DOCSLIB.ORG

High Circulating Angiopoietin-2 Levels Exacerbate Pulmonary

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
High Circulating Angiopoietin-2 Levels Exacerbate Pulmonary Thorax Online First, published on September 25, 2017 as 10.1136/thoraxjnl-2017-210413 Pulmonary vasculature Thorax: first published as 10.1136/thoraxjnl-2017-210413 on 25 September 2017. Downloaded from ORIGINAL artiCLE High circulating angiopoietin-2 levels exacerbate pulmonary inflammation but not vascular leak or mortality in endotoxin-induced lung injury in mice Kenny Schlosser,1 Mohamad Taha,1,2 Yupu Deng,1 Lauralyn A McIntyre,3 Shirley H J Mei,1 Duncan J Stewart1,2,4 ► Additional material is ABSTRACT published online only. To view Background Elevated plasma levels of angiopoietin-2 Key messages please visit the journal online (http:// dx. doi. org/ 10. 1136/ (ANGPT2) have been reported in patients with acute thoraxjnl- 2017- 210413). lung injury (ALI); however, it remains unclear whether What is the key question? this increase contributes to, or just marks, the underlying ► Elevated plasma levels of angiopoietin-2 1Regenerative Medicine vasculopathic inflammation and leak associated with (ANGPT2) in acute lung injury (ALI)/acute Program, Ottawa Hospital ALI. Here we investigated the biological consequences respiratory distress syndrome patients are Research Institute , University associated with poor prognosis; however, of Ottawa, Ottawa, Ontario, of inducing high circulating levels of ANGPT2 in a mouse Canada model of endotoxin-induced ALI. it remains unclear whether these elevated 2Department of Cellular and Methods Transgenic mice (ANGPT2OVR) with elevated circulating levels are just a marker or mediator Molecular Medicine, University circulating levels of ANGPT2, achieved through of underlying pulmonary vascular dysfunction. of Ottawa, Ottawa, Ontario, conditional hepatocyte-specific overexpression, Canada What is the bottom line? 3 were examined from 3 to 72 hours following Clinical Epidemiology Program, ► For the first time, this study demonstrates Ottawa Hospital Research lipopolysaccharide (LPS)-induced ALI. An aptamer-based that elevated plasma levels of ANGPT2 play Institute, Ottawa, Canada inhibitor was used to neutralise the effects of circulating 4 a context-dependent role in fine-tuning the Department of Medicine, ANGPT2 in LPS-exposed ANGPT2OVR mice. Division of Cardiology, inflammatory response to ALI. University of Ottawa, Ottawa, Results Total cells, neutrophils and macrophages, Ontario, Canada as well as inflammatory cytokines, were significantly Why read on? OVR higher in bronchoalveolar lavage (BAL) of ANGPT2 ► The isolated elevation of circulating ANGPT2 Correspondence to versus littermate controltTA mice at 48 hours and 6 hours via hepatocyte-specific overexpression and Dr Duncan J Stewart, post-LPS, respectively. In contrast, LPS-induced vascular secretion exacerbated pulmonary inflammation, Regenerative Medicine, Ottawa leak, evidenced by total BAL protein levels and lung but not vascular leak, and did not alter Hospital Research Institute & OVR University of Ottawa, Ottawa, wet/dry ratio, was unchanged between ANGPT2 and mortality in a murine model of bacterial tTA http://thorax.bmj.com/ Ontario K1H8L6, Canada; controls , while BAL levels of IgM and albumin were endotoxin-induced ALI. djstewart@ ohri. ca decreased in ANGPT2OVR mice between 24 hours and 48 hours suggesting a partial attenuation of vascular Received 18 April 2017 Revised 3 August 2017 leak. There was no significant difference in LPS-induced OVR tTA (ANGPT2) are ligands for the endothelial cell Accepted 29 August 2017 mortality between ANGPT2 and controls . An ANGPT2-neutralising aptamer partially attenuated (EC)-enriched TIE2 receptor tyrosine kinase. Para- alveolar cell infiltration while exacerbating vascular crine release of ANGPT1 from pericytes promotes leak in LPS-exposed ANGPT2OVR mice, supported TIE2 receptor phosphorylation and downstream on October 1, 2021 by guest. Protected copyright. by underlying time-dependent changes in the lung activation of signalling pathways that protect 3 4 5–7 transcriptional profiles of multiple genes linked to against inflammation and vascular leak. neutrophil recruitment/adhesion and endothelial In contrast, ANGPT2 (stored in Weibel-Palade integrity. bodies of ECs) has been shown to competitively Conclusions Our findings suggest that high inhibit ANGPT1-induced TIE2 phosphorylation circulating ANGPT2 potentiates endotoxin-induced lung in vitro, and its transgenic overexpression in the inflammation but may also exert other pleiotropic effects mouse embryo has been reported to cause defects to help fine-tune the vascular response to lung injury. in vascular development mimicking those seen in ANGPT1 and TIE2 knockout animals.8–10 While these early observations support the classic view of ANGPT2 as a natural TIE2 antagonist and vascular INTRODUCTION destabilising factor,9 there is increasing evidence Acute respiratory distress syndrome (ARDS) is that ANGPT2 may also function as a TIE2 agonist a life-threatening condition for which there is and vasculoprotective factor in a context-dependent currently no specific pharmacological treatment.1 manner. A number of in vitro studies have shown To cite: Schlosser K, Taha M, Pulmonary inflammation and vascular leak are that ANGPT2 can activate the TIE2 receptor under Deng Y, et al. Thorax Published Online First: [please hallmarks of acute lung injury (ALI) seen in ARDS, various circumstances including in non-ECs lacking 11 include Day Month Year]. which may be mediated in part through dysregu- inhibitory coreceptors, over extended periods of doi:10.1136/ lation of the angiopoietin–Tie2 signalling axis.2 time12 or at very high concentrations.13 14 In vivo thoraxjnl-2017-210413 Angiopoietin-1 (ANGPT1) and angiopoietin-2 studies in mice have also shown that ANGPT2 Schlosser K, et al. Thorax 2017;0:1–14. doi:10.1136/thoraxjnl-2017-210413 1 Copyright Article author (or their employer) 2017. Produced by BMJ Publishing Group Ltd (& BTS) under licence. Pulmonary vasculature Thorax: first published as 10.1136/thoraxjnl-2017-210413 on 25 September 2017. Downloaded from can inhibit vascular leak induced by inflammatory stimuli such confirmed by PCR genotyping using DNA extracted from ear as mustard oil.15 Thus, the role of ANGPT2 may vary widely biopsies and transgene-specific primers as described previously.23 from vasculopathic to vasculoprotective factor depending on the Mice were on a CD1 genetic strain background. ANGPT2OVR specific biological context. mice were indistinguishable in size and appearance from litter- In clinical settings, plasma levels of ANGPT2 have been mate controls and represented approximately 25% of each litter. shown to be elevated in patients with inflammatory disorders, 16–20 in particular ALI/ARDS and sepsis, and in some cases were LPS-induced model of ALI 21 17 associated with the severity of lung injury and mortality. Mice received an intratracheal instillation of LPS (Esche- However, while these observational studies establish the clinical richia coli 055:B5; 1 mg/kg or 500 000 EU/kg body weight relevance of ANGPT2 and suggest a potential role as a prog- in normal saline; Sigma), and blood, bronchoalveolar lavage nostic biomarker, they provide limited information on whether (BAL) and lungs were collected after 3 hours, 6 hours, 24 hours, the elevated circulating levels contribute causally to underlying 48 hours and 72 hours. Of note, data for each time point repre- disease activity in ALI. To date, and to the best of our knowledge, sent a separate set of mice rather than serial measurements from no study has directly interrogated the potential contributory role a single set of mice. An LPS dose of 10 mg/kg was used in exper- of high circulating levels of ANGPT2 in an animal model of ALI. iments to assess LPS-induced mortality. Here, we hypothesised that endotoxin-induced ALI would be exacerbated by systemic ANGPT2 overexpression. High plasma Anti-ANGPT2 aptamer treatment in ANGPT2OVR mice levels of ANGPT2 were induced in transgenic mice (ANGP- The anti-ANGPT2 RNA aptamer, which binds to hANGPT2 T2OVR) independent of lung injury, via conditional hepato- protein, was developed previously.24 The aptamer and a scram- cyte-driven overexpression and secretion, and the effects on bled sequence control RNA were synthesised by Samchully pulmonary vascular inflammation, permeability and mortality Pharmaceutical (Seoul, Korea), with 2′-fluoropyrimidines and were then evaluated in the lipopolysaccharide (LPS)-induced terminal 3′−3′ inverted deoxythymidine caps for nuclease resis- model of ALI. Neutralisation of the circulating ANGPT2 in tance. The non-functional control RNA was composed of the ANGPT2OVR mice, via aptamer-based inhibition, was used to same number and type of chemically modified nucleotides, but further probe the potential causal role of ANGPT2 on pulmo- the sequence of nucleotides was randomly scrambled. Aptamer nary inflammation and leak and identify molecular pathways or scrambled-sequence control RNA (0.1 mg/kg, dissolved in involved in ANGPT2-mediated pulmonary transcriptional phosphate buffered saline (PBS)) were injected in ANGPT2OVR reprogramming. mice via tail vein injection by an operator that was blinded to the treatment status. No transfection agent was used with the MATERIALS AND METHODS aptamer or scrambled control RNA to minimise the potential Peripheral blood samples from healthy subjects were obtained for cellular uptake. All mice were then given LPS (1 mg/kg) via with informed written consent between years 2011 and 2014 intratracheal instillation (within 5 min). Mice were euthanised at a single centre,
Load more

Recommended publications
  • Epha4/Tie2 Crosstalk Regulates Leptomeningeal Collateral Remodeling Following Ischemic Stroke
    EphA4/Tie2 crosstalk regulates leptomeningeal collateral remodeling following ischemic stroke Benjamin Okyere, … , John B. Matson, Michelle H. Theus J Clin Invest. 2019. https://doi.org/10.1172/JCI131493. Research In-Press Preview Neuroscience Vascular biology Leptomeningeal anastomoses or pial collateral vessels play a critical role in cerebral blood flow (CBF) restoration following ischemic stroke. The magnitude of this adaptive response is postulated to be controlled by the endothelium, although the underlying molecular mechanisms remain under investigation. Here we demonstrated that endothelial genetic deletion, using EphA4f/f/Tie2-Cre and EphA4f/f/VeCahderin-CreERT2 mice and vessel painting strategies, implicated EphA4 receptor tyrosine kinase as a major suppressor of pial collateral remodeling, CBF and functional recovery following permanent middle cerebral artery occlusion. Pial collateral remodeling is limited by the cross talk between EphA4-Tie2 signaling in vascular endothelial cells, which is mediated through p-Akt regulation. Furthermore, peptide inhibition of EphA4 resulted in acceleration of the pial arteriogenic response. Our findings demonstrate EphA4 is a negative regulator of Tie2 receptor signaling which limits pial collateral arteriogenesis following cerebrovascular occlusion. Therapeutic targeting of EphA4 and/or Tie2 represents an attractive new strategy for improving collateral function, neural tissue health and functional recovery following ischemic stroke. Find the latest version: https://jci.me/131493/pdf 1 EphA4/Tie2
    [Show full text]
  • The Interplay Between Angiopoietin-Like Proteins and Adipose Tissue: Another Piece of the Relationship Between Adiposopathy and Cardiometabolic Diseases?
    International Journal of Molecular Sciences Review The Interplay between Angiopoietin-Like Proteins and Adipose Tissue: Another Piece of the Relationship between Adiposopathy and Cardiometabolic Diseases? Simone Bini *,† , Laura D’Erasmo *,†, Alessia Di Costanzo, Ilenia Minicocci , Valeria Pecce and Marcello Arca Department of Translational and Precision Medicine, Sapienza University of Rome, Viale del Policlinico 155, 00185 Rome, Italy; [email protected] (A.D.C.); [email protected] (I.M.); [email protected] (V.P.); [email protected] (M.A.) * Correspondence: [email protected] (S.B.); [email protected] (L.D.) † These authors contributed equally to this work. Abstract: Angiopoietin-like proteins, namely ANGPTL3-4-8, are known as regulators of lipid metabolism. However, recent evidence points towards their involvement in the regulation of adipose tissue function. Alteration of adipose tissue functions (also called adiposopathy) is considered the main inducer of metabolic syndrome (MS) and its related complications. In this review, we intended to analyze available evidence derived from experimental and human investigations highlighting the contribution of ANGPTLs in the regulation of adipocyte metabolism, as well as their potential role in common cardiometabolic alterations associated with adiposopathy. We finally propose a model of ANGPTLs-based adipose tissue dysfunction, possibly linking abnormalities in the angiopoietins to the induction of adiposopathy and its related disorders. Keywords: adipose tissue; adiposopathy; brown adipose tissue; ANGPTL3; ANGPTL4; ANGPTL8 Citation: Bini, S.; D’Erasmo, L.; Di Costanzo, A.; Minicocci, I.; Pecce, V.; Arca, M. The Interplay between 1. Introduction Angiopoietin-Like Proteins and Adipose tissue (AT) is an important metabolic organ and accounts for up to 25% of Adipose Tissue: Another Piece of the healthy individuals’ weight.
    [Show full text]
  • A Computational Approach for Defining a Signature of Β-Cell Golgi Stress in Diabetes Mellitus
    Page 1 of 781 Diabetes A Computational Approach for Defining a Signature of β-Cell Golgi Stress in Diabetes Mellitus Robert N. Bone1,6,7, Olufunmilola Oyebamiji2, Sayali Talware2, Sharmila Selvaraj2, Preethi Krishnan3,6, Farooq Syed1,6,7, Huanmei Wu2, Carmella Evans-Molina 1,3,4,5,6,7,8* Departments of 1Pediatrics, 3Medicine, 4Anatomy, Cell Biology & Physiology, 5Biochemistry & Molecular Biology, the 6Center for Diabetes & Metabolic Diseases, and the 7Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202; 2Department of BioHealth Informatics, Indiana University-Purdue University Indianapolis, Indianapolis, IN, 46202; 8Roudebush VA Medical Center, Indianapolis, IN 46202. *Corresponding Author(s): Carmella Evans-Molina, MD, PhD ([email protected]) Indiana University School of Medicine, 635 Barnhill Drive, MS 2031A, Indianapolis, IN 46202, Telephone: (317) 274-4145, Fax (317) 274-4107 Running Title: Golgi Stress Response in Diabetes Word Count: 4358 Number of Figures: 6 Keywords: Golgi apparatus stress, Islets, β cell, Type 1 diabetes, Type 2 diabetes 1 Diabetes Publish Ahead of Print, published online August 20, 2020 Diabetes Page 2 of 781 ABSTRACT The Golgi apparatus (GA) is an important site of insulin processing and granule maturation, but whether GA organelle dysfunction and GA stress are present in the diabetic β-cell has not been tested. We utilized an informatics-based approach to develop a transcriptional signature of β-cell GA stress using existing RNA sequencing and microarray datasets generated using human islets from donors with diabetes and islets where type 1(T1D) and type 2 diabetes (T2D) had been modeled ex vivo. To narrow our results to GA-specific genes, we applied a filter set of 1,030 genes accepted as GA associated.
    [Show full text]
  • Single-Cell RNA Sequencing Demonstrates the Molecular and Cellular Reprogramming of Metastatic Lung Adenocarcinoma
    ARTICLE https://doi.org/10.1038/s41467-020-16164-1 OPEN Single-cell RNA sequencing demonstrates the molecular and cellular reprogramming of metastatic lung adenocarcinoma Nayoung Kim 1,2,3,13, Hong Kwan Kim4,13, Kyungjong Lee 5,13, Yourae Hong 1,6, Jong Ho Cho4, Jung Won Choi7, Jung-Il Lee7, Yeon-Lim Suh8,BoMiKu9, Hye Hyeon Eum 1,2,3, Soyean Choi 1, Yoon-La Choi6,10,11, Je-Gun Joung1, Woong-Yang Park 1,2,6, Hyun Ae Jung12, Jong-Mu Sun12, Se-Hoon Lee12, ✉ ✉ Jin Seok Ahn12, Keunchil Park12, Myung-Ju Ahn 12 & Hae-Ock Lee 1,2,3,6 1234567890():,; Advanced metastatic cancer poses utmost clinical challenges and may present molecular and cellular features distinct from an early-stage cancer. Herein, we present single-cell tran- scriptome profiling of metastatic lung adenocarcinoma, the most prevalent histological lung cancer type diagnosed at stage IV in over 40% of all cases. From 208,506 cells populating the normal tissues or early to metastatic stage cancer in 44 patients, we identify a cancer cell subtype deviating from the normal differentiation trajectory and dominating the metastatic stage. In all stages, the stromal and immune cell dynamics reveal ontological and functional changes that create a pro-tumoral and immunosuppressive microenvironment. Normal resident myeloid cell populations are gradually replaced with monocyte-derived macrophages and dendritic cells, along with T-cell exhaustion. This extensive single-cell analysis enhances our understanding of molecular and cellular dynamics in metastatic lung cancer and reveals potential diagnostic and therapeutic targets in cancer-microenvironment interactions. 1 Samsung Genome Institute, Samsung Medical Center, Seoul 06351, Korea.
    [Show full text]
  • 4 Transcription and Secretion Novel Regulator of Angiopoietin-Like Protein A
    Acute-Phase Protein α1-Antitrypsin−−A Novel Regulator of Angiopoietin-like Protein 4 Transcription and Secretion This information is current as Eileen Frenzel, Sabine Wrenger, Stephan Immenschuh, of September 28, 2021. Rembert Koczulla, Ravi Mahadeva, H. Joachim Deeg, Charles A. Dinarello, Tobias Welte, A. Mario Q. Marcondes and Sabina Janciauskiene J Immunol 2014; 192:5354-5362; Prepublished online 23 April 2014; Downloaded from doi: 10.4049/jimmunol.1400378 http://www.jimmunol.org/content/192/11/5354 Supplementary http://www.jimmunol.org/content/suppl/2014/04/23/jimmunol.140037 http://www.jimmunol.org/ Material 8.DCSupplemental References This article cites 56 articles, 25 of which you can access for free at: http://www.jimmunol.org/content/192/11/5354.full#ref-list-1 Why The JI? Submit online. by guest on September 28, 2021 • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2014 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Acute-Phase Protein a1-Antitrypsin—A Novel Regulator of Angiopoietin-like Protein 4 Transcription and Secretion Eileen Frenzel,* Sabine Wrenger,* Stephan Immenschuh,† Rembert Koczulla,‡ Ravi Mahadeva,x H.
    [Show full text]
  • Angiocrine Endothelium: from Physiology to Cancer Jennifer Pasquier1,2*, Pegah Ghiabi2, Lotf Chouchane3,4,5, Kais Razzouk1, Shahin Rafi3 and Arash Rafi1,2,3
    Pasquier et al. J Transl Med (2020) 18:52 https://doi.org/10.1186/s12967-020-02244-9 Journal of Translational Medicine REVIEW Open Access Angiocrine endothelium: from physiology to cancer Jennifer Pasquier1,2*, Pegah Ghiabi2, Lotf Chouchane3,4,5, Kais Razzouk1, Shahin Rafi3 and Arash Rafi1,2,3 Abstract The concept of cancer as a cell-autonomous disease has been challenged by the wealth of knowledge gathered in the past decades on the importance of tumor microenvironment (TM) in cancer progression and metastasis. The sig- nifcance of endothelial cells (ECs) in this scenario was initially attributed to their role in vasculogenesis and angiogen- esis that is critical for tumor initiation and growth. Nevertheless, the identifcation of endothelial-derived angiocrine factors illustrated an alternative non-angiogenic function of ECs contributing to both physiological and pathological tissue development. Gene expression profling studies have demonstrated distinctive expression patterns in tumor- associated endothelial cells that imply a bilateral crosstalk between tumor and its endothelium. Recently, some of the molecular determinants of this reciprocal interaction have been identifed which are considered as potential targets for developing novel anti-angiocrine therapeutic strategies. Keywords: Angiocrine, Endothelium, Cancer, Cancer microenvironment, Angiogenesis Introduction of blood vessels in initiation of tumor growth and stated Metastatic disease accounts for about 90% of patient that in the absence of such angiogenesis, tumors can- mortality. Te difculty in controlling and eradicating not expand their mass or display a metastatic phenotype metastasis might be related to the heterotypic interaction [7]. Based on this theory, many investigators assumed of tumor and its microenvironment [1].
    [Show full text]
  • The Angiopoietin-2 and TIE Pathway As a Therapeutic Target for Enhancing Antiangiogenic Therapy and Immunotherapy in Patients with Advanced Cancer
    International Journal of Molecular Sciences Review The Angiopoietin-2 and TIE Pathway as a Therapeutic Target for Enhancing Antiangiogenic Therapy and Immunotherapy in Patients with Advanced Cancer Alessandra Leong and Minah Kim * Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY 10032, USA; afl[email protected] * Correspondence: [email protected] Received: 26 September 2020; Accepted: 13 November 2020; Published: 18 November 2020 Abstract: Despite significant advances made in cancer treatment, the development of therapeutic resistance to anticancer drugs represents a major clinical problem that limits treatment efficacy for cancer patients. Herein, we focus on the response and resistance to current antiangiogenic drugs and immunotherapies and describe potential strategies for improved treatment outcomes. Antiangiogenic treatments that mainly target vascular endothelial growth factor (VEGF) signaling have shown efficacy in many types of cancer. However, drug resistance, characterized by disease recurrence, has limited therapeutic success and thus increased our urgency to better understand the mechanism of resistance to inhibitors of VEGF signaling. Moreover, cancer immunotherapies including immune checkpoint inhibitors (ICIs), which stimulate antitumor immunity, have also demonstrated a remarkable clinical benefit in the treatment of many aggressive malignancies. Nevertheless, the emergence of resistance to immunotherapies associated with an immunosuppressive tumor microenvironment has restricted therapeutic response, necessitating the development of better therapeutic strategies to increase treatment efficacy in patients. Angiopoietin-2 (ANG2), which binds to the receptor tyrosine kinase TIE2 in endothelial cells, is a cooperative driver of angiogenesis and vascular destabilization along with VEGF. It has been suggested in multiple preclinical studies that ANG2-mediated vascular changes contribute to the development and persistence of resistance to anti-VEGF therapy.
    [Show full text]
  • Stromal Cell Interactions Mediated by Hypoxia-Inducible Factors Promote Angiogenesis, Lymphangiogenesis, and Metastasis
    Oncogene (2013) 32, 4057–4063 & 2013 Macmillan Publishers Limited All rights reserved 0950-9232/13 www.nature.com/onc REVIEW Cancer–stromal cell interactions mediated by hypoxia-inducible factors promote angiogenesis, lymphangiogenesis, and metastasis GL Semenza Interactions between cancer cells and stromal cells, including blood vessel endothelial cells (BECs), lymphatic vessel endothelial cells (LECs), bone marrow-derived angiogenic cells (BMDACs) and other bone marrow-derived cells (BMDCs) play important roles in cancer progression. Intratumoral hypoxia, which affects both cancer and stromal cells, is associated with a significantly increased risk of metastasis and mortality in many human cancers. Recent studies have begun to delineate the molecular mechanisms underlying the effect of intratumoral hypoxia on cancer progression. Reduced O2 availability induces the activity of hypoxia- inducible factors (HIFs), which activate the transcription of target genes encoding proteins that play important roles in many critical aspects of cancer biology. Included among these are secreted factors, including angiopoietin 2, angiopoietin-like 4, placental growth factor, platelet-derived growth factor B, stem cell factor (kit ligand), stromal-derived factor 1, and vascular endothelial growth factor. These factors are produced by hypoxic cancer cells and directly mediate functional interactions with BECs, LECs, BMDACs and other BMDCs that promote angiogenesis, lymphangiogenesis, and metastasis. In addition, lysyl oxidase (LOX) and LOX-like proteins,
    [Show full text]
  • Human Epidermal Growth Factor Receptor 2 Regulates Angiopoietin-2 Expression in Breast Cancer Via AKT and Mitogen-Activated Protein Kinase Pathways Guilian Niu and W
    Research Article Human Epidermal Growth Factor Receptor 2 Regulates Angiopoietin-2 Expression in Breast Cancer via AKT and Mitogen-Activated Protein Kinase Pathways Guilian Niu and W. Bradford Carter Don and Erika Wallace Comprehensive Breast Program, H. Lee Moffitt Cancer Center and Research Institute, Department of Interdisciplinary Oncology, University of South Florida College of Medicine, Tampa, Florida Abstract signaling pathways. None of the ligands bind HER2, but HER2 is Abnormal activation of human epidermal growth factor the preferred dimerization partner for all of the ErbB receptors. receptor 2 (HER2; ErbB-2) in breast tumors results in The role of HER2 as an important predictor of patient outcome increased metastasis and angiogenesis, as well as reduced and response to various therapies in breast cancer has been clearly survival.Here, we show that angiopoietin-2 (Ang-2) expression established (2, 5–7). Patients with HER2-overexpressing breast correlates with HER2 activity in human breast cancer cell tumors have an increased incidence of metastasis and a poorer lines.Inhibiting HER2 activity with anti-HER2 monoclonal survival rate when compared with patients whose tumors express antibody trastuzumab (Herceptin) or HER2 short interfering HER2 at normal levels. The angiopoietins (Ang) are novel endothelial growth factors, RNA in tumor cells down-regulates Ang-2 expression.Consis- tent with the important roles of AKT and mitogen-activated found to be ligands for the endothelium-specific tyrosine receptor protein kinase in the HER2 signaling pathway, AKT and ERK Tie-2 (8, 9). Ang-1 plays a role in maintaining and stabilizing mitogen-activated protein kinase (MAPK) kinase activity is mature vessels by promoting the interaction between endothelial necessary for Ang-2 up-regulation by HER2.Moreover, over- cells and the surrounding support cells (10–12).
    [Show full text]
  • Altiratinib Inhibits Tumor Growth, Invasion, Angiogenesis, and Microenvironment-Mediated Drug Resistance Via Balanced Inhibition of MET, TIE2, and VEGFR2 Bryan D
    Published OnlineFirst August 18, 2015; DOI: 10.1158/1535-7163.MCT-14-1105 Small Molecule Therapeutics Molecular Cancer Therapeutics Altiratinib Inhibits Tumor Growth, Invasion, Angiogenesis, and Microenvironment-Mediated Drug Resistance via Balanced Inhibition of MET, TIE2, and VEGFR2 Bryan D. Smith1, Michael D. Kaufman1, Cynthia B. Leary1, Benjamin A. Turner1, Scott C. Wise1, Yu Mi Ahn1, R. John Booth1, Timothy M. Caldwell1, Carol L. Ensinger1, Molly M. Hood1, Wei-Ping Lu1, Tristan W. Patt1, William C. Patt1, Thomas J. Rutkoski1, Thiwanka Samarakoon1, Hanumaiah Telikepalli1, Lakshminarayana Vogeti1, Subha Vogeti1, Karen M. Yates1, Lawrence Chun2, Lance J. Stewart2, Michael Clare1, and Daniel L. Flynn1,3 Abstract Altiratinib (DCC-2701) was designed based on the rationale of wild-type and mutated forms, in vitro and in vivo. Through its engineering a single therapeutic agent able to address multiple balanced inhibitory potency versus MET, TIE2, and VEGFR2, hallmarks of cancer (1). Specifically, altiratinib inhibits not only altiratinib provides an agent that inhibits three major evasive mechanisms of tumor initiation and progression, but also drug (re)vascularization and resistance pathways (HGF, ANG, and resistance mechanisms in the tumor and microenvironment VEGF) and blocks tumor invasion and metastasis. Altiratinib through balanced inhibition of MET, TIE2 (TEK), and VEGFR2 exhibits properties amenable to oral administration and exhibits (KDR) kinases. This profile was achieved by optimizing binding substantial blood–brain barrier penetration, an attribute of into the switch control pocket of all three kinases, inducing type II significance for eventual treatment of brain cancers and brain inactive conformations. Altiratinib durably inhibits MET, both metastases. Mol Cancer Ther; 14(9); 1–12.
    [Show full text]
  • The Metabolic Effects of Angiopoietin-Like Protein 8 (ANGPLT8) Are Differentially Regulated By
    bioRxiv preprint doi: https://doi.org/10.1101/734954; this version posted August 15, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. The Metabolic Effects of Angiopoietin-like protein 8 (ANGPLT8) are Differentially Regulated by Insulin and Glucose in Adipose Tissue and Liver and are Controlled by AMPK Signaling Lu Zhang1, Chris E. Shannon1, Terry M. Bakewell1, Muhammad A. Abdul-Ghani1, Marcel Fourcaudot1, and Luke Norton1* Affiliations: 1Diabetes Division, University of Texas Health Science Center, San Antonio, TX Key words: ANGPTL8, Insulin, Lipid, Adipose Tissue, Liver, Transcription factor Running title: Regulation and function of ANGPTL8 Word Count (main): 3,493 Word Count (abstract): 249 Figures and Tables: 6 Figures, 3 Tables, 4 Supplementary Figures *Address all correspondence to: Luke Norton, PhD Email: [email protected] bioRxiv preprint doi: https://doi.org/10.1101/734954; this version posted August 15, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. Abstract Objective: The angiopoietin-like protein (ANGPTL) family represents a promising therapeutic target for dyslipidemia, which is a feature of obesity and type 2 diabetes (T2DM). The aim of the present study was to determine the metabolic role of ANGPTL8 and to investigate its nutritional, hormonal and molecular regulation in key metabolic tissues.
    [Show full text]
  • Cardiovascular Disease Products
    Cardiovascular Disease Products For more information, visit: www.bosterbio.com Cardiovascular Disease Research Cardiovascular disease is the leading cause of death in developed nations. Boster Bio aims to supply researchers with high-quality antibodies and ELISA kits so they can make new discoveries and help save lives. In this catalogue you will find a comprehensive list of high-affinity Boster antibodies and high sensitivity Boster ELISA kits targeted at proteins associated with cardiovascular disease. Boster: The Fastest Growing About Bosterbio Antibody Company In 2015 Boster is an antibody manufacturer founded in 1993 by histologist Steven Xia. Over the past two decades, Boster and its products have been cited in over 20,000 publications and counting. The firm specializes in developing antibodies and ELISA kits that feature high affinity, Boster Bio received the CitaAb award for high specificity at affordable the greatest increase in number of prices. citations during 2015 than any other antibody manufacturer. Table of Contents Boster Cardiovascular Disease Related Antibodies…………..………..... 2 Boster Cardiovascular Disease Related ELISA Kits……………………..…. 9 1 High Affinity Boster Antibodies Boster supplies only the highest quality antibodies. Our high-affinity polyclonal and monoclonal antibodies are thoroughly validated by Western Blotting, Immunohistochemistry and ELISA. This is our comprehensive catalog of our antibody products related to cardiovascular disease, sorted in alphabetical order by target gene name. Catalog No Product Name
    [Show full text]