DOCSLIB.ORG

Ligand-Dependent Platelet-Derived Growth Factor Receptor (PDGFR)-A Activation Sensitizes Rare Lung Cancer and Sarcoma Cells to PDGFR Kinase Inhibitors

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Ligand-Dependent Platelet-Derived Growth Factor Receptor (PDGFR)-A Activation Sensitizes Rare Lung Cancer and Sarcoma Cells to PDGFR Kinase Inhibitors Published OnlineFirst April 14, 2009; DOI: 10.1158/0008-5472.CAN-08-4327 Research Article Ligand-Dependent Platelet-Derived Growth Factor Receptor (PDGFR)-A Activation Sensitizes Rare Lung Cancer and Sarcoma Cells to PDGFR Kinase Inhibitors Ultan McDermott,1 Rachel Y. Ames,1 A. John Iafrate,2 Shyamala Maheswaran,1 Hannah Stubbs,2 Patricia Greninger,1 Kaitlin McCutcheon,1 Randy Milano,1 Angela Tam,1 Diana Y. Lee,1 Laury Lucien,1 Brian W. Brannigan,1 Lindsey E. Ulkus,1 Xiao-Jun Ma,3 Mark G. Erlander,3 Daniel A. Haber,1 Sreenath V. Sharma,1 and Jeffrey Settleman1 1Center for Molecular Therapeutics, Massachusetts General Hospital Cancer Center and Harvard Medical School, Charlestown, Massachusetts; 2Molecular Diagnostics Laboratory, Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts; and 3AviaraDx, Inc., Carlsbad, California Abstract Introduction Platelet-derived growth factor (PDGF) receptors (PDGFR) and Sunitinib is a multitargeted tyrosine kinase inhibitor that their ligands play critical roles in several human malignan- potentlyinhibits vascular endothelial growth factor (VEGF), cies. Sunitinib is a clinically approved multitargeted tyrosine platelet-derived growth factor (PDGF), and c-KIT receptor kinases kinase inhibitor that inhibits vascular endothelial growth (1). In renal cell carcinoma, sunitinib showed superiorityover factor receptor, c-KIT, and PDGFR, and has shown clinical standard IFN-a therapy(2); sunitinib is now recommended for activity in various solid tumors. Activation of PDGFR previouslyuntreated patients with advanced renal cell carcinoma. signaling has been described in gastrointestinal stromal Sunitinib is also approved for treatment of imatinib-refractory tumors (PDGFRA mutations) as well as in chronic myeloid gastrointestinal stromal tumors (GIST), manyof which harbor leukemia (BCR-PDGFRA translocation), and sunitinib can activating c-KIT or PDGF receptor (PDGFR) kinase domain yield clinical benefit in both settings. However, the discovery mutations (3). A recent phase II clinical studyhas revealed efficacy of PDGFR activating mutations or gene rearrangements in of single-agent sunitinib in advanced non–small-cell lung cancer other tumor types could reveal additional patient populations (NSCLC) patients (4). Accumulating evidence indicates that who might benefit from treatment with anti-PDGFR therapies, inhibition of VEGF signaling using various antiangiogenic agents such as sunitinib. Using a high-throughput cancer cell line can suppress tumor growth and improve patient survival (2, 5, 6); screening platform, we found that only 2 of 637 tested human however, it is unclear from studies involving multikinase inhibitors, tumor-derived cell lines show significant sensitivity to single- such as sunitinib, as to the relative contribution of VEGF receptor agent sunitinib exposure. These two cell lines [a non–small- inhibition in suppressing tumor growth. cell lung cancer (NSCLC) and a rhabdomyosarcoma] showed The PDGFR/PDGF system includes two receptors (PDGFRA and expression of highly phosphorylated PDGFRA. In the suniti- PDGFRB) and four ligands (PDGFA, PDGFB, PDGFC, and PDGFD; nib-sensitive adenosquamous NSCLC cell line, PDGFRA ref. 7). Ligand binding induces receptor dimerization, enabling expression was associated with focal PFGRA gene amplifica- autophosphorylation of specific tyrosine residues and subsequent tion, which was similarly detected in a small fraction of recruitment of a varietyof signal transduction molecules (8). squamous cell NSCLC primary tumor specimens. Moreover, in PDGFR regulates normal cellular growth