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https://www.readbyqxmd.com/read/28930565/role-of-fibroblast-growth-factor-receptor-2-splicing-in-normal-and-cancer-cells
#1
Toshiyuki Ishiwata
Types 1-4 of fibroblast growth factor receptors (FGFR) are all expressed in various cancers. Because of its prominent role in carcinogenesis and cancer progression, FGFR-2, is being considered as a novel target in cancer treatment. Owing to the alternative splicing of its extracellular domain, FGFR-2 exists in two variants: IIIb and IIIc. FGFR-2 IIIb is mainly expressed in normal epithelial cells, as well as in oral mucosal, esophageal, gastric, colorectal, pancreatic, pulmonary, breast, endometrial, cervical, and prostate cancers...
January 1, 2018: Frontiers in Bioscience (Landmark Edition)
https://www.readbyqxmd.com/read/28928360/tumor-associated-b-cells-induce-tumor-heterogeneity-and-therapy-resistance
#2
Rajasekharan Somasundaram, Gao Zhang, Mizuho Fukunaga-Kalabis, Michela Perego, Clemens Krepler, Xiaowei Xu, Christine Wagner, Denitsa Hristova, Jie Zhang, Tian Tian, Zhi Wei, Qin Liu, Kanika Garg, Johannes Griss, Rufus Hards, Margarita Maurer, Christine Hafner, Marius Mayerhöfer, Georgios Karanikas, Ahmad Jalili, Verena Bauer-Pohl, Felix Weihsengruber, Klemens Rappersberger, Josef Koller, Roland Lang, Courtney Hudgens, Guo Chen, Michael Tetzlaff, Lawrence Wu, Dennie Tompers Frederick, Richard A Scolyer, Georgina V Long, Manashree Damle, Courtney Ellingsworth, Leon Grinman, Harry Choi, Brian J Gavin, Margaret Dunagin, Arjun Raj, Nathalie Scholler, Laura Gross, Marilda Beqiri, Keiryn Bennett, Ian Watson, Helmut Schaider, Michael A Davies, Jennifer Wargo, Brian J Czerniecki, Lynn Schuchter, Dorothee Herlyn, Keith Flaherty, Meenhard Herlyn, Stephan N Wagner
In melanoma, therapies with inhibitors to oncogenic BRAF(V600E) are highly effective but responses are often short-lived due to the emergence of drug-resistant tumor subpopulations. We describe here a mechanism of acquired drug resistance through the tumor microenvironment, which is mediated by human tumor-associated B cells. Human melanoma cells constitutively produce the growth factor FGF-2, which activates tumor-infiltrating B cells to produce the growth factor IGF-1. B-cell-derived IGF-1 is critical for resistance of melanomas to BRAF and MEK inhibitors due to emergence of heterogeneous subpopulations and activation of FGFR-3...
September 19, 2017: Nature Communications
https://www.readbyqxmd.com/read/28927233/fibroblast-growth-factor-2-mediated-fgfr-erk-signaling-supports-maintenance-of-cancer-stem-like-cells-in-esophageal-squamous-cell-carcinoma
#3
Osamu Maehara, Goki Suda, Mitsuteru Natsuizaka, Shunsuke Ohnishi, Yoshito Komatsu, Fumiyuki Sato, Masato Nakai, Takuya Sho, Kenichi Morikawa, Koji Ogawa, Tomoe Shimazaki, Megumi Kimura, Ayaka Asano, Yoshiyuki Fujimoto, Shinya Ohashi, Shingo Kagawa, Hideaki Kinugasa, Seiji Naganuma, Kelly A Whelan, Hiroshi Nakagawa, Koji Nakagawa, Hiroshi Takeda, Naoya Sakamoto
In esophageal squamous cell carcinoma (ESCC), a subset of cells defined by high expression of CD44 and low expression of CD24 has been reported to possess characteristics of cancer stem-like cells (CSCs). Novel therapies directly targeting CSCs have the potential to improve prognosis of ESCC patients. Although fibroblast growth factor-2 (FGF-2) expression correlates with recurrence and poor survival in ESCC patients, the role of FGF-2 in regulation of ESCC CSCs has yet to be elucidated. We report that FGF-2 is significantly upregulated in CSCs and significantly increases CSC content in ESCC cell lines by inducing epithelial-mesenchymal transition (EMT)...
