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https://www.readbyqxmd.com/read/29749499/stable-silencing-of-dll4-gene-suppresses-the-growth-and-metastasis-of-esophagus-cancer-cells-by-attenuating-akt-phosphorylation
#1
Xianzhi Guo, Yingchun Duan, Xiaolei Ye, Lina Hu, Tong Xu, Li Tong, Minghua Yu
δ‑Like ligand 4 (DLL4) has recently been reported to be involved in the process of cancer angiogenesis and considered to play a vital role in vascular endothelial growth factor (VEGF) signaling, while the role of DLL4 in cancer metastasis and growth has not been systematically studied. In the present study, the esophagus cancer cell line Eca109 was infected in vitro with a lentiviral vector loaded with dll4‑shRNA to obtain a stable cell line of DLL4 expression which was downregulated through puromycin screening...
May 8, 2018: Oncology Reports
https://www.readbyqxmd.com/read/29744869/isolation-and-identification-of-chemotherapy-enriched-sphere-forming-cells-from-a-patient-with-gastric-cancer
#2
Vahid Bagheri, Bahram Memar, Ramezan Behzadi, Mohsen Aliakbarian, Ali Jangjoo, Mostafa Mehrabi Bahar, Samaneh Talebi, Mehran Gholamin, Mohammad R Abbaszadegan
Gastric cancer (GC) is the third and fifth cause of cancer-associated mortality for men and women throughout the world, respectively. Despite the use of surgery and chemotherapy for GC therapy, there are no efficient therapeutic protocols for it to date. Cancer stem cells (CSCs) due to their pivotal role in tumor initiation, growth, progression, invasion, distant metastasis, recurrence and resistance to anticancer drugs are very appealing targets for cancer therapies. Here, we isolated and identified CSCs from a chemotherapy-treated patient...
May 10, 2018: Journal of Cellular Physiology
https://www.readbyqxmd.com/read/29739946/notch-signaling-specifies-arterial-type-definitive-hemogenic-endothelium-from-human-pluripotent-stem-cells
#3
Gene I Uenishi, Ho Sun Jung, Akhilesh Kumar, Mi Ae Park, Brandon K Hadland, Ethan McLeod, Matthew Raymond, Oleg Moskvin, Catherine E Zimmerman, Derek J Theisen, Scott Swanson, Owen J Tamplin, Leonard I Zon, James A Thomson, Irwin D Bernstein, Igor I Slukvin
NOTCH signaling is required for the arterial specification and formation of hematopoietic stem cells (HSCs) and lympho-myeloid progenitors in the embryonic aorta-gonad-mesonephros region and extraembryonic vasculature from a distinct lineage of vascular endothelial cells with hemogenic potential. However, the role of NOTCH signaling in hemogenic endothelium (HE) specification from human pluripotent stem cell (hPSC) has not been studied. Here, using a chemically defined hPSC differentiation system combined with the use of DLL1-Fc and DAPT to manipulate NOTCH, we discover that NOTCH activation in hPSC-derived immature HE progenitors leads to formation of CD144+ CD43- CD73- DLL4+ Runx1 + 23-GFP+ arterial-type HE, which requires NOTCH signaling to undergo endothelial-to-hematopoietic transition and produce definitive lympho-myeloid and erythroid cells...
May 8, 2018: Nature Communications
https://www.readbyqxmd.com/read/29686270/spatial-patterning-of-the-notch-ligand-dll4-controls-endothelial-sprouting-in-vitro
#4
L A Tiemeijer, J-P Frimat, O M J A Stassen, C V C Bouten, C M Sahlgren
Angiogenesis, the formation of new blood vessels, is a vital process for tissue growth and development. The Notch cell-cell signalling pathway plays an important role in endothelial cell specification during angiogenesis. Dll4 - Notch1 signalling directs endothelial cells into migrating tip or proliferating stalk cells. We used the directing properties of Dll4 to spatially control endothelial cell fate and the direction of endothelial sprouts. We created linear arrays of immobilized Dll4 using micro contact printing...