and differentiation (9), this NSCLC cell line, focal amplification of the gene encoding and expression of activated PDGFR promotes oncogenic transfor- the PDGFR ligand PDGFC was also detected, and silencing mation (10), suggesting that activating mutations or gene PDGFRA or PDGFC expression by RNA interference inhibited rearrangements could playa role in human tumorigenesis. in vitro in vivo proliferation. A similar codependency on PDGFRA and PDGFC Numerous and studies showed that inhibition of was observed in the sunitinib-sensitive rhabdomyosarcoma PDGFRA signaling disrupts cancer cell survival in the subset of PDGFRA cell line. These findings suggest that, in addition to GISTs with activating mutations (11, 12). In a recent study gastrointestinal stromal tumors, rare tumors that show of 150 NSCLC patient samples, activated PDGFRA was detected in PDGFC-mediated PDGFRA activation may also be clinically 13% of cases (13), suggesting that a subset of these patients might responsive to pharmacologic PDGFRA or PDGFC inhibition. benefit from therapies directed against PDGFRA. Moreover, [Cancer Res 2009;69(9):3937–46] PDGFRA overexpression has been observed in metastatic versus nonmetastatic medulloblastoma patient samples, and disrupting PDGFRA function inhibited the metastatic potential of medullo- blastoma cells in vitro (14). We recentlyreported the development of a high-throughput platform for profiling a large panel of human cancer cell lines with Note: Supplementarydata for this article are available at Cancer Research Online molecularlytargeted inhibitors to identifysubsets with significant (http://cancerres.aacrjournals.org/). Requests for reprints: JeffreySettleman, Center for Molecular Therapeutics, sensitivity(15). That analysisrevealed several examples of Massachusetts General Hospital Cancer Center and Harvard Medical School, 149 13th genotype-associated sensitivities to selective kinase inhibitors, Street, Charlestown, MA 02129. Phone: 617-724-9556; Fax: 617-726-7808; E-mail: showing the utilityof this strategyto reveal cell autonomous [email protected]. I2009 American Association for Cancer Research. tumor cell responses to anticancer agents. Here, we describe the doi:10.1158/0008-5472.CAN-08-4327 profiling of 637 cancer cell lines for sensitivityto single-agent www.aacrjournals.org 3937 Cancer Res 2009; 69: (9). May 1, 2009 Downloaded from cancerres.aacrjournals.org on September 26, 2021. © 2009 American Association for Cancer Research. Published OnlineFirst April 14, 2009; DOI: 10.1158/0008-5472.CAN-08-4327 Cancer Research sunitinib, using a monoculture format that precludes any additional wash in PBS/0.5% BSA, cells were stained with 10 Ag/mL contribution of drug effects on angiogenesis. Our studies revealed propidium iodide (Sigma) and treated with RNase A (Sigma) before two- that the majorityof tested cell lines are highlyrefractoryto dimensional fluorescence-activated cell sorting analysis using CellQuest sunitinib. Of the two cell lines showing sunitinib sensitivity, both software (Becton Dickinson). SNP and gene expression analyses. Gene copynumbers were were found to express high levels of PDGFRA and PDGFC mRNA determined as previouslydescribed using the GeneChip Human Mapping and phosphorylated PDGFRA protein. ShRNA knockdown of 250K. The arraywas then scanned on the GeneChip Scanner 3000 7G and PDGFRA was as effective as sunitinib in decreasing cell analyzed using GTYPE version 4.0 with the Dynamic Model Mapping proliferation in both cell lines, and targeting the PDGFC ligand Algorithm and the GeneChip Human Mapping 500K Set libraryfiles alone was similarlyeffective. (Mapping 250K_Nsp). Our findings suggest that whereas antiangiogenesis activity For gene expression studies, RNA was extracted using the Qiagen RNA probablyaccounts for the majorityof the clinical benefit associated easykit (P/N 74106) and amplified and biotin labeled with the Arcturus with sunitinib treatment in solid tumors, in