3793.
Texte intégralRésumé :
Abstract Signaling by vascular endothelial growth factors (VEGFs) through VEGF receptors (VEGFRs) plays important roles in vascular development and hematopoiesis. The authors analyzed the function of VEGF-C signaling through both VEGFR-2 and VEGFR-3 in vasculoangiogenesis and hematopoiesis using a coculture of para-aortic splanchnopleural mesoderm (P-Sp) explants from mouse embryos with stromal cells (OP9). Vasculogenesis and angiogenesis were evaluated by the extent of vascular bed and network formation, respectively. Addition of VEGF-C to the P-Sp culture enhanced vascular bed formation and suppressed definitive hematopoiesis. Both vascular bed and network formations were completely suppressed by addition of soluble VEGFR-1–Fc competitor protein. Formation of vascular beds but not networks could be rescued by VEGF-C in the presence of the competitor, while both were rescued by VEGF-A. VEGFR-3–deficient embryos show the abnormal vasculature and severe anemia. Consistent with these in vivo findings, vascular bed formation in the P-Sp from the VEGFR-3–deficient embryos was enhanced to that in wild-type or heterozygous embryos, and hematopoiesis was severely suppressed. When VEGFR-3–Fc chimeric protein was added to trap endogenous VEGF-C in the P-Sp culture of the VEGFR-3–deficient embryos, vascular bed formation was suppressed and hematopoiesis was partially rescued. These results demonstrate that because VEGF-C signaling through VEGFR-2 works synergistically with VEGF-A, the binding of VEGF-C to VEGFR-3 consequently regulates VEGFR-2 signaling. In VEGFR-3–deficient embryos, an excess of VEGF-C signals through VEGFR-2 induced the disturbance of vasculogenesis and hematopoiesis during embryogenesis. This indicates that elaborated control through VEGFR-3 signaling is critical in vasculoangiogenesis and hematopoiesis.
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Mouawad, R., C. Soubrane et D. Khayat. « Prognostic relevance of pretreatment soluble vascular endothelial growth factors (A,C,D) and their receptors (R1, R2, and R3) in advanced melanoma patients ». Journal of Clinical Oncology 25, no 18_suppl (20 juin 2007) : 8540. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.8540.
Texte intégralRésumé :
8540 Background and aims: Circulating vascular endothelial growth factors (VEGFs) and their receptors (VEGFRs) were described as prognostic factors in several cancers. The aim of this study is to evaluate the prognostic values of these parameters in metastatic malignant melanoma diseases. Methods and Patients: Using enzyme-linked immunosorbent assays, VEGFs (A, C, D) and their receptors (1, 2, and 3) were measured in sera of 75 patients with metastatic malignant melanoma in comparison to 30 healthy controls. Disease free survival (DFS) and overall survival (OS) were calculated from the beginning of the treatment until either the progression or the death and analyzed using the Kaplan-Meier method. Results: Pretreatment median sVEGF-A, sVEGF-C as well as VEGFR-3 levels were significantly higher in MMM patients as compared to healthy ones p=0.0017, p=0.005, p<0.00001 respectively). None of the studied markers correlated with gender, age or LDH levels. An inverse correlation between soluble VEGFR-2 and VEGF-D levels was observed (r=−0.33 p=0.040). High soluble VEGF-C and VEGFR-3 were correlated to high tumor burden (p=0.02, p=0.045). However, a relationship with lymph node metastasis was observed with sVEGF-A but not with sVEGFR-3. As shown by univariate analysis, only elevated levels of sVEGF-R1 concentration were found to exert a significantly unfavorable impact on both disease-free (χ2=6.64, p= 0.014) and overall survival (χ2=8.03, p= 0.0046). Conclusions: Our results suggest that, in metastatic malignant melanoma patients, soluble VEGF-A and VEGF-R3 pretreatment levels may prospectively identify high-risk patients with a worse prognosis; serum VEGFR-1 level may be a predictive factor of time to progression and overall survival. A multivariate analysis (Cox test) is ongoing in order to confirm if this parameter is an independent prognostic factor. No significant financial relationships to disclose.
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Sugao, Toshihiko, Yoko Oka, Haruko Tashiro, Ryosuke Shirasaki, Nobu Akiyama, Kazuo Kawasugi et Naoki Shirafuji. « VEGF Autocrine System Is Demonstrated in Some of Acute Promyelocytic Leukemia Cases : Relationship to WBC Count at the Disease Onset. » Blood 114, no 22 (20 novembre 2009) : 4127. http://dx.doi.org/10.1182/blood.v114.22.4127.4127.
Texte intégralRésumé :
Abstract Abstract 4127 Aims: In acute promyelocytic leukemia (M3), a prominent production of vascular endothelial growth factor (VEGF) is reported, and the obvious angiogenesis is observed in bone marrow specimens; however, VEGF receptors (VEGFRs) are not expressed in M3 cells in general. We analyzed VEGF systems in M3 blasts. Materials and Methods: Bone marrow cells were obtained from informed M3 patients, whose mononuclear cells were prepared with density-sedimentation method. Cells were cultured for one day for the elimination of an adherent cell-fraction. RNA was extracted from the non-adherent mononuclear cell-fraction, and cDNA was synthesized. Reverse transcription-polymerase chain reaction (RT-PCR) was performed to determine the expression of VEGF and VEGFRs. When the expression of VEGFR type-1 and -2 was demonstrated with RT-PCR, cells were analyzed on the protein level with FACS. VEGF-A levels in sera and in the conditioned media from the cultured M3 cells were determined with ELISA kit. When M3 blasts expressed VEGFR type-1, -2, and also secreted VEGF-A, a growth-inhibition by anti-VEGF antibody was assayed in in vitro cultures. Results and Discussion: In all 25 cases examined VEGF-A production was observed, in which VEGFR type-3 was not expressed in any cases. VEGFR type-1 and -2 were expressed in 3 cases, in all of which WBC count at the onset of the disease was above 20,000/μl. When VEGF antibody was added to the blast cell-cultures, the cell-growth was inhibited significantly. These observations indicate that VEGF system works on proliferation in a few of M3 cases with hyper-leukocytosis. Disclosures: No relevant conflicts of interest to declare.
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Donnem, T., S. Al-Saad, K. Al-Shibli, M. P. Delghandi, M. Persson, M. Nilsen, L. T. Busund et R. M. Bremnes. « Prognostic impact of angiogenic markers in tumor and stromal cells in non-small cell lung cancer (NSCLC) ». Journal of Clinical Oncology 25, no 18_suppl (20 juin 2007) : 10596. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.10596.
Texte intégralRésumé :
10596 Background: The vascular endothelial growth factors (VEGFs) -A, -C, -D and the vascular endothelial growth factor Receptors (VEGFRs) -1, -2 and -3 are important molecular markers in angiogenesis and lymphangiogenesis. This study elucidates the prognostic significance of these molecular markers in tumor cells as well as in the tumor stroma of resected NSCLC tumors. Methods: Tumor tissue samples from 335 resected patients with stage I to IIIA were obtained and tissue microarrays were constructed from duplicate cores of tumor cells and surrounding stromal tissue from each resected specimen. Immunohistochemistry was used to evaluate the expression of each molecular marker. Results: In univariate analyses, high tumor cell expression of VEGF-A (P = .0005), VEGFR-1 (P = .013), VEGFR-2 (P = .006) and VEGFR-3 (P = .0003), were negative prognostic indicators for disease-specific survival (DSS). The most significant correlations between angiogenic marker expression and DSS were observed in patients with T2 stage and/or with sqamous cell carcinomas. In tumor stroma, however, high expression of VEGF-A (P = .017), VEGF-C (P = .003), VEGF-D (P = .009), VEGFR-1 (P = .01) and VEGFR-2 (P = .019), correlated with good prognosis. In multivariate analyses, high expression in tumor cells of VEGFR-3 (P = .007) was an independent negative prognostic factor for DSS, whereas high VEGF-C (P = .004) expression in stromal cells had an independent positive impact on survival. Conclusions: While high tumor cell expression of VEGFR-3 is an independent predictor of reduced survival in primary NSCLC, high VEGF-C expression in stromal cells is, in contrast, a favorable independent prognostic indicator. No significant financial relationships to disclose.
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Wimberger, Pauline, Issam Chebouti, Jan Dominik Kuhlmann, Rainer Kimmig, Eberhart Kuhlisch, Robert Lachmann et Sabine Kasimir-Bauer. « Clinical relevance of VEGF-receptor status in primary ovarian cancer : A pilot study for future biomarker analyses. » Journal of Clinical Oncology 31, no 15_suppl (20 mai 2013) : 5556. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.5556.
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5556 Background: Antiangiogenic treatment in addition to platinum/taxane based chemotherapy was shown to improve progression-free survival in first- and second-line chemotherapy in ovarian cancer patients. Predictive markers for antiangiogenic treatment are of high interest. Therefore we investigated VEGF-receptor (VEGFR) expression as possible biomarker candidate in primary ovarian cancer tissue and its clinical impact. Methods: A total of 82 patients with primary ovarian cancer were enrolled into this study. Primary tumor tissue was analyzed for the expression of VEGFR1, VEGFR2 and VEGFR3 by immunhistochemistry. Moreover, the presence of circulating tumor cells (CTC) in the blood was detected by immunomagnetic enrichment and multiplex reverse transcriptase-polymerase chain reaction (Adnatest Ovarian Cancer, Adnagen). Disseminated tumor cells (DTC) in the BM were identified by immunocytochemistry using the pancytokeratin antibodyA45B/B3 and subsequent automatic detection based on staining and cytomorphology. Results: Positivity for at least one VEGFR was observed in 43% of cases. The positivity rates for VEGFR1, -2 and -3 were 34%, 17% and 27%, respectively. VEGFR-status of the primary tumor neither correlated with established clinicopathogical parameters (age, FIGO-stage, nodal status, grading, histological subtype) nor with the presence of CTC or DTC. In addition, VEGFR-status does not provide prognostic significance in regard to progression-free and overall survival (OS). Nevertheless, a trend was observed that patients, being positive for VEGFR3 at primary diagnosis, were more likely to experience suboptimal debulking (p = 0.074). CTC-positivity after adjuvant therapy significantly correlated with OS, but multivariable analysis showed only residual tumor as prognostic factor for OS. Conclusions: The VEGFR-family, albeit frequently expressed in our patient cohort, provided neither prognostic nor predictive relevance, but could probably be a predictor for debulking efficiency. The implementation of VEGFR-status into future biomarker studies should carefully be considered.
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Ghasemali, Samaneh, Safar Farajnia, Abolfazl Barzegar, Mohammad Rahmati, Babak Negahdari, Leila Rahbarnia et Hamidreza Yousefi-nodeh. « Rational Design of Anti-Angiogenic Peptides to Inhibit VEGF/VEGFR2 Interactions for Cancer Therapeutics ». Anti-Cancer Agents in Medicinal Chemistry 22, no 10 (juin 2022) : 2026–35. http://dx.doi.org/10.2174/1871520621666211118104051.
Texte intégralRésumé :
Background: Angiogenesis is a critical physiological process that plays a key role in tumor progression, metastatic dissemination, and invasion. In the last two decades, the vascular endothelial growth factor (VEGF) signaling pathway has been the area of extensive researches. VEGF executes its special effects by binding to vascular endothelial growth factor receptors (VEGFRs), particularly VEGFR-2. Objective: The inhibition of VEGF/VEGFR2 interaction is known as an effective cancer therapy strategy. The current study pointed to design and model an anti-VEGF peptide based on VEGFR2 binding regions. Method: The large-scale peptide mutation screening was used to achieve a potent peptide with high binding affinity to VEGF for possible application in inhibition of VEGF/VEGFR2 interaction. The AntiCP and Peptide Ranker servers were used to generate the possible peptides library with anticancer activities and prediction of peptides bioactivity. Then, the interaction of VEGF and all library peptides were analyzed using Hex 8.0.0 and ClusPro tools. A number of six peptides with favorable docking scores were achieved. All of the best docking scores of peptides in complexes with VEGF were evaluated to confirm their stability, using molecular dynamics simulation (MD) with the help of the GROMACS software package. Results: As a result, two antiangiogenic peptides with 13 residues of PepA (NGIDFNRDFFLGL) and PepC (NGIDFNRDKFLFL) were achieved and introduced to inhibit VEGF/VEGFR2 interactions Conclusions: In summary, this study provided new insights into peptide-based therapeutics development for targeting VEGF signaling pathway in tumor cells. PepA and PepC are recommended as potentially promising anticancer agents for further experimental evaluations.
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Zhang, Cheng, Ning Wang, Hor-Yue Tan, Wei Guo, Sha Li et Yibin Feng. « Targeting VEGF/VEGFRs Pathway in the Antiangiogenic Treatment of Human Cancers by Traditional Chinese Medicine ». Integrative Cancer Therapies 17, no 3 (28 mai 2018) : 582–601. http://dx.doi.org/10.1177/1534735418775828.
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Bearing in mind the doctrine of tumor angiogenesis hypothesized by Folkman several decades ago, the fundamental strategy for alleviating numerous cancer indications may be the strengthening application of notable antiangiogenic therapies to inhibit metastasis-related tumor growth. Under physiological conditions, vascular sprouting is a relatively infrequent event unless when specifically stimulated by pathogenic factors that contribute to the accumulation of angiogenic activators such as the vascular endothelial growth factor (VEGF) family and basic fibroblast growth factor (bFGF). Since VEGFs have been identified as the principal cytokine to initiate angiogenesis in tumor growth, synthetic VEGF-targeting medicines containing bevacizumab and sorafenib have been extensively used, but prominent side effects have concomitantly emerged. Traditional Chinese medicines (TCM)–derived agents with distinctive safety profiles have shown their multitarget curative potential by impairing angiogenic stimulatory signaling pathways directly or eliciting synergistically therapeutic effects with anti-angiogenic drugs mainly targeting VEGF-dependent pathways. This review aims to summarize ( a) the up-to-date understanding of the role of VEGF/VEGFR in correlation with proangiogenic mechanisms in various tissues and cells; ( b) the elaboration of antitumor angiogenesis mechanisms of 4 representative TCMs, including Salvia miltiorrhiza, Curcuma longa, ginsenosides, and Scutellaria baicalensis; and ( c) circumstantial clarification of TCM-driven therapeutic actions of suppressing tumor angiogenesis by targeting VEGF/VEGFRs pathway in recent years, based on network pharmacology.
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Kinget, Lisa, Eduard Roussel, Annelies Verbiest, Maarten Albersen, Cristina Rodríguez-Antona, Osvaldo Graña-Castro, Lucía Inglada-Pérez et al. « MicroRNAs Targeting HIF-2α, VEGFR1 and/or VEGFR2 as Potential Predictive Biomarkers for VEGFR Tyrosine Kinase and HIF-2α Inhibitors in Metastatic Clear-Cell Renal Cell Carcinoma ». Cancers 13, no 12 (21 juin 2021) : 3099. http://dx.doi.org/10.3390/cancers13123099.
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Metastatic clear-cell renal cell carcinoma (m-ccRCC) is characterized by increased hypoxia-induced factor (HIF)-2α and vascular endothelial growth factor receptor (VEGFR)-dependent angiogenesis through loss of function of the von Hippel–Lindau protein. VEGFR tyrosine kinase inhibitors (VEGFR-TKIs) are a cornerstone of m-ccRCC treatment, and new treatments targeting HIF-2α are currently under investigation. However, predictive biomarkers for these treatments are lacking. In this retrospective cohort study including 109 patients treated with VEGFR-targeted therapies as first-line treatment, we aimed to study the possible predictive function of microRNAs (miRNAs) targeting HIF-2α, VEGFR1 and VEGFR2. We selected miRNAs inversely correlated with HIF-2α, VEGFR1 and/or VEGFR2 expression and with predicted target sites in the respective genes and subsequently studied their impact on therapeutic outcomes. We identified four miRNAs (miR-34c-5p, miR-221-3p, miR-222-3p and miR-3529-3p) inversely correlated with VEGFR1 and/or VEGFR2 expression and associated with tumor shrinkage and progression-free survival (PFS) upon treatment with VEGFR-TKIs, highlighting the potential predictive value of these miRNAs. Moreover, we identified three miRNAs (miR-185-5p, miR-223-3p and miR-3529-3p) inversely correlated with HIF-2α expression and associated with tumor shrinkage and PFS upon treatment with VEGFR-TKIs. These three miRNAs can have a predictive value not only upon treatment with VEGFR-TKIs but possibly also upon treatment with the upcoming HIF-2α inhibitor belzutifan.
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Kilvaer, Thomas K., Andrej Valkov, Sveinung Sorbye, Eivind Smeland, Roy M. Bremnes, Lill-Tove Busund et Tom Donnem. « Profiling of VEGFs and VEGFRs as Prognostic Factors in Soft Tissue Sarcoma : VEGFR-3 Is an Independent Predictor of Poor Prognosis ». PLoS ONE 5, no 12 (14 décembre 2010) : e15368. http://dx.doi.org/10.1371/journal.pone.0015368.
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Shaik, Faheem, Gary Cuthbert, Shervanthi Homer-Vanniasinkam, Stephen Muench, Sreenivasan Ponnambalam et Michael Harrison. « Structural Basis for Vascular Endothelial Growth Factor Receptor Activation and Implications for Disease Therapy ». Biomolecules 10, no 12 (15 décembre 2020) : 1673. http://dx.doi.org/10.3390/biom10121673.
Texte intégralRésumé :
Vascular endothelial growth factors (VEGFs) bind to membrane receptors on a wide variety of cells to regulate diverse biological responses. The VEGF-A family member promotes vasculogenesis and angiogenesis, processes which are essential for vascular development and physiology. As angiogenesis can be subverted in many disease states, including tumour development and progression, there is much interest in understanding the mechanistic basis for how VEGF-A regulates cell and tissue function. VEGF-A binds with high affinity to two VEGF receptor tyrosine kinases (VEGFR1, VEGFR2) and with lower affinity to co-receptors called neuropilin-1 and neuropilin-2 (NRP1, NRP2). Here, we use a structural viewpoint to summarise our current knowledge of VEGF-VEGFR activation and signal transduction. As targeting VEGF-VEGFR activation holds much therapeutic promise, we examine the structural basis for anti-angiogenic therapy using small-molecule compounds such as tyrosine kinase inhibitors that block VEGFR activation and downstream signalling. This review provides a rational basis towards reconciling VEGF and VEGFR structure and function in developing new therapeutics for a diverse range of ailments.
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Yang, Yan, Peng Xie, Yarden Opatowsky et Joseph Schlessinger. « Direct contacts between extracellular membrane-proximal domains are required for VEGF receptor activation and cell signaling ». Proceedings of the National Academy of Sciences 107, no 5 (11 janvier 2010) : 1906–11. http://dx.doi.org/10.1073/pnas.0914052107.
Texte intégralRésumé :
Structural analyses of the extracellular region of stem cell factor (SCF) receptor (also designated KIT) in complex with SCF revealed a sequence motif in a loop in the fourth Ig-like domain (D4) that is responsible for forming homotypic receptor contacts and for ligand-induced KIT activation and cell signaling. An identical motif was identified in the most membrane-proximal seventh Ig-like domain (D7) of vascular endothelial growth factor receptor 1 (VEGFR1), VEGFR2, and VEGFR3. In this report we demonstrate that ligand-induced tyrosine autophosphorylation and cell signaling via VEGFR1 or VEGFR2 harboring mutations in critical residues (Arg726 or Asp731) in D7 are strongly impaired. We also describe the crystal structure of D7 of VEGFR2 to a resolution of 2.7 Å. The structure shows that homotypic D7 contacts are mediated by salt bridges and van der Waals contacts formed between Arg726 of one protomer and Asp731 of the other protomer. The structure of D7 dimer is very similar to the structure of D4 dimers seen in the crystal structure of KIT extracellular region in complex with SCF. The high similarity between VEGFR D7 and KIT D4 in both structure and function provides further evidence for common ancestral origins of type III and type V RTKs. It also reveals a conserved mechanism for RTK activation and a novel target for pharmacological intervention of pathologically activated RTKs.
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Korchagina, A. A., S. A. Shein, O. I. Gurina et V. P. Chekhonin. « VEGFRS IN NEOPLASTIC ANGIOGENESIS AND PROSPECTS FOR THERAPY ОF BRAIN TUMORS ». Annals of the Russian academy of medical sciences 68, no 11 (12 novembre 2013) : 104–14. http://dx.doi.org/10.15690/vramn.v68i11.851.
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Glioblastoma (GBM) is the most common type of primary brain cancer that characterized by poor prognosis due to the rapid progression, active angiogenesis, enhanced tumor cell invasion and the emergence of resistance toward conventional therapy. In this connection, nowadays, new approaches for selective inhibition of crucial steps in tumor progression are actively developing. The key feature of tumor growth and development is angiogenesis. VEGF and its receptor VEGFR2 play the pivotal role in regulation of tumor vessel formation. Therefore, VEGFR2, as the main receptor of VEGF’s pro-angiogenic signal transducer, is a promising molecular target for anti-angiogenic therapy. There is evidence that inhibitors of VEGF and VEGFR2 reduce endothelial cell proliferation, migration and survival that lead to regression of vessel density and decrease vascular permeability, thereby slowing tumor growth. Currently, a number of VEGFR2 inhibitors are under clinical trials (ramucirumab, cediranib) and several were approved (sunitinib, sorafenib). Despite the promising results of preclinical studies, the efficacy of antiangiogenic drugs in the clinical practice is significantly lower, mainly, due to rapid adaptation of malignant cells that consists of alternative pro-angiogenic pathways activation, recruitment of endothelial progenitor cells from bone marrow and increasing of the invasive growth. Given the diversity of pro-angiogenic mechanisms, enhancement of the efficacy of tumor therapy could be achieved by specific inhibition of VEGFR2 functions that will be supplemented by other antiangiogenic drugs (anti-VEGF,-PlGF,-HIF1α). In addition, multitargeting therapy should focus on the combined inhibition of angiogenesis, invasion, metastasis, proliferation and survival of tumor cells.
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Trapiella-Alfonso, Laura, Sylvain Broussy, Wang-Qing Liu, Michel Vidal, Edouard Lecarpentier, Vassilis Tsatsaris et Nathalie Gagey-Eilstein. « Colorimetric immunoassays for the screening and specificity evaluation of molecules disturbing VEGFs/VEGFRs interactions ». Analytical Biochemistry 544 (mars 2018) : 114–20. http://dx.doi.org/10.1016/j.ab.2017.12.029.
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Ankita, P., Z. Romana et A. Sanjar. « Benzimidazoles as Anti-VEGFRs : A Review ». International Journal for Pharmaceutical Research Scholars 7, no 1 (2018) : 82–95. http://dx.doi.org/10.31638/ijprs.v7.i1.00013.
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Hamerlik, Petra, Justin D. Lathia, Rikke Rasmussen, Qiulian Wu, Jirina Bartkova, MyungHee Lee, Pavel Moudry et al. « Autocrine VEGF–VEGFR2–Neuropilin-1 signaling promotes glioma stem-like cell viability and tumor growth ». Journal of Experimental Medicine 209, no 3 (5 mars 2012) : 507–20. http://dx.doi.org/10.1084/jem.20111424.
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Although vascular endothelial growth factor (VEGF) receptor 2 (VEGFR2) is traditionally regarded as an endothelial cell protein, evidence suggests that VEGFRs may be expressed by cancer cells. Glioblastoma multiforme (GBM) is a lethal cancer characterized by florid vascularization and aberrantly elevated VEGF. Antiangiogenic therapy with the humanized VEGF antibody bevacizumab reduces GBM tumor growth; however, the clinical benefits are transient and invariably followed by tumor recurrence. In this study, we show that VEGFR2 is preferentially expressed on the cell surface of the CD133+ human glioma stem-like cells (GSCs), whose viability, self-renewal, and tumorigenicity rely, at least in part, on signaling through the VEGF-VEGFR2–Neuropilin-1 (NRP1) axis. We find that the limited impact of bevacizumab-mediated VEGF blockage may reflect ongoing autocrine signaling through VEGF–VEGFR2–NRP1, which is associated with VEGFR2–NRP1 recycling and a pool of active VEGFR2 within a cytosolic compartment of a subset of human GBM cells. Whereas bevacizumab failed to inhibit prosurvival effects of VEGFR2-mediated signaling, GSC viability under unperturbed or radiation-evoked stress conditions was attenuated by direct inhibition of VEGFR2 tyrosine kinase activity and/or shRNA-mediated knockdown of VEGFR2 or NRP1. We propose that direct inhibition of VEGFR2 kinase may block the highly dynamic VEGF–VEGFR2–NRP1 pathway and inspire a GBM treatment strategy to complement the currently prevalent ligand neutralization approach.
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Alarcón, Tomás, et Karen M. Page. « Mathematical models of the VEGF receptor and its role in cancer therapy ». Journal of The Royal Society Interface 4, no 13 (21 novembre 2006) : 283–304. http://dx.doi.org/10.1098/rsif.2006.0170.
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We present an analysis of a stochastic model of the vascular endothelial growth factor (VEGF) receptor. This analysis addresses the contribution of ligand-binding-induced oligomerization, activation of src-homology 2 domain-carrying kinases and receptor internalization in the overall behaviour of the VEGF/VEGF receptor (VEGFR) system. The analysis is based upon a generalization of a Wentzel–Kramers–Brillouin (WKB) approximation of the solution of the corresponding master equation. We predict that tumour-mediated overexpression of VEGFRs in the endothelial cells (ECs) of tumour-engulfed vessels leads to an increased sensitivity of the ECs to low concentrations of VEGF, thus endowing the tumour with increased resistance to anti-angiogenic treatment.
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Robinson, C. J., et S. E. Stringer. « The splice variants of vascular endothelial growth factor (VEGF) and their receptors ». Journal of Cell Science 114, no 5 (1 mars 2001) : 853–65. http://dx.doi.org/10.1242/jcs.114.5.853.
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Vascular endothelial growth factor (VEGF) is a secreted mitogen highly specific for cultured endothelial cells. In vivo VEGF induces microvascular permeability and plays a central role in both angiogenesis and vasculogenesis. VEGF is a promising target for therapeutic intervention in certain pathological conditions that are angiogenesis dependent, most notably the neovascularisation of growing tumours. Through alternative mRNA splicing, a single gene gives rise to several distinct isoforms of VEGF, which differ in their expression patterns as well as their biochemical and biological properties. Two VEGF receptor tyrosine kinases (VEGFRs) have been identified, VEGFR-1 (Flt-1) and VEGFR-2 (KDR/Flk-1). VEGFR-2 seems to mediate almost all observed endothelial cell responses to VEGF, whereas roles for VEGFR-1 are more elusive. VEGFR-1 might act predominantly as a ligand-binding molecule, sequestering VEGF from VEGFR-2 signalling. Several isoform-specific VEGF receptors exist that modulate VEGF activity. Neuropilin-1 acts as a co-receptor for VEGF(165), enhancing its binding to VEGFR-2 and its bioactivity. Heparan sulphate proteoglycans (HSPGs), as well as binding certain VEGF isoforms, interact with both VEGFR-1 and VEGFR-2. HSPGs have a wide variety of functions, such as the ability to partially restore lost function to damaged VEGF(165) and thereby prolonging its biological activity.
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Zhao, Bin, Peimin Yang, Jing Yang et Duan Cai. « A Randomized Trial of Somatostatin to Regulate the VEGFs/VEGFRs in Patients with Gastric Cancer ». Hepatogastroenterology 58, no 109 (août 2011) : 1425–30. http://dx.doi.org/10.5754/hge10749.
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Carrillo Arias, F., E. Carrillo de Santa Pau, E. Pérez Rodríguez, M. Toledo Lobo',, I. Sánchez Hernandez, G. Muñoz Molina, I. Muguruza Trueba, P. Navio Martin, S. Dominguez Reboiras et E. Caso Peláez. « P-013 Expression of VEGFs and VEGFRs according to TNMc and TNMq. Reality or fiction ? » Lung Cancer 49 (juillet 2005) : S118. http://dx.doi.org/10.1016/s0169-5002(05)80507-0.
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Carrillo de Santa Pau, E., M. Toledo Lobo, E. Caso Peláez, E. Pérez Rodríguez, I. Sánchez Hernández, G. Muñoz Molina, I. Muguruza Trueba, S. Sacristán, G. Gómez López et F. Carillo Arias. « P-014 Discriminate capacity of VEGFs and VEGFRs in lung cancer. Arethe different subtypes outstanding ? » Lung Cancer 49 (juillet 2005) : S118—S119. http://dx.doi.org/10.1016/s0169-5002(05)80508-2.
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Wu, Florence T. H., Marianne O. Stefanini, Feilim Mac Gabhann, Christopher D. Kontos, Brian H. Annex et Aleksander S. Popel. « Computational kinetic model of VEGF trapping by soluble VEGF receptor-1 : effects of transendothelial and lymphatic macromolecular transport ». Physiological Genomics 38, no 1 (juin 2009) : 29–41. http://dx.doi.org/10.1152/physiolgenomics.00031.2009.
Texte intégralRésumé :
Vascular endothelial growth factor (VEGF) signal transduction through the cell surface receptors VEGFR1 and VEGFR2 regulates angiogenesis—the growth of new capillaries from preexistent microvasculature. Soluble VEGF receptor-1 (sVEGFR1), a nonsignaling truncated variant of VEGFR1, has been postulated to inhibit angiogenic signaling via direct sequestration of VEGF ligands or dominant-negative heterodimerization with surface VEGFRs. The relative contributions of these two mechanisms to sVEGFR1's purported antiangiogenic effects in vivo are currently unknown. We previously developed a computational model for predicting the compartmental distributions of VEGF and sVEGFR1 throughout the healthy human body by simulating the molecular interaction networks of the VEGF ligand-receptor system as well as intercompartmental macromolecular biotransport processes. In this study, we decipher the dynamic processes that led to our prior prediction that sVEGFR1, through its ligand trapping mechanism alone, does not demonstrate significant steady-state antiangiogenic effects. We show that sVEGFR1-facilitated tissue-to-blood shuttling of VEGF accounts for a counterintuitive and drastic elevation in plasma free VEGF concentrations after both intramuscular and intravascular sVEGFR1 infusion. While increasing intramuscular VEGF production reduces free sVEGFR1 levels through increased VEGF-sVEGFR1 complex formation, we demonstrate a competing and opposite effect in which increased VEGF occupancy of neuropilin-1 (NRP1) and the corresponding reduction in NRP1 availability for internalization of sVEGFR1 unexpectedly increases free sVEGFR1 levels. In conclusion, dynamic intercompartmental transport processes give rise to our surprising prediction that VEGF trapping alone does not account for sVEGFR1's antiangiogenic potential. sVEGFR1's interactions with cell surface receptors such as NRP1 are also expected to affect its molecular interplay with VEGF.
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Masłowska, Katarzyna, Paweł Krzysztof Halik, Dagmara Tymecka, Aleksandra Misicka et Ewa Gniazdowska. « The Role of VEGF Receptors as Molecular Target in Nuclear Medicine for Cancer Diagnosis and Combination Therapy ». Cancers 13, no 5 (3 mars 2021) : 1072. http://dx.doi.org/10.3390/cancers13051072.
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One approach to anticancer treatment is targeted anti-angiogenic therapy (AAT) based on prevention of blood vessel formation around the developing cancer cells. It is known that vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptors (VEGFRs) play a pivotal role in angiogenesis process; hence, application of angiogenesis inhibitors can be an effective approach in anticancer combination therapeutic strategies. Currently, several types of molecules have been utilised in targeted VEGF/VEGFR anticancer therapy, including human VEGF ligands themselves and their derivatives, anti-VEGF or anti-VEGFR monoclonal antibodies, VEGF binding peptides and small molecular inhibitors of VEGFR tyrosine kinases. These molecules labelled with diagnostic or therapeutic radionuclides can become, respectively, diagnostic or therapeutic receptor radiopharmaceuticals. In targeted anti-angiogenic therapy, diagnostic radioagents play a unique role, allowing the determination of the emerging tumour, to monitor the course of treatment, to predict the treatment outcomes and, first of all, to refer patients for AAT. This review provides an overview of design, synthesis and study of radiolabelled VEGF/VEGFR targeting and imaging agents to date. Additionally, we will briefly discuss their physicochemical properties and possible application in combination targeted radionuclide tumour therapy.
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Stevens, Megan, et Sebastian Oltean. « Modulation of Receptor Tyrosine Kinase Activity through Alternative Splicing of Ligands and Receptors in the VEGF-A/VEGFR Axis ». Cells 8, no 4 (28 mars 2019) : 288. http://dx.doi.org/10.3390/cells8040288.
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Vascular endothelial growth factor A (VEGF-A) signaling is essential for physiological and pathological angiogenesis. Alternative splicing of the VEGF-A pre-mRNA gives rise to a pro-angiogenic family of isoforms with a differing number of amino acids (VEGF-Axxxa), as well as a family of isoforms with anti-angiogenic properties (VEGF-Axxxb). The biological functions of VEGF-A proteins are mediated by a family of cognate protein tyrosine kinase receptors, known as the VEGF receptors (VEGFRs). VEGF-A binds to both VEGFR-1, largely suggested to function as a decoy receptor, and VEGFR-2, the predominant signaling receptor. Both VEGFR-1 and VEGFR-2 can also be alternatively spliced to generate soluble isoforms (sVEGFR-1/sVEGFR-2). The disruption of the splicing of just one of these genes can result in changes to the entire VEGF-A/VEGFR signaling axis, such as the increase in VEGF-A165a relative to VEGF-A165b resulting in increased VEGFR-2 signaling and aberrant angiogenesis in cancer. Research into this signaling axis has recently focused on manipulating the splicing of these genes as a potential therapeutic avenue in disease. Therefore, further research into understanding the mechanisms by which the splicing of VEGF-A/VEGFR-1/VEGFR-2 is regulated will help in the development of drugs aimed at manipulating splicing or inhibiting specific splice isoforms in a therapeutic manner.
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Verdes, Doina, Roxana Popescu, Smaranda Rodica Gotia, Laura Gotia, Marioara Nicoleta Filimon et Theodoros Karabitsakos. « VEGF and VEGFRs expression in psoriasis lesions ». Current Opinion in Biotechnology 22 (septembre 2011) : S114. http://dx.doi.org/10.1016/j.copbio.2011.05.367.
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Imoukhuede, P. I., Ayotunde O. Dokun, Brian H. Annex et Aleksander S. Popel. « Endothelial cell-by-cell profiling reveals the temporal dynamics of VEGFR1 and VEGFR2 membrane localization after murine hindlimb ischemia ». American Journal of Physiology-Heart and Circulatory Physiology 304, no 8 (15 avril 2013) : H1085—H1093. http://dx.doi.org/10.1152/ajpheart.00514.2012.
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VEGF receptor (VEGFR) cell surface localization plays a critical role in transducing VEGF signaling toward angiogenic outcomes, and quantitative characterization of these parameters is critical to advancing computational models for predictive medicine. However, studies to this point have largely examined intact muscle; thus, essential data on the cellular localization of the receptors within the tissue are currently unknown. Therefore, our aims were to quantitatively analyze VEGFR localization on endothelial cells (ECs) from mouse hindlimb skeletal muscles after the induction of hindlimb ischemia, an established model for human peripheral artery disease. Flow cytometry was used to measure and compare the ex vivo surface localization of VEGFR1 and VEGFR2 on CD31+/CD34+ECs 3 and 10 days after unilateral ligation of the femoral artery. We determined that 3 days after hindlimb ischemia, VEGFR2 surface levels were decreased by 80% compared with ECs from the nonischemic limb; 10 days after ischemia, we observed a twofold increase in surface levels of the modulatory receptor, VEGFR1, along with increased proliferating cell nuclear antigen, urokinase plasminogen activator, and urokinase plasminogen activator receptor mRNA expression compared with the nonischemic limb. The significant upregulation of VEGFR1 surface levels indicates that VEGFR1 indeed plays a critical role in the ischemia-induced perfusion recovery process, a process that includes both angiogenesis and arteriogenesis. The quantification of these dissimilarities, for the first time ex vivo, provides insights into the balance of modulatory (VEGFR1) and proangiogenic (VEGFR2) receptors in ischemia and lays the foundation for systems biology approaches toward therapeutic angiogenesis.
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Reumann, Marie K., Turya Nair, Olga Strachna, Adele L. Boskey et Philipp Mayer-Kuckuk. « Production of VEGF receptor 1 and 2 mRNA and protein during endochondral bone repair is differential and healing phase specific ». Journal of Applied Physiology 109, no 6 (décembre 2010) : 1930–38. http://dx.doi.org/10.1152/japplphysiol.00839.2010.
Texte intégralRésumé :
Physiological disturbances, including temporary hypoxia, are expected to drive angiogenesis during bone repair. Evidence suggests that the angiogenic ligand vascular endothelial growth factor (VEGF)-A plays an important role in this process. We characterized the expression of two receptors that are essential for mediating VEGF signaling, VEGFR1/Flt-1 and VEGFR2/Flk-1/KDR, in a mouse rib fracture model. Their mRNA and protein levels were assessed in four healing phases, which were characterized histologically as hemorrhage formation on postfracture day (PFD) 1, inflammatory response on PFD 3, initiation of callus development on PFD 7, and the presence of a mature callus on PFD 14. Transcript was detected for VEGFR1 and VEGFR2, as well as VEGF. While mRNA expression of VEGFR1 was monophasic throughout all healing phases, VEGFR2 showed a biphasic profile with significantly increased mRNA expression during callus formation and maturation. Expression of VEGF mRNA was characterized by a more gradual increase during callus formation. The protein level for VEGFR1 was below detection sensitivity during the initial healing phase. It was then restored to a stable level, detectable through the subsequent healing phases. Hence, the VEGFR1 protein levels partially mirrored the transcript expression profile. In comparison, the protein level of VEGFR2 increased gradually during the healing phases and peaked at callus maturation. This correlated well with the transcriptional expression of VEGFR2. Intact bone from age-matched male mice had considerable protein levels of VEGFR1 and VEGF, but no detectable VEGFR2. Together, these findings uncovered expression signatures of the VEGF-VEGFR axis in endochondral bone repair.
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Durante, Cosimo, Giovanni Tallini, Efisio Puxeddu, Marialuisa Sponziello, Sonia Moretti, Claudia Ligorio, Antonio Cavaliere et al. « BRAFV600E mutation and expression of proangiogenic molecular markers in papillary thyroid carcinomas ». European Journal of Endocrinology 165, no 3 (septembre 2011) : 455–63. http://dx.doi.org/10.1530/eje-11-0283.
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ObjectiveTyrosine kinase inhibitors (TKIs) are evaluated for treatment of radioiodine refractory thyroid cancer. Their effects in this setting are based on blockade of proangiogenic signaling mediated by receptors for vascular endothelial growth factors (VEGFs) and platelet-derived growth factors (PDGF). Most TKIs also block other cancer-relevant kinases, such as B-type Raf kinase (BRAF), which are constitutively activated in approximately half of papillary thyroid carcinomas (PTCs), but the impact of these effects is not clear.DesignThe aim of our study was to investigate the impact of BRAFV600E on proangiogenic gene expression and microvascular features of PTCs.MethodsmRNA levels for VEGFA, VEGF receptors, and coreceptors (VEGFRs 1, 2, and 3, neuropilin-1), and PDGF receptor β (PDGFRβ or PDGFRB) were measured with real-time PCR in BRAFV600E (n=55) and wild-type BRAF (BRAF-wt; n=35) PTCs. VEGF and VEGFR protein expression and microvessel densities (MVD) and lymphatic vessel densities (LVDs) were assessed by immunohistochemistry in 22 of the 90 PTCs (including 11 BRAFV600E cases). Angiogenic gene expression was also studied in vitro after induction/silencing of the BRAFV600E mutation in thyrocyte lines.ResultsTranscript levels of proangiogenic factors were significantly lower in BRAFV600E PTCs versus BRAF-wt PTCs (P<0.0001), but MVD and LVDs were not significantly different. VEGFA mRNA levels in thyroid cell lines decreased when BRAFV600E mutation was induced (P=0.01) and increased when it was silenced (P=0.01).ConclusionsCompared with BRAF-wt PTCs, those harboring BRAFV600E exhibit downregulated VEGFA, VEGFR, and PDGFRβ expression, suggesting that the presence of BRAF mutation does not imply a stronger prediction of response to drugs targeting VEGF and PDGFB signaling pathways.
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Bruns, Alexander F., Leyuan Bao, John H. Walker et Sreenivasan Ponnambalam. « VEGF-A-stimulated signalling in endothelial cells via a dual receptor tyrosine kinase system is dependent on co-ordinated trafficking and proteolysis ». Biochemical Society Transactions 37, no 6 (19 novembre 2009) : 1193–97. http://dx.doi.org/10.1042/bst0371193.
Texte intégralRésumé :
The mammalian endothelium expresses two related but distinct receptor tyrosine kinases, VEGFR1 and VEGFR2 [VEGF (vascular endothelial growth factor) receptor 1 and 2], that regulate the vascular response to a key cytokine, VEGF-A. In the present review, we suggest a model for integrating the signals from these receptor tyrosine kinases by co-ordinating the spatial and temporal segregation of these membrane proteins linked to distinct signalling outputs associated with each intracellular location. Activation of pro-angiogenic VEGFR2 stimulates a programme of tyrosine phosphorylation, ubiquitination and proteolysis. This is linked to ESCRT (endosomal sorting complex required for transport)-mediated recognition of activated VEGFR2 and sorting in endosomes before arrival in lysosomes for terminal degradation. In addition, Rab GTPases regulate key events in VEGFR2 trafficking between the plasma membrane, early and late endosomes, with distinct roles for Rab4a, Rab5a and Rab7a. Manipulation of GTPase levels affects not only VEGFR2 activation and intracellular signalling, but also functional outputs such as VEGF-A-stimulated endothelial cell migration. In contrast, VEGFR1 displays stable Golgi localization that can be perturbed by cell stimuli that elevate cytosolic Ca2+ ion levels. One model is that VEGFR1 translocates from the trans-Golgi network to the plasma membrane via a calcium-sensitive trafficking step. This allows rapid and preferential sequestration of VEGF-A by the higher-affinity VEGFR1, thus blocking further VEGFR2 activation. Recycling or degradation of VEGFR1 allows resensitization of the VEGFR2-dependent signalling pathway. Thus a dual VEGFR system with a built-in negative-feedback loop is utilized by endothelial cells to sense a key cytokine in vascular tissues.