April 23, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29674611/inhibition-of-dll4-notch1-pathway-promotes-angiogenesis-of-masquelet-s-induced-membrane-in-rats
#5
Qian Tang, Haimin Jin, Minji Tong, Gang Zheng, Zhongjie Xie, Shangkun Tang, Jialei Jin, Ping Shang, Huazi Xu, Liyan Shen, Yu Zhang, Haixiao Liu
The Masquelet's induced membrane technique for repairing bone defects has been demonstrated to be a promising treatment strategy. Previous studies have shown that the vessel density of induced membrane is decreased in the late stage of membrane formation, which consequently disrupts the bone healing process. However, relatively little is known about certain mechanisms of vessel degeneration in the induced membrane tissue and whether promotion of angiogenesis in induced membranes can improve bone regeneration...
April 20, 2018: Experimental & Molecular Medicine
https://www.readbyqxmd.com/read/29629872/radical-and-lunatic-fringes-modulate-notch-ligands-to-support-mammalian-intestinal-homeostasis
#6
Preetish Kadur Lakshminarasimha Murthy, Tara Srinivasan, Matthew S Bochter, Rui Xi, Anastasia Kristine Varanko, Kuei-Ling Tung, Fatih Semerci, Keli Xu, Mirjana Maletic-Savatic, Susan E Cole, Xiling Shen
Notch signalling maintains stem cell regeneration at the mouse intestinal crypt base and balances the absorptive and secretory lineages in the upper crypt and villus. Here we report the role of Fringe family of glycosyltransferases in modulating Notch activity in the two compartments. At the crypt base, RFNG is enriched in the Paneth cells and increases cell surface expression of DLL1 and DLL4. This promotes Notch activity in the neighbouring Lgr5 + stem cells assisting their self-renewal. Expressed by various secretory cells in the upper crypt and villus, LFNG promotes DLL surface expression and suppresses the secretory lineage ...
April 9, 2018: ELife
https://www.readbyqxmd.com/read/29620522/mpdz-promotes-dll4-induced-notch-signaling-during-angiogenesis
#7
Fabian Tetzlaff, M Gordian Adam, Anja Feldner, Iris Moll, Amitai Menuchin, Juan Rodriguez-Vita, David Sprinzak, Andreas Fischer
Angiogenesis is coordinated by VEGF and Notch signaling. DLL4-induced Notch signaling inhibits tip cell formation and vessel branching. To ensure proper Notch signaling, receptors and ligands are clustered at adherens junctions. However, little is known about factors that control Notch activity by influencing the cellular localization of Notch ligands. Here we show that the multiple PDZ domain protein (MPDZ) enhances Notch signaling activity. MPDZ physically interacts with the intracellular carboxyterminus of DLL1 and DLL4 and enables their interaction with the adherens junction protein Nectin-2...
April 5, 2018: ELife
https://www.readbyqxmd.com/read/29618931/upregulated-vegfa-and-dll4-act-as-potential-prognostic-genes-for-clear-cell-renal-cell-carcinoma
#8
Xilong Wang, Jun Zhang, Yangyun Wang, Minqi Tu, Ying Wang, Guowei Shi
Purpose: As a typical hypervascular tumor, clear cell renal cell carcinoma (ccRCC) is the most common type of RCC. This study was aimed to explore the prognostic genes for ccRCC, focusing on the roles of vascular endothelial growth factor A ( VEGFA ) and Delta-like ligand 4 ( DLL4 ) in the disease. Materials and methods: The mRNA-sequencing data of kidney renal clear cell carcinoma (KIRC) were obtained from The Cancer Genome Atlas (TCGA) database, including 469 tumor samples and 68 adjacent normal samples...
2018: OncoTargets and Therapy
https://www.readbyqxmd.com/read/29606343/the-missed-notch-to-bring-down-diabetes
#9
Peter Mirtschink, Triantafyllos Chavakis
Notch signaling contributes to maintenance of adult tissue homeostasis and is also involved in disease. A recent study demonstrates that inhibition of Dll4-Notch signaling by anti-Dll4 improves pancreatic islet function and insulin production by multiple complementary mechanisms. Thus, anti-Dll4 represents a therapeutic approach for compromised insulin production in diabetes.
March 29, 2018: Trends in Endocrinology and Metabolism: TEM
https://www.readbyqxmd.com/read/29599924/asiatic-acid-attenuates-lipopolysaccharide-induced-injury-by-suppressing-activation-of-the-notch-signaling-pathway
#10
Xiong Yuyun, Cheng Xi, Yin Qing, Xia Lin, Rui Ke, Sun Bingwei
Sepsis is a severe multisystem disease with high mortality rates and limited treatment options. However, advances during the last decade have opened opportunities to develop novel therapeutic strategies. The Notch signaling pathway plays a critical role in inflammation, and its inhibition offers an avenue to treat inflammatory diseases, such as sepsis. Asiatic acid (AA), a triterpenoid isolated from Centella asiatica, reportedly exerts anti-oxidant, anti-tumor, and anti-inflammatory effects, but its mechanisms remain unclear...
March 13, 2018: Oncotarget
https://www.readbyqxmd.com/read/29592882/abt-165-a-dual-variable-domain-immunoglobulin-dvd-ig-targeting-dll4-and-vegf-demonstrates-superior-efficacy-and-favorable-safety-profiles-in-preclinical-models
#11
Yingchun Li, Jonathan A Hickson, Dominic J Ambrosi, Deanna L Haasch, Kelly D Foster-Duke, Lucia J Eaton, Enrico L Digiammarino, Sanjay C Panchal, Fang Jiang, Sarah R Mudd, Catherine Zhang, Surekha S Akella, Wenqing Gao, Sherry L Ralston, Louie Naumovski, Jijie Gu, Susan E Morgan-Lappe
Anti-angiogenic therapy is a clinically validated modality in cancer treatment. To date, all approved anti-angiogenic drugs primarily inhibit the vascular endothelial growth factor (VEGF) pathway. Delta-like ligand 4 (DLL4) has been identified as a potential drug target in VEGF-independent angiogenesis and tumor initiating cell (TIC) survival. A dual-specific biologic targeting both VEGF and DLL4 could be an attractive strategy to improve the effectiveness of anti-VEGF therapy. ABT-165 was uniquely engineered using a proprietary dual-variable domain immunoglobulin (DVD-Ig) technology based on its ability to bind and inhibit both DLL4 and VEGF...
March 28, 2018: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/29571073/concurrent-treatment-with-anti-dll4-enhances-antitumor-and-proapoptotic-efficacy-of-a-%C3%AE-secretase-inhibitor-in-gastric-cancer
#12
Muxing Kang, Yaoyi Zhang, Xiaoli Jin, Guofeng Chen, Yi Huang, Dan Wu, Guogang Li, Jianzhen Shan, Pintong Huang, Jian Chen
The Notch signaling pathway has been identified as a therapeutic target for cancers. γ-Secretase inhibitors (GSIs) have been progressively recognized as potential anticancer drugs. The present study aimed to investigate the effects of anti-delta like legend 4 (anti-DLL4) treatment on the anticancer efficacy of GSIs in gastric cancer. SGC-7901-GFP human gastric cancer cells were tested for DLL4 expression by rosette formation test and immunofluorescence, and then were treated with anti-DLL4 antibody N-[N-(3,5-difluorophenacetyl)-L-ananyl]-S-phenylglycine t-butyl ester (DAPT, a type of GSI), or a combination of anti-DLL4 antibody and DAPT...
March 15, 2018: Translational Oncology
https://www.readbyqxmd.com/read/29541959/extracellular-vesicle-carried-jagged-1-inhibits-huvec-sprouting-in-a-3d-microenvironment
#13
Evan Tan, Harry H Asada, Ruowen Ge
NOTCH signalling is an evolutionarily conserved juxtacrine signalling pathway that is essential in development. Jagged1 (JAG1) and Delta-like ligand 4 (DLL4) are transmembrane NOTCH ligands that regulate angiogenesis by controlling endothelial cell (EC) differentiation, vascular development and maturation. In addition, DLL4 could bypass its canonical cell-cell contact-dependent signalling to influence NOTCH signalling and angiogenesis at a distance when it is packaged into extracellular vesicles (EVs). However, it is not clear whether JAG1 could also be packaged into EVs to influence NOTCH signalling and angiogenesis...
March 14, 2018: Angiogenesis
https://www.readbyqxmd.com/read/29535000/pentoxifylline-inhibits-angiogenesis-via-decreasing-dll4-and-notch1-expression-in-mouse-proepicardial-explant-cultures
#14
Justyna Niderla-Bielińska, Krzysztof Bartkowiak, Bogdan Ciszek, Eric Czajkowski, Ewa Jankowska-Steifer, Alicja Krejner, Anna Ratajska
Pentoxifylline (PTX), a non-specific inhibitor of cAMP phosphodiesterases, is commonly used for treatment of peripheral vascular disorders although its direct action on endothelial cells is not well described. The aim of this study was to determine the influence of PTX on tubule formation and mRNA expression for angiogenesis-related proteins in endothelial cell line C166 and mouse proepicardial explants cultured on collagen. C166 cells and explants were stimulated with proangiogenic cocktail containing bFGF/VEGF-A120 /VEGF-A164 and with proangiogenic cocktail enriched with PTX...
March 10, 2018: European Journal of Pharmacology
https://www.readbyqxmd.com/read/29449267/single-cell-transcriptome-analyses-reveal-endothelial-cell-heterogeneity-in-tumors-and-changes-following-antiangiogenic-treatment
#15
Qi Zhao, Alexandra Eichten, Asma Parveen, Christina Adler, Ying Huang, Wei Wang, Yueming Ding, Alexander Adler, Thomas Nevins, Min Ni, Yi Wei, Gavin Thurston
Angiogenesis involves dynamic interactions between specialized endothelial tip and stalk cells that are believed to be regulated in part by VEGF and Dll4-Notch signaling. However, our understanding of this process is hampered by limited knowledge of the heterogeneity of endothelial cells and the role of different signaling pathways in specifying endothelial phenotypes. Here, we characterized by single-cell transcriptomics the heterogeneity of mouse endothelial cells and other stromal cells during active angiogenesis in xenograft tumors as well as from adult normal heart, following pharmacologic inhibition of VEGF and Dll4-Notch signaling...
May 1, 2018: Cancer Research
https://www.readbyqxmd.com/read/29398116/dynamic-ligand-discrimination-in-the-notch-signaling-pathway
#16
Nagarajan Nandagopal, Leah A Santat, Lauren LeBon, David Sprinzak, Marianne E Bronner, Michael B Elowitz
The Notch signaling pathway comprises multiple ligands that are used in distinct biological contexts. In principle, different ligands could activate distinct target programs in signal-receiving cells, but it is unclear how such ligand discrimination could occur. Here, we show that cells use dynamics to discriminate signaling by the ligands Dll1 and Dll4 through the Notch1 receptor. Quantitative single-cell imaging revealed that Dll1 activates Notch1 in discrete, frequency-modulated pulses that specifically upregulate the Notch target gene Hes1...
February 8, 2018: Cell
https://www.readbyqxmd.com/read/29391273/knockdown-of-long-noncoding-rna-meg3-impairs-vegf-stimulated-endothelial-sprouting-angiogenesis-via-modulating-vegfr2-expression-in-human-umbilical-vein-endothelial-cells
#17
Wenchen Ruan, Feng Zhao, Shunyi Zhao, Luyong Zhang, Lei Shi, Tao Pang
Long noncoding RNAs is a novel class of RNA molecules, which is closely related to the occurrence and development of human disease. Recent studies have highlighted the importance of MEG3 in angiogenesis and the maintenance of normal function of vascular endothelial cells. However, whether MEG3 contributes to human endothelial cell angiogenesis as well as potential mechanisms are largely unknown. In this work, we found that the high expression level of MEG3 in primary HUVEC was controlled by DNA methylation, and its expression in HUVEC was regulated by HIF-1α under hypoxia condition...
April 5, 2018: Gene
https://www.readbyqxmd.com/read/29386132/delta-like-ligand-4-notch-signaling-inhibition-regulates-pancreatic-islet-function-and-insulin-secretion
#18
Fabienne Billiard, Sevasti Karaliota, Bei Wang, Dimitrios Stellas, Ioannis Serafimidis, Antigoni Manousopoulou, Yiassemi Koutmani, Elpiniki Ninou, Jacquelynn Golubov, Amanda DaNave, Panagiotis Tsakanikas, Yurong Xin, Wen Zhang, Matthew Sleeman, George D Yancopoulos, Andrew J Murphy, Spiros D Garbis, Katia Karalis, Dimitris Skokos
Although Notch signaling has been proposed as a therapeutic target for type-2 diabetes, liver steatosis, and atherosclerosis, its direct effect on pancreatic islets remains unknown. Here, we demonstrated a function of Dll4-Notch signaling inhibition on the biology of insulin-producing cells. We confirmed enhanced expression of key Notch signaling genes in purified pancreatic islets from diabetic NOD mice and showed that treatment with anti-Dll4 antibody specifically abolished Notch signaling pathway activation...
January 23, 2018: Cell Reports
https://www.readbyqxmd.com/read/29380370/endothelial-immune-activation-programmes-cell-fate-decisions-and-angiogenesis-by-inducing-angiogenesis-regulator-dll4-through-tlr4-erk-foxc2-signalling
#19
Sheng Xia, Heather L Menden, Thomas R Korfhagen, Tsutomu Kume, Venkatesh Sampath
KEY POINTS: The mechanisms by which bacteria alter endothelial cell phenotypes and programme inflammatory angiogenesis remain unclear. In lung endothelial cells, we demonstrate that toll-like receptor 4 (TLR4) signalling induces activation of forkhead box protein C2 (FOXC2), a transcriptional factor implicated in lymphangiogenesis and endothelial specification, in an extracellular signal-regulated kinase (ERK)-dependent manner. TLR4-ERK-FOXC2 signalling regulates expression of the Notch ligand DLL4 and signals inflammatory angiogenesis in vivo and in vitro...
April 15, 2018: Journal of Physiology
https://www.readbyqxmd.com/read/29380239/vegf-pkd-1-signaling-mediates-arteriogenic-gene-expression-and-angiogenic-responses-in-reversible-human-microvascular-endothelial-cells-with-extended-lifespan
#20
Brad Best, Patrick Moran, Bin Ren
Microvascular ECs (MVECs) are an ideal model in angiogenesis research. The aim of this study was to determine vascular endothelial growth factor (VEGF)/protein kinase D1 (PKD-1) signaling in expression of arteriogenic genes in human MVECs. To achieve this aim, we transduced specific SV40 large T antigen and telomerase into primary human dermal MVECs (HMVEC-D) to establish reversible HMVECs with extended lifespan (HMVECi-D). HMVECi-D was then exposed to VEGF/VEGF-inducer GS4012 or transduced with constitutively active protein kinase PKD-1 (PKD-CA)...
January 29, 2018: Molecular and Cellular Biochemistry
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