rare cases, beyond RiboAmp RNA Amplification Kit using biotinylated ribonucleotides (Perkin- PDGFRA-mutant GISTs, activated PDGFRA maybe the critical Elmer PN Biotin-11-UTP, NEL543001EA/Biotin-11-CTP, NEL542001EA) in vitro target, and that selective PDGFRA inhibitors maybe useful in the during transcription. Labeled aRNA was hybridized to Affymetric GeneChip Human X3P (GPL1352) using protocols described within the clinical management of a subset of tumors that exhibit PDGFRA Affymetrix GeneChip Expression Analysis Technical Manual (PN701021 Rev. activation. Moreover, in tumors with evidence of PDGFC ligand 3). Data were acquired using the Affymetrix GeneChip 3000 Scanner with overexpression, neutralizing antibodies maybe an equallyeffective autoloader and 7G upgrade. GCOS ver 1.4 software was used to run the therapeutic modality. scanner and analyze the data. The expression value for each gene was calculated using Affymetrix GeneChip software and data were analyzed using dChip software4 (17). Probe sets were filtered using two criteria: (a) Materials and Methods coefficient of variation between 0.5 and 1,000 and (b) P call rate in arrays Human cancer cell lines and cell viability assays. Human cancer cell z20%. lines were obtained from commercial vendors and were maintained and Quantitative PCR. Total RNA was isolated and purified from cells using tested for viabilityusing an automated platform, as previouslydescribed STAT-60 (Tel-Test, Inc.). cDNA was transcribed from 2 Ag of total RNA using (15). Cells were treated for 72 h with 1 Amol/L sunitinib and then assayed the AffinityScript Multi Temperature cDNA Synthesis kit (Stratagene). for cytostatic or cytotoxic responses. We elected to use this concentration Quantitative PCR was done using the QuantiTect SYBR Green PCR kit based on steady-state plasma concentrations of f0.2 Amol/L at clinically (Qiagen) and with an ABI PRISM 7000 real-time cycler (Applied
Load more

Recommended publications
  • Platelet-Derived Growth Factor Receptor Expression and Amplification in Choroid Plexus Carcinomas
    Modern Pathology (2008) 21, 265–270 & 2008 USCAP, Inc All rights reserved 0893-3952/08 $30.00 www.modernpathology.org Platelet-derived growth factor receptor expression and amplification in choroid plexus carcinomas Nina N Nupponen1,*, Janna Paulsson2,*, Astrid Jeibmann3, Brigitte Wrede4, Minna Tanner5, Johannes EA Wolff 6, Werner Paulus3, Arne O¨ stman2 and Martin Hasselblatt3 1Molecular Cancer Biology Program, University of Helsinki, Helsinki, Finland; 2Department of Oncology–Pathology, Cancer Centrum Karolinska, Karolinska Institutet, Stockholm, Sweden; 3Institute of Neuropathology, University Hospital Mu¨nster, Mu¨nster, Germany; 4Department of Pediatric Oncology, University of Regensburg, Regensburg, Germany; 5Department of Oncology, Tampere University Hospital, Tampere, Finland and 6Children’s Cancer Hospital, MD Anderson Cancer Center, Houston, TX, USA Platelet-derived growth factor (PDGF) receptor signaling has been implicated in the development of glial tumors, but not yet been examined in choroid plexus carcinomas, pediatric tumors with dismal prognosis for which novel treatment options would be desirable. Therefore, protein expression of PDGF receptors a and b as well as amplification status of the respective genes, PDGFRA and PDGFRB, were examined in a series of 22 patients harboring choroid plexus carcinoma using immunohistochemistry and chromogenic in situ hybridization (CISH). The majority of choroid plexus carcinomas expressed PDGF receptors with 6 cases (27%) displaying high staining scores for PDGF receptor a and 13 cases (59%) showing high staining scores for PDGF receptor b. Correspondingly, copy-number gains of PDGFRA were observed in 8 cases out of 12 cases available for CISH and 1 case displayed amplification (six or more signals per nucleus). The proportion of choroid plexus carcinomas with amplification of PDGFRB was even higher (5/12 cases).
