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T Azad, H J Janse van Rensburg, E D Lightbody, B Neveu, A Champagne, A Ghaffari, V R Kay, Y Hao, H Shen, B Yeung, B A Croy, K L Guan, F Pouliot, J Zhang, C J B Nicol, X Yang
The Hippo pathway is a central regulator of tissue development and homeostasis, and has been reported to have a role during vascular development. Here we develop a bioluminescence-based biosensor that monitors the activity of the Hippo core component LATS kinase. Using this biosensor and a library of small molecule kinase inhibitors, we perform a screen for kinases modulating LATS activity and identify VEGFR as an upstream regulator of the Hippo pathway. We find that VEGFR activation by VEGF triggers PI3K/MAPK signaling, which subsequently inhibits LATS and activates the Hippo effectors YAP and TAZ...
March 13, 2018: Nature Communications
Yongchang Lai, Zhijian Zhao, Tao Zeng, Xiongfa Liang, Dong Chen, Xiaolu Duan, Guohua Zeng, Wenqi Wu
Clear cell renal cell carcinoma (ccRCC) is the most common subtype of renal cell carcinoma (RCC), and is frequently accompanied by the genetic features of von Hippel-Lindau (VHL) loss. VHL loss increases the expression of hypoxia-inducible factors (HIFs) and their targets, including epidermal growth factor (EGF), vascular endothelial growth factor (VEGF), and platelet-derived growth factor (PDGF). The primary treatment for metastatic RCC (mRCC) is molecular-targeted therapy, especially anti-angiogenic therapy...
2018: Cancer Cell International
Athanasia Bletsa, Hisham Abdalla, Sigbjørn Løes, Ellen Berggreen
BACKGROUND: The lymphatic growth factors vascular endothelial growth factor (VEGF) -C and -D are important for maintenance and growth of lymphatic vessels (lymphangiogenesis), but their localization in human gingiva is unknown. This study investigated the expression of VEGF-C and -D in human gingiva and isolated human gingival fibroblasts (HGFs). In addition, the localization of their main receptor VEGFR-3 was explored. METHODS: Non-inflamed gingiva from 6 donors was used for immunohistochemistry or isolation of HGFs...
February 19, 2018: Journal of Periodontology
Silvia Martina Ferrari, Guido Bocci, Teresa Di Desidero, Ilaria Ruffilli, Giusy Elia, Francesca Ragusa, Anna Fioravanti, Paola Orlandi, Sabrina Rosaria Paparo, Armando Patrizio, Simona Piaggi, Concettina La Motta, Salvatore Ulisse, Enke Baldini, Gabriele Materazzi, Paolo Miccoli, Alessandro Antonelli, Poupak Fallahi
The antitumor activity of vandetanib [a multiple signal transduction inhibitor including the RET tyrosine kinase, epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF) receptor (VEGFR), ERK and with antiangiogenic activity], in primary anaplastic thyroid cancer (ATC) cells, in the human cell line 8305C [undifferentiated thyroid cancer (TC)] and in an ATC‑cell line (AF), was investigated in the present study. Vandetanib (1 and 100 nM; 1, 10, 25 and 50 µM) was tested by WST‑1, apoptosis, migration and invasion assays: in primary ATC cells, in the 8305C continuous cell line, and in AF cells; and in 8305C cells in CD nu/nu mice...
March 8, 2018: Oncology Reports
Pedro Miguel Lacal, Maria Grazia Atzori, Federica Ruffini, Lucio Tentori, Grazia Graziani
The vascular endothelial growth factor receptor-1 (VEGFR-1) is a tyrosine kinase receptor activated by the angiogenic factors VEGF‑A and placental growth factor (PlGF). While VEGF‑A binds to both VEGFR‑1 and VEGFR‑2, PlGF interacts exclusively with VEGFR‑1 triggering a signaling pathway involved in: i) tumor‑associated angiogenesis; ii) chemotaxis and invasion of the extracellular matrix (ECM) by cancer cells; and iii) mobilization of bone marrow‑derived myeloid cells that generate tumor‑associated macrophages...
March 5, 2018: Oncology Reports
Haitao Li, Yunfei Teng, Xia Xu, Jianyong Liu
The most common tumors in children are infantile hemangiomas which could cause morbidity and severe complications. The development of novel alternative drugs to treat infantile hemangiomas is necessary, since Hemangeol is the only US Food and Drug Administration-approved drug for infantile hemangiomas. However, Hemangeol has several disadvantages, including a high frequency of administration and adverse effects. Rapamycin is a well‑established antiangiogenic drug, and we have previously developed rapamycin lipid polymer nanoparticles (R‑PLNPs) as a local sustained‑release drug delivery system to achieve controlled rapamycin release and to decrease the frequency of administration and side effects of rapamycin...
February 28, 2018: International Journal of Molecular Medicine
Feng Wang, Hongyan Li, Ela Markovsky, Ryan Glass, Elisa de Stanchina, Simon N Powell, Gary K Schwartz, Adriana Haimovitz-Friedman
Recent data in our laboratory indicate that engagement of host-derived microenvironmental elements impact tumor response to single high dose radiation therapy (SDRT). In these studies we showed that microvascular endothelial damage plays a critical role in tumor response as regulator of direct lethal damage of SDRT. Using a genetic model of Acid Sphingomyelinase (ASMase)-deficient mice we showed that activation of this enzyme by SDRT-induced damage in the endothelium is mandatory for tumor cure. ASMase activation triggers ceramide-mediated apoptosis, and therein microvascular dysfunction, which increased the vulnerability of tumor cells to lethal damage by radiation...
February 6, 2018: Oncotarget
Emese Szabo, Douglas J Phillips, Miriam Droste, Andrea Marti, Titus Kretzschmar, Abdijapar Shamshiev, Michael Weller
Angiogenesis mediated by vascular endothelial growth factor (VEGF) is a hallmark of glioblastoma. Based on response rate and improved progression-free survival (PFS), although not overall survival (OS), the 149 kDa anti-VEGF-A IgG antibody bevacizumab (Avastin® ) has been approved in the US and Japan for recurrent glioblastoma and in Japan for newly diagnosed glioblastoma. However, it is not approved in the EU. Here we characterize the biological activity of DLX1008, a 26 kDa anti-VEGF-A single chain antibody fragment (scFv) which shows 30-fold stronger affinity to human VEGF-A than bevacizumab...
March 5, 2018: Journal of Pharmacology and Experimental Therapeutics
Katherine M Thieltges, Dragana Avramovic, Chayne L Piscitelli, Sandra Markovic-Mueller, Hans Kaspar Binz, Kurt Ballmer-Hofer
Vascular endothelial growth factors (VEGFs) regulate blood and lymph vessel development upon activation of three receptor tyrosine kinases (VEGFRs). The extracellular domain of VEGFRs consists of seven Ig-homology domains, of which D2-3 form the ligand-binding site, while the membrane proximal domains D4-7 are involved in homotypic interactions in ligand-bound receptor dimers. Based on low-resolution structures, we identified allosteric sites in D4-5 and D7 of vascular endothelial growth factor receptor 2 (VEGFR-2) accomplishing regulatory functions...
March 3, 2018: Angiogenesis
Nozlena Abdul Samad, Ahmad Bustamam Abdul, Heshu Sulaiman Rahman, Abdullah Rasedee, Tengku Azmi Tengku Ibrahim, Yeap Swee Keon
Context: Due to increase in the number of patients with impaired immunity, the incidence of liver cancer has increased considerably. Aims: The aim of this study is the investigation the in vitro anticancer effect of zerumbone (ZER) on hepatocellular carcinoma (HCC). Materials and Methods: The anticancer mechanism of ZER was determined by the rat aortic ring, human umbilical vein endothelial cells (HUVECs) proliferation, chorioallantoic membrane, cell migration, and proliferation inhibition assays...
January 2018: Pharmacognosy Magazine
Xiaoshuang Zhu, Xiaonan Guo, Dakan Liu, Yubin Gong, Jin Sun, Changxian Dong
Infantile hemangiomas are the most common tumors affecting children. Although infantile hemangiomas are benign, they could result in morbidity and mortality. The only US Food and Drug Administration-approved drug for infantile hemangiomas is propranolol hydrochloride (Hemangeol™); however, its adverse effects and high frequency of administration hamper its clinical application. Vascular endothelial growth factor receptor (VEGFR) is crucial to the angiogenesis of infantile hemangiomas, and thus it is considered a valuable therapeutic target for infantile hemangiomas...
December 1, 2017: Journal of Biomedical Nanotechnology
Heinz Läubli, Philipp Müller, Lucia D'Amico, Mélanie Buchi, Abhishek S Kashyap, Alfred Zippelius
Cancer immunotherapies have significantly improved the prognosis of cancer patients. Despite the clinical success of targeting inhibitory checkpoint receptors, including PD-1 and/or CTLA-4 on T cells, only a minority of patients derive benefit from these therapies. New strategies to improve cancer immunotherapy are therefore needed. Combination therapy of checkpoint inhibitors with targeted agents has promisingly shown to increase the efficacy of immunotherapy. Here, we analyzed the immunomodulatory effects of the multi-receptor tyrosine kinase inhibitor axitinib and its efficacy in combination with immunotherapies...
February 27, 2018: Cancer Immunology, Immunotherapy: CII
Nizar M Tannir, Sumanta K Pal, Michael B Atkins
The management of advanced clear-cell renal cell carcinoma has steadily improved over the past decade with the introduction of antiangiogenic and targeted therapies. Recently, three new therapies have been approved for use as second-line options that further advance the treatment armamentarium: nivolumab, a monoclonal antibody targeting the programmed cell death receptor; cabozantinib, a small-molecule tyrosine kinase inhibitor (TKI) of vascular endothelial growth factor receptor (VEGFR), MET, and AXL; and lenvatinib, a small-molecule TKI of VEGF and fibroblast growth factor receptors that is used in combination with everolimus, an inhibitor of the mechanistic target of rapamycin...
February 27, 2018: Oncologist
G O Oludare, O J Ilo, B A Lamidi
This study investigated the effect of high salt water intake and lipopolysaccharide injection as probable rat models of preeclampsia during pregnancy. Thirty-three female Sprague-Dawley rats weighing between 150-170g were divided into 4 groups of the control (normal saline), high salt water intake (1.8% NaCl from days 13-18 of pregnancy), lipopolysaccharide group (40 µg/kg b.w. ip injection from day 16-18 of pregnancy) and high salt water (1.8% NaCl) and lipopolysaccharide injection (40 µg/kg b.w i.p. from days 16-18 of pregnancy)...
December 30, 2017: Nigerian Journal of Physiological Sciences: Official Publication of the Physiological Society of Nigeria
Karla B Neves, Francisco J Rios, Lucas van der Mey, Rheure Alves-Lopes, Alan C Cameron, Massimo Volpe, Augusto C Montezano, Carmine Savoia, Rhian M Touyz
Although VEGF (vascular endothelial growth factor) inhibitors (VEGFIs), are effective anticancer therapies, they cause hypertension through unknown mechanisms. We questioned whether changes in vascular redox state may be important, because VEGF signaling involves nitric oxide (NO) and reactive oxygen species. Molecular mechanisms, including NOS, NADPH oxidase (Nox)-derived reactive oxygen species, antioxidant systems, and vasoconstrictor signaling pathways, were probed in human endothelial cells and vascular smooth muscle exposed to vatalanib, a VEGFI...
February 26, 2018: Hypertension
Xing Yuan, Lin Han, Peng Fu, Huawu Zeng, Chao Lv, Wanlin Chang, R Scott Runyon, Momoko Ishii, Liwen Han, Kechun Liu, Taiping Fan, Weidong Zhang, Runhui Liu
The bark of Cinnamomum cassia (C. cassia) has been used for the management of coronary heart disease (CHD) and diabetes mellitus. C. cassia may target the vasculature, as it stimulates angiogenesis, promotes blood circulation and wound healing. However, the active components and working mechanisms of C. cassia are not fully elucidated. The Shexiang Baoxin pill (SBP), which consists of seven medicinal materials, including C. cassia etc., is widely used as a traditional Chinese patent medicine for the treatment of CHD...
February 20, 2018: Laboratory Investigation; a Journal of Technical Methods and Pathology
Shalini Nath, Chhabinath Mandal, Uttara Chatterjee, Chitra Mandal
Modulation of sialylation by sialyltransferases and sialidases plays essential role in carcinogenesis. There are few reports on sialyltransferase, however, the contribution of cytosolic sialidase (Neu2) remains unexplored in pancreatic ductal adenocarcinoma (PDAC). We observed lower expression of Neu2 in different PDAC cells, patient tissues, and a significant strong association with clinicopathological characteristics. Neu2 overexpression guided drug-resistant MIAPaCa2 and AsPC1 cells toward apoptosis as evidenced by decreased Bcl2/Bax ratio, activation of caspase-3/caspase-6/caspase-8, PARP reduction, reduced CDK2/CDK4/CDK6, and cyclin-B1/cyclin-E with unaffected caspase-9...
February 12, 2018: Cell Death & Disease
Marzena Dworacka, Galina Chukanova, Saule Iskakova, Yergen Kurmambayev, Anna Wesołowska, Bartosz A Frycz, Paweł P Jagodziński, Grzegorz Dworacki
PURPOSE: Alpha-lipoic acid (ALA), widely known as an antioxidant, modifies also serum levels of angiogenic factors in type 2 diabetic patients. These pharmacological activities may influence the status of the cardiovascular system. Taking into consideration that diabetes is related to the increased cardiovascular risk we investigated several effects of ALA on angiogenic factors in the myocardium and in the aortal wall using a rat model of type 2 diabetes. METHODS: Diabetes was induced in Wistar rats by a fat-rich diet and by intraperitoneal injection of a small dose of streptozotocin (30 mg/kg)...
February 7, 2018: European Journal of Pharmaceutical Sciences
Yanchao Deng, Yang Yang, Bei Yao, Lei Ma, Qipeng Wu, Zhicheng Yang, Luyong Zhang, Bing Liu
High expression of tumoral vascular endothelial growth factor C (VEGF-C) is correlated with clinical non-small cell lung cancer (NSCLC) metastasis and patient survival. Nevertheless, the comprehensive mechanisms accounting for VEGF-C-mediated cancer progression remain largely unclear. The present study found that VEGF-C expression was upregulated in various NSCLC cell lines. By utilizing transwell migration assay, we found that both recombinant VEGF-C protein and overexpression of VEGF-C in NSCLC cells (A549 and H441 cell lines) could efficiently enhance RAW264...
March 15, 2018: Experimental Cell Research
Tao Jiang, Meng Qiao, Chao Zhao, Xuefei Li, Guanghui Gao, Chunxia Su, Shengxiang Ren, Caicun Zhou
BACKGROUND: To investigate the association between pretreatment blood neutrophil-to-lymphocyte ratio (NLR) and clinical outcomes for advanced-stage cancer patients treated with immunotherapy. METHODS: We conducted a comprehensive literature search to assess the relationship between pretreatment blood NLR and overall survival (OS) or progression-free survival (PFS) in advanced-stage cancer patients treated with immunotherapy. Published data including hazard ratios (HRs) and related 95% confidence interval (CI) were extracted...
February 8, 2018: Cancer Immunology, Immunotherapy: CII
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