September 13, 2017: Carcinogenesis
https://www.readbyqxmd.com/read/28924004/basic-fibroblast-growth-factor-2-is-a-determinant-of-cd4-t-cell-airway-smooth-muscle-cell-communication-through-membrane-conduits
#4
Soroor Farahnak, Toby K McGovern, Rachael Kim, Michael O'Sullivan, Brian Chen, Minhyoung Lee, Haruka Yoshie, Anna Wang, Joyce Jang, Saba Al Heialy, Anne-Marie Lauzon, James G Martin
Activated CD4 T cells connect to airway smooth muscle cells (ASMCs) in vitro via lymphocyte-derived membrane conduits (LMCs) structurally similar to membrane nanotubes with unknown intercellular signals triggering their formation. We examined the structure and function of CD4 T cell-derived LMCs, and we established a role for ASMC-derived basic fibroblast growth factor 2 (FGF2b) and FGF receptor (FGFR)1 in LMC formation. Blocking FGF2b's synthesis and FGFR1 function reduced LMC formation. Mitochondrial flux from ASMCs to T cells was partially FGF2b and FGFR1 dependent...
September 18, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28923346/role-of-fibroblast-growth-factor-receptors-fgfr-and-fgfr-like-1-fgfrl1-in-mesenchymal-stromal-cell-differentiation-to-osteoblasts-and-adipocytes
#5
T E Kähkönen, K K Ivaska, M Jian, K G Büki, H K Väänänen, P L Härkönen
Fibroblast growth factors (FGF) and their receptors (FGFRs) regulate many developmental processes including differentiation of mesenchymal stromal cells (MSC). We developed two MSC lines capable of differentiating to osteoblasts and adipocytes and studied the role of FGFRs in this process. We identified FGFR2 and fibroblast growth factor receptor like-1 (FGFRL1) as possible actors in MSC differentiation with gene microarray and qRT-PCR. FGFR2 and FGFRL1 mRNA expression strongly increased during MSC differentiation to osteoblasts...
September 16, 2017: Molecular and Cellular Endocrinology
https://www.readbyqxmd.com/read/28919046/fgf23-activates-injury-primed-renal-fibroblasts-via-fgfr4-dependent-signalling-and-enhancement-of-tgf-%C3%AE-autoinduction
#6
Edward R Smith, Stephen G Holt, Tim D Hewitson
Bone-derived fibroblast growth factor 23 (FGF23) is an important endocrine regulator of mineral homeostasis with effects transduced by cognate FGF receptor (FGFR)1-α-Klotho complexes. Circulating FGF23 levels rise precipitously in patients with kidney disease and portend to worse renal and cardiovascular outcomes. De novo expression of FGF23 has been found in the heart and kidney following injury but its significance remains unclear. Studies showing that exposure to chronically high FGF23 concentrations activates hypertrophic gene programmes in the cardiomyocyte, has spawned intense interest in other pathological off-target effects of FGF23 excess...
September 14, 2017: International Journal of Biochemistry & Cell Biology
https://www.readbyqxmd.com/read/28915889/anti-fibrotic-efficacy-of-nintedanib-in-pulmonary-fibrosis-via-the-inhibition-of-fibrocyte-activity
#7
Seidai Sato, Shintaro Shinohara, Shinya Hayashi, Shun Morizumi, Shuichi Abe, Hiroyasu Okazaki, Yanjuan Chen, Hisatsugu Goto, Yoshinori Aono, Hirohisa Ogawa, Kazuya Koyama, Haruka Nishimura, Hiroshi Kawano, Yuko Toyoda, Hisanori Uehara, Yasuhiko Nishioka
BACKGROUND: Nintedanib, a tyrosine kinase inhibitor that is specific for platelet-derived growth factor receptors (PDGFR), fibroblast growth factor receptors (FGFR), and vascular endothelial growth factor receptors (VEGFR), has recently been approved for idiopathic pulmonary fibrosis. Fibrocytes are bone marrow-derived progenitor cells that produce growth factors and contribute to fibrogenesis in the lungs. However, the effects of nintedanib on the functions of fibrocytes remain unclear...
September 15, 2017: Respiratory Research
https://www.readbyqxmd.com/read/28905937/somcl-085-a-novel-multi-targeted-fgfr-inhibitor-displays-potent-anticancer-activity-in-fgfr-addicted-human-cancer-models
#8
Xi-Fei Jiang, Yang Dai, Xia Peng, Yan-Yan Shen, Yi Su, Man-Man Wei, Wei-Ren Liu, Zhen-Bin Ding, Ao Zhang, Ying-Hong Shi, Jing Ai
Aberrant fibroblast growth factor receptor (FGFR) activation is found across a diverse spectrum of malignancies, especially those lacking effective treatments. SOMCL-085 is a novel FGFR-dominant multi-target kinase inhibitor. Here, we explored the FGFR-targeting anticancer activity of SOMCL-085 both in vitro and in vivo. Among a panel of 20 tyrosine kinases screened, SOMCL-085 potently inhibited FGFR1, FGFR2 and FGFR3 kinase activity, with IC50 values of 1.8, 1.9 and 6.9 nmol/L, respectively. This compound simultaneously inhibited the angiogenesis kinases VEGFR and PDGFR, but without obvious inhibitory effect on other 12 tyrosine kinases...
September 14, 2017: Acta Pharmacologica Sinica
https://www.readbyqxmd.com/read/28900173/fgfr-inhibitor-azd4547-impedes-the-stemness-of-mammary-epithelial-cells-in-the-premalignant-tissues-of-mmtv-erbb2-transgenic-mice
#9
Qingxia Zhao, Amanda B Parris, Erin W Howard, Ming Zhao, Zhikun Ma, Zhiying Guo, Ying Xing, Xiaohe Yang
The fibroblast growth factor receptor (FGFR) family of receptor tyrosine kinases (RTKs) regulates signaling pathways involved in cell proliferation and differentiation. Currently, the anti-tumor properties of FGFR inhibitors are being tested in preclinical and clinical studies. Nevertheless, reports on FGFR inhibitor-mediated breast cancer prevention are sparse. In this study, we investigated the anti-cancer benefits of AZD4547, an FGFR1-3 inhibitor, in ErbB2-overexpressing breast cancer models. AZD4547 (1-5 µM) demonstrated potent anti-proliferative effects, inhibition of stemness, and suppression of FGFR/RTK signaling in ErbB2-overexpressing human breast cancer cells...
September 12, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28899582/fgf2-mediated-attenuation-of-myofibroblast-activation-is-modulated-by-distinct-mapk-signaling-pathways-in-human-dermal-fibroblasts
#10
David M Dolivo, Sara A Larson, Tanja Dominko
BACKGROUND: Previous human and animal studies have demonstrated the ability of exogenously administered basic fibroblast growth factor (FGF2) to act as an antifibrotic agent in the skin. Though the activity of FGF2 as an anti-scarring agent is well-established for fibrotic skin wounds, the mechanisms by which FGF2 exerts these actions are not entirely understood. Canonical FGF2 signaling proceeds in part via FGFR/MAPK pathways in human dermal fibroblasts, and FGF2 has been described to prevent or reverse the fibroblast-to-myofibroblast transition, which is driven by TGFβ signaling and understood to be an important step in the formation of a fibrotic scar in vivo...
September 1, 2017: Journal of Dermatological Science
https://www.readbyqxmd.com/read/28895785/preclinical-pharmacokinetic-characterization-of-an-adipose-tissue-targeting-monoclonal-antibody-in-obese-and-non-obese-animals
#11
Sharmila Rajan, Danielle Mandikian, Amos Baruch, Thomas R Gelzleichter, Dale Stevens, Junichiro Sonoda, Kyra Cowan, C Andrew Boswell, Eric Stefanich
Target receptor levels can influence pharmacokinetics (PK) or pharmacodynamics (PD) of monoclonal antibodies (mAbs), and can affect drug development of this class of molecules. We generated an effector-less humanized bispecific antibody that selectively activates fibroblast growth factor receptor (FGFR)1 and βKlotho receptor, a FGF21 receptor complex highly expressed in both white and brown adipocytes. The molecule shows cross-species binding with comparable equilibrium binding affinity (Kd) for human, cynomolgus monkey, and mouse FGFR1/βKlotho...
September 12, 2017: MAbs
https://www.readbyqxmd.com/read/28889064/spiroplasma-eriocheiris-induces-mouse-3t6-swiss-albino-cell-apoptosis-that-associated-with-the-infection-mechanism
#12
Libo Hou, Wei Gu, Huanxi Zhu, Wei Yao, Wen Wang, Qingguo Meng
Spiroplasma eriocheiris is a novel pathogen similar to the Spiroplasma mirum and also had an ability to infect the newborn mice and caused cataract. Our study was designed to study how S. eriocheiris infects mouse 3T6-Swiss albino cells and to elucidate the cellular molecular pathogenesis of Spiroplasma. FCM analysis and MTT analysis clearly shown that S. eriocheiris could induce 3T6 cell apoptosis and cause cell viability decreased seriously. Immunofluorescence experiments and TEM analysis shown that S. eriocheiris can invade 3T6 cells and form typical inclusion bodies and exhibit vacuolization in vitro...
September 7, 2017: Molecular Immunology
https://www.readbyqxmd.com/read/28885691/fibroblast-growth-factor-2-induces-proliferation-and-distribution-of-g2-m-phase-of-bovine-endometrial-cells-involving-activation-of-pi3k-akt-and-mapk-cell-signaling-and-prevention-of-effects-of-er-stress
#13
Whasun Lim, Hyocheol Bae, Fuller W Bazer, Gwonhwa Song
Fibroblast growth factor 2 (FGF2) is abundantly expressed in conceptuses and endometria during pregnancy in diverse animal models including domestic animals. However, its intracellular mechanism of action has not been reported for bovine endometrial cells. Therefore, the aim of this study was to identify functional roles of FGF2 in bovine endometrial (BEND) cell line which has served as a good model system for investigating regulation of signal transduction following treatment with interferon-tau (IFNT) in vitro...
September 8, 2017: Journal of Cellular Physiology
https://www.readbyqxmd.com/read/28883546/api5-induces-cisplatin-resistance-through-fgfr-signaling-in-human-cancer-cells
#14
Han Sol Jang, Seon Rang Woo, Kwon-Ho Song, Hanbyoul Cho, Doo Byung Chay, Soon-Oh Hong, Hyo-Jung Lee, Se Jin Oh, Joon-Yong Chung, Jae-Hoon Kim, Tae Woo Kim
Most tumors frequently undergo initial treatment with a chemotherapeutic agent but ultimately develop resistance, which limits the success of chemotherapies. As cisplatin exerts a high therapeutic effect in a variety of cancer types, it is often used in diverse strategies, such as neoadjuvant, adjuvant and combination chemotherapies. However, cisplatin resistance has often manifested regardless of cancer type, and it represents an unmet clinical need. Since we found that API5 expression was positively correlated with chemotherapy resistance in several specimens from patients with cervical cancer, we decided to investigate whether API5 is involved in the development of resistance after chemotherapy and to explore whether targeting API5 or its downstream effectors can reverse chemo-resistance...
September 8, 2017: Experimental & Molecular Medicine
https://www.readbyqxmd.com/read/28882160/intrinsic-fluorescence-of-the-clinically-approved-multikinase-inhibitor-nintedanib-reveals-lysosomal-sequestration-as-resistance-mechanism-in-fgfr-driven-lung-cancer
#15
Bernhard Englinger, Sebastian Kallus, Julia Senkiv, Daniela Heilos, Lisa Gabler, Sushilla van Schoonhoven, Alessio Terenzi, Patrick Moser, Christine Pirker, Gerald Timelthaler, Walter Jäger, Christian R Kowol, Petra Heffeter, Michael Grusch, Walter Berger
BACKGROUND: Studying the intracellular distribution of pharmacological agents, including anticancer compounds, is of central importance in biomedical research. It constitutes a prerequisite for a better understanding of the molecular mechanisms underlying drug action and resistance development. Hyperactivated fibroblast growth factor receptors (FGFRs) constitute a promising therapy target in several types of malignancies including lung cancer. The clinically approved small-molecule FGFR inhibitor nintedanib exerts strong cytotoxicity in FGFR-driven lung cancer cells...
September 7, 2017: Journal of Experimental & Clinical Cancer Research: CR
https://www.readbyqxmd.com/read/28878133/exome-capture-rna-sequencing-of-decade-old-breast-cancers-and-matched-decalcified-bone-metastases
#16
Nolan Priedigkeit, Rebecca J Watters, Peter C Lucas, Ahmed Basudan, Rohit Bhargava, William Horne, Jay K Kolls, Zhou Fang, Margaret Q Rosenzweig, Adam M Brufsky, Kurt R Weiss, Steffi Oesterreich, Adrian V Lee
Bone metastases (BoM) are a significant cause of morbidity in patients with estrogen receptor-positive (ER-positive) breast cancer; yet, characterizations of human specimens are limited. In this study, exome-capture RNA sequencing (ecRNA-seq) on aged (8-12 years), formalin-fixed, paraffin-embedded (FFPE), and decalcified cancer specimens was evaluated. Gene expression values and ecRNA-seq quality metrics from FFPE or decalcified tumor RNA showed minimal differences when compared with matched flash-frozen or nondecalcified tumors...
September 7, 2017: JCI Insight
https://www.readbyqxmd.com/read/28877471/kif5b-ret-oncoprotein-signals-through-a-multi-kinase-signaling-hub
#17
Tirtha Kamal Das, Ross Leigh Cagan
Gene fusions are increasingly recognized as important cancer drivers. The KIF5B-RET gene has been identified as a primary driver in a subset of lung adenocarcinomas. Targeting human KIF5B-RET to epithelia in Drosophila directed multiple aspects of transformation, including hyperproliferation, epithelial-to-mesenchymal transition, invasion, and extension of striking invadopodia-like processes. The KIF5B-RET-transformed human bronchial cell line showed similar aspects of transformation, including invadopodia-like processes...
September 5, 2017: Cell Reports
https://www.readbyqxmd.com/read/28870993/klf5-maintains-the-balance-of-primitive-endoderm-to-epiblast-specification-during-mouse-embryonic-development-by-suppression-of-fgf4
#18
Takuya Azami, Tsuyoshi Waku, Ken Matsumoto, Hyojung Jeon, Masafumi Muratani, Akihiro Kawashima, Jun Yanagisawa, Ichiro Manabe, Ryozo Nagai, Tilo Kunath, Tomonori Nakamura, Kazuki Kurimoto, Mitinori Saitou, Satoru Takahashi, Masatsugu Ema
The inner cell mass of the mouse blastocyst gives rise to the pluripotent epiblast (EPI), which forms the embryo proper, and the primitive endoderm (PrE), which forms extra-embryonic yolk sac tissues. All inner cells co-express lineage markers such as Nanog and Gata6 at embryonic day (E) 3.25, and the EPI and PrE precursor cells eventually segregate to exclusively express Nanog and Gata6, respectively. Fibroblast growth factor (FGF)/extracellular signal-regulated kinase (ERK) signalling is involved in segregation of the EPI and PrE lineages; however, the mechanism involved in Fgf4-regulation is poorly understood...
September 4, 2017: Development
https://www.readbyqxmd.com/read/28870991/receptor-protein-tyrosine-phosphatase-ptprb-negatively-regulates-fgf2-dependent-branching-morphogenesis
#19
Kelly J Soady, Giusy Tornillo, Howard Kendrick, Valerie Meniel, Daria Olijnyk-Dallis, Joanna S Morris, Torsten Stein, Barry A Gusterson, Clare M Isacke, Matthew J Smalley
PTPRB is a transmembrane protein tyrosine phosphatase known to regulate blood vessel remodelling and angiogenesis. Here we demonstrate that PTPRB negatively regulates branching morphogenesis in the mammary epithelium. We show that Ptprb is highly expressed in adult mammary stem cells and also, although at lower levels, in estrogen receptor positive luminal cells. During mammary development Ptprb expression is down-regulated during puberty, a period of extensive of ductal outgrowth and branching. In vivo shRNA knockdown of Ptprb in the cleared mammary fat pad transplant assay resulted in smaller epithelial outgrowths with an increased branching density and also increased branching in an in vitro organoid assay...
September 4, 2017: Development
https://www.readbyqxmd.com/read/28857247/fgfr2-regulation-by-picrasidine-q-inhibits-the-cell-growth-and-induces-apoptosis-in-esophageal-squamous-cell-carcinoma
#20
Yuanyuan Shi, Xuejiao Liu, Mangaladoss Fredimoses, Mengqiu Song, Hanyong Chen, Kangdong Liu, Mee-Hyun Lee, Zigang Dong
Fibroblast growth factor receptor (FGFR) 2 and its downstream signaling cascades, PI3K/AKT/mTOR is playing an important role in cell survival and proliferations. In this study, we firstly found that picrasidine Q (PQ), an alkaloid component extracted from Angelica keiskei species, has the capacity of anti-cell transformation and anti-cancer. After ligand shape similarity approach of PQ, we found that PQ targeted FGFR 2 and verified by FGFR2 kinase assay as well as computational docking model. FGFR2 highly expressed in esophageal cancer tissues and PQ inhibited fibroblast growth factor (FGF)-induced cell transformation...
August 31, 2017: Journal of Cellular Biochemistry
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