    [Show full text]
  • The Receptor Tyrosine Kinase Trka Is Increased and Targetable in HER2-Positive Breast Cancer
    biomolecules Article The Receptor Tyrosine Kinase TrkA Is Increased and Targetable in HER2-Positive Breast Cancer Nathan Griffin 1,2, Mark Marsland 1,2, Severine Roselli 1,2, Christopher Oldmeadow 2,3, 2,4 2,4 1,2, , 1,2, John Attia , Marjorie M. Walker , Hubert Hondermarck * y and Sam Faulkner y 1 School of Biomedical Sciences and Pharmacy, Faculty of Health and Medicine, University of Newcastle, Callaghan, NSW 2308, Australia; nathan.griffi[email protected] (N.G.); [email protected] (M.M.); [email protected] (S.R.); [email protected] (S.F.) 2 Hunter Medical Research Institute, University of Newcastle, New Lambton Heights, NSW 2305, Australia; [email protected] (C.O.); [email protected] (J.A.); [email protected] (M.M.W.) 3 School of Mathematical and Physical Sciences, Faculty of Science and Information Technology, University of Newcastle, Callaghan, NSW 2308, Australia 4 School of Medicine and Public Health, Faculty of Health and Medicine, University of Newcastle, Callaghan, NSW 2308, Australia * Correspondence: [email protected]; Tel.: +61-2492-18830; Fax: +61-2492-16903 Contributed equally to the study. y Received: 19 August 2020; Accepted: 15 September 2020; Published: 17 September 2020 Abstract: The tyrosine kinase receptor A (NTRK1/TrkA) is increasingly regarded as a therapeutic target in oncology. In breast cancer, TrkA contributes to metastasis but the clinicopathological significance remains unclear. In this study, TrkA expression was assessed via immunohistochemistry of 158 invasive ductal carcinomas (IDC), 158 invasive lobular carcinomas (ILC) and 50 ductal carcinomas in situ (DCIS).
    [Show full text]
  • Role and Regulation of Pdgfra Signaling in Liver Development and Regeneration
    The American Journal of Pathology, Vol. 182, No. 5, May 2013 ajp.amjpathol.org GROWTH FACTORS, CYTOKINES, AND CELL CYCLE MOLECULES Role and Regulation of PDGFRa Signaling in Liver Development and Regeneration Prince K. Awuah,* Kari N. Nejak-Bowen,* and Satdarshan P.S. Monga*y From the Division of Experimental Pathology,* Department of Pathology, and the Department of Medicine,y University of Pittsburgh, Pittsburgh, Pennsylvania Accepted for publication January 22, 2013. Aberrant platelet-derived growth factor receptor-a (PDGFRa) signaling is evident in a subset of hepato- cellular cancers (HCCs). However, its role and regulation in hepatic physiology remains elusive. In the Address correspondence to a fi Satdarshan P.S. Monga, M.D., current study, we examined PDGFR signaling in liver development and regeneration. We identi ed a a Divisions of Experimental notable PDGFR activation in hepatic morphogenesis that, when interrupted by PDGFR -blocking anti- Pathology, Pathology and body, led to decreased hepatoblast proliferation and survival in embryonic liver cultures. We also identified Medicine, University of Pitts- temporal PDGFRa overexpression, which is regulated by epidermal growth factor (EGF) and tumor necrosis burgh School of Medicine, 200 factor a, and its activation at 3 to 24 hours after partial hepatectomy. Through generation of hepatocyte- Lothrop St., S-422 BST, Pitts- specific PDGFRA knockout (KO) mice that lack an overt phenotype, we show that absent PDGFRa burgh, PA 15261. E-mail: compromises extracelluar signal-regulated kinases and AKT activation 3 hours after partial hepatectomy, [email protected]. which, however, is alleviated by temporal compensatory increases in the EGF receptor (EGFR) and the hepatocyte growth factor receptor (Met) expression and activation along with rebound activation of extracellular signal-regulated kinases and AKT at 24 hours.
    [Show full text]
  • N-Glycosylation As Determinant of Epidermal Growth Factor Receptor Conformation in Membranes
    N-Glycosylation as determinant of epidermal growth factor receptor conformation in membranes Karol Kaszubaa,1, Michał Grzybekb,c,1, Adam Orłowskia, Reinis Dannea, Tomasz Róga, Kai Simonsd,2, Ünal Coskunb,c,2, and Ilpo Vattulainena,e,2 aDepartment of Physics, Tampere University of Technology, FI-33101 Tampere, Finland; bPaul Langerhans Institute Dresden of the Helmholtz Centre Munich at the University Clinic Carl Gustav Carus, TU Dresden, 01307 Dresden, Germany; cGerman Center for Diabetes Research (DZD e.V.), 85764 Neuherberg, Germany; dMax Planck Institute for Molecular Cell Biology and Genetics, 01307 Dresden, Germany; and eCenter for Biomembrane Physics (MEMPHYS), University of Southern Denmark, 5230 Odense, Denmark Contributed by Kai Simons, February 24, 2015 (sent for review April 10, 2014; reviewed by Helmut Grubmüller and Paul M. P. Van Bergen en Henegouwen) The epidermal growth factor receptor (EGFR) regulates several data at the single-molecule level stipulate a greater distance critical cellular processes and is an important target for cancer between the ECD of the receptor and the membrane in the therapy. In lieu of a crystallographic structure of the complete absence of ligand (9, 10). receptor, atomistic molecular dynamics (MD) simulations have To resolve this discrepancy, the present study considers two recently shown that they can excel in studies of the full-length key parameters that were not included in previous simulations of receptor. Here we present atomistic MD simulations of the mono- the monomeric EGFR: N-glycosylation of the ectodomain of meric N-glycosylated human EGFR in biomimetic lipid bilayers that EGFR that contributes up to 50 kDa of the total molecular are, in parallel, also used for the reconstitution of full-length recep- weight of ∼178 kDa (11, 12), and a lipid environment that pre- tors.
    [Show full text]
  • (HER2/Neu) Status of Breast Carcinoma and Their Correlation with Clinico-Pathological Parameters
    Research Article ISSN: 2574 -1241 DOI: 10.26717/BJSTR.2020.25.004173 Expression of Hormone Receptor and Human Epidermal Growth Factor Receptor (HER2/neu) Status of Breast Carcinoma and Their Correlation with Clinico-Pathological Parameters Bushra Sikandar1, Yusra Shafique1*, Uzma Bukhari1 and Sidra Memon2 1Department of Pathology, Dow Medical College, Pakistan 2Department of Surgery, Dow Medical College, Pakistan *Corresponding author: nd Yusra Shafique, Department of Pathology, 2 floor, Dow Medical College, Dow University of Health Sciences, Karachi, Sindh, Pakistan ARTICLE INFO Abstract Received: Objectives: Published: January 20, 2020 To investigate, the expression profiling of ER, PgR and HER2/neu in February 03, 2020 breast cancer cases of tertiary care hospital and to correlate the hormone receptors and Design: Citation: HER2/neu expression with clinico-pathological parameters. Setting: Case series study Bushra Sikandar, Yusra Shafique, Uzma Bukhari, Sidra Memon. Expression of Histopathology section of Dow Diagnostic Research and Reference Laboratory,Methodology: (DDRRL) Karachi Hormone Receptor and Human Epidermal Growth Factor Receptor (HER2/neu) Status A total of 104 mastectomy samples were collected retrospectively between January 2018 to August 2019 at Histopathology section of Dow Diagnostic of Breast Carcinoma and Their Correlation Research and Reference Laboratory, (DDRRL) Karachi. Clinico-pathological parameters with Clinico-Pathological Parameters. of tumors were recorded, and receptor status was evaluated by immunohistochemistry Biomed J Sci & Tech Res 25(2)-2020. BJSTR. using α-ER, α-PgR and α-HER2/neu antibodies. SPSS version21 was used. Result analysis Keywords:MS.ID.004173. was done by using Chi-square and Fisher’s exact tests. A p-value of <0.05 was considered as statisticallyResults: significant.
    [Show full text]
  • Erbb3 Is Involved in Activation of Phosphatidylinositol 3-Kinase by Epidermal Growth Factor STEPHEN P
    MOLECULAR AND CELLULAR BIOLOGY, June 1994, p. 3550-3558 Vol. 14, No. 6 0270-7306/94/$04.00+0 Copyright C 1994, American Society for Microbiology ErbB3 Is Involved in Activation of Phosphatidylinositol 3-Kinase by Epidermal Growth Factor STEPHEN P. SOLTOFF,l* KERMIT L. CARRAWAY III,1 S. A. PRIGENT,2 W. G. GULLICK,2 AND LEWIS C. CANTLEY' Division of Signal Transduction, Department ofMedicine, Beth Israel Hospital, Boston, Massachusetts 02115,1 and Molecular Oncology Laboratory, ICRF Oncology Group, Hammersmith Hospital, London W12 OHS, United Kingdom2 Received 11 October 1993/Returned for modification 11 November 1993/Accepted 24 February 1994 Conflicting results concerning the ability of the epidermal growth factor (EGF) receptor to associate with and/or activate phosphatidylinositol (Ptdlns) 3-kinase have been published. Despite the ability of EGF to stimulate the production of Ptdlns 3-kinase products and to cause the appearance of PtdIns 3-kinase activity in antiphosphotyrosine immunoprecipitates in several cell lines, we did not detect EGF-stimulated Ptdlns 3-kinase activity in anti-EGF receptor immunoprecipitates. This result is consistent with the lack of a phosphorylated Tyr-X-X-Met motif, the p85 Src homology 2 (SH2) domain recognition sequence, in this receptor sequence. The EGF receptor homolog, ErbB2 protein, also lacks this motif. However, the ErbB3 protein has seven repeats of the Tyr-X-X-Met motif in the carboxy-terminal unique domain. Here we show that in A431 cells, which express both the EGF receptor and ErbB3, Ptdlns 3-kinase coprecipitates with the ErbB3 protein (pl80eR3) in response to EGF. p180B3 is also shown to be tyrosine phosphorylated in response to EGF.
    [Show full text]
  • The Thrombopoietin Receptor : Revisiting the Master Regulator of Platelet Production
    This is a repository copy of The thrombopoietin receptor : revisiting the master regulator of platelet production. White Rose Research Online URL for this paper: https://eprints.whiterose.ac.uk/175234/ Version: Published Version Article: Hitchcock, Ian S orcid.org/0000-0001-7170-6703, Hafer, Maximillian, Sangkhae, Veena et al. (1 more author) (2021) The thrombopoietin receptor : revisiting the master regulator of platelet production. Platelets. pp. 1-9. ISSN 0953-7104 https://doi.org/10.1080/09537104.2021.1925102 Reuse This article is distributed under the terms of the Creative Commons Attribution (CC BY) licence. This licence allows you to distribute, remix, tweak, and build upon the work, even commercially, as long as you credit the authors for the original work. More information and the full terms of the licence here: https://creativecommons.org/licenses/ Takedown If you consider content in White Rose Research Online to be in breach of UK law, please notify us by emailing [email protected] including the URL of the record and the reason for the withdrawal request. [email protected] https://eprints.whiterose.ac.uk/ Platelets ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/iplt20 The thrombopoietin receptor: revisiting the master regulator of platelet production Ian S. Hitchcock, Maximillian Hafer, Veena Sangkhae & Julie A. Tucker To cite this article: Ian S. Hitchcock, Maximillian Hafer, Veena Sangkhae & Julie A. Tucker (2021): The thrombopoietin receptor: revisiting the master regulator of platelet production, Platelets, DOI: 10.1080/09537104.2021.1925102 To link to this article: https://doi.org/10.1080/09537104.2021.1925102 © 2021 The Author(s).
    [Show full text]
  • PDGF-C and PDGF-D Signaling in Vascular Diseases and Animal Models
    Molecular Aspects of Medicine 62 (2018) 1e11 Contents lists available at ScienceDirect Molecular Aspects of Medicine journal homepage: www.elsevier.com/locate/mam PDGF-C and PDGF-D signaling in vascular diseases and animal models * Erika Folestad a, Anne Kunath b, Dick Wågsater€ b, a Division of Vascular Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden b Division of Drug Research, Department of Medical and Health Sciences, Linkoping€ University, Linkoping,€ Sweden article info abstract Article history: Members of the platelet-derived growth factor (PDGF) family are well known to be involved in different Received 31 August 2017 pathological conditions. The cellular and molecular mechanisms induced by the PDGF signaling have Received in revised form been well studied. Nevertheless, there is much more to discover about their functions and some 14 November 2017 important questions to be answered. This review summarizes the known roles of two of the PDGFs, Accepted 22 January 2018 PDGF-C and PDGF-D, in vascular diseases. There are clear implications for these growth factors in several Available online 14 February 2018 vascular diseases, such as atherosclerosis and stroke. The PDGF receptors are broadly expressed in the cardiovascular system in cells such as fibroblasts, smooth muscle cells and pericytes. Altered expression Keywords: Aneurysm of the receptors and the ligands have been found in various cardiovascular diseases and current studies fi Atherosclerosis have shown important implications of PDGF-C and PDGF-D signaling in brosis, neovascularization, Growth factor atherosclerosis and restenosis. Myocardial infarction © 2018 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND Smooth muscle cells license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
    [Show full text]
  • Intratumoral Heterogeneity of Receptor Tyrosine Kinases EGFR and PDGFRA Amplification in Glioblastoma Defines Subpopulations with Distinct Growth Factor Response
    Intratumoral heterogeneity of receptor tyrosine kinases EGFR and PDGFRA amplification in glioblastoma defines subpopulations with distinct growth factor response Nicholas J. Szerlipa, Alicia Pedrazab, Debyani Chakravartyb, Mohammad Azimc, Jeremy McGuirec, Yuqiang Fangd, Tatsuya Ozawae, Eric C. Hollande,f,g,h, Jason T. Hused,h, Suresh Jhanward, Margaret A. Levershac, Tom Mikkelseni, and Cameron W. Brennanb,f,h,1 aDepartment of Neurosurgery, Wayne State University Medical School, Detroit, MI 48201; bHuman Oncology and Pathogenesis Program, cMolecular Cytogenetic Core Laboratory, dDepartment of Pathology, eCancer Biology and Genetics Program, fDepartment of Neurosurgery, gDepartment of Surgery, and hBrain Tumor Center, Memorial Sloan-Kettering Cancer Center, New York, NY 10065; and iDepartments of Neurology and Neurosurgery, Henry Ford Health System, Detroit, MI 48202 Edited by Webster K. Cavenee, Ludwig Institute, University of California at San Diego, La Jolla, CA, and approved December 29, 2011 (received for review August 29, 2011) Glioblastoma (GBM) is distinguished by a high degree of intra- demonstrated in GBM and has been shown to mediate resistance tumoral heterogeneity, which extends to the pattern of expression to single-RTK inhibition through “RTK switching” in cell lines and amplification of receptor tyrosine kinases (RTKs). Although (11). Although such RTK coactivation has been measured at the most GBMs harbor RTK amplifications, clinical trials of small-mole- protein level, its significance in maintaining tumor cell sub- cule inhibitors targeting individual RTKs have been disappointing to populations has not been established. date. Activation of multiple RTKs within individual GBMs provides We have previously reported prominent PDGFR activation by a theoretical mechanism of resistance; however, the spectrum of platelet-derived growth factor beta (PDGFB) ligand in GBMs EGFR MET fi functional RTK dependence among tumor cell subpopulations in with or ampli cation (12).
    [Show full text]
  • (C-Erbb-2) and Epidermal Growth Factor Receptor in Cervical Cancer
    Gynecologic Oncology 93 (2004) 209–214 www.elsevier.com/locate/ygyno Expression of HER2neu (c-erbB-2) and epidermal growth factor receptor in cervical cancer: prognostic correlation with clinical characteristics, and comparison of manual and automated imaging analysis$ Christopher M. Lee,a R. Jeffrey Lee,b Elizabeth Hammond,c Alexander Tsodikov,d Mark Dodson,e Karen Zempolich,e and David K. Gaffneya,* a Department of Radiation Oncology, University of Utah, Salt Lake City, UT 84132, USA b Department of Radiation Oncology, LDS Hospital, Salt Lake City, UT, USA c Department of Pathology, LDS Hospital, Salt Lake City, UT, USA d Department of Biostatistics, Huntsman Cancer Institute, Salt Lake City, UT, USA e Department of Gynecologic Oncology, University of Utah, Salt Lake City, UT, USA Received 8 October 2003 Abstract Objectives. To evaluate HER2neu and epidermal growth factor receptor (EGFR) expression with respect to overall survival and disease- free survival (DFS), and correlate expression with pretreatment factors. Comparative evaluations of manual and automated immunohistochemical imaging systems for HER2neu and EGFR expression were made. Methods. Fifty-five patients with stages I–IVA carcinoma of the cervix were treated with definitive radiation therapy. Immunohistochemistry was performed for HER2neu and EGFR, and scored by both manual and automated methods. Univariate and multivariate analyses were performed with disease-free survival (DFS) and overall survival (OS) as primary endpoints, and biomarkers were evaluated for correlation between prognostic factors. Results. Strong correlations in HER2neu and EGFR protein expression were observed between digitally and manually analyzed staining ( P V 0.0001). Increased FIGO stage and decreased HER2neu expression were significant for reduced DFS on univariate analysis ( P V 0.001 and P = 0.03, respectively).
    [Show full text]
  • PDGFRB FISH for Gleevec Eligibility in Myelodysplastic Syndrome/Myeloproliferative Disease (MDS/MPD)
    PDGFRB FISH PRODUCT DATASHEET Proprietary Name: PDGFRB FISH for Gleevec Eligibility in Myelodysplastic Syndrome/Myeloproliferative Disease (MDS/MPD) Established Name: PDGFRB FISH for Gleevec in MDS/MPD INTENDED USE Humanitarian Device. Authorized by Federal law for use in the qualitative detection of PDGFRB gene rearrangement in patients with MDS/MPD. The effectiveness of this device for this use has not been demonstrated. Caution: Federal Law restricts this device to sale by or on the order of a licensed practitioner. PDGFRB FISH for Gleevec Eligibility in Myelodysplastic Syndrome/Myeloproliferative Disease (MDS/MPD) is an in vitro diagnostic test intended for the qualitative detection of PDGFRB gene rearrangement from fresh bone marrow samples of patients with MDS/MPD with a high index of suspicion based on karyotyping showing a 5q31~33 anomaly. The PDGFRB FISH assay is indicated as an aid in the selection of MDS/MPD patients for whom Gleevec® (imatinib mesylate) treatment is being considered. This assay is for professional use only and is to be performed at a single laboratory site. SUMMARY AND EXPLANATION OF THE TEST The PDGFRB FISH assay detects rearrangement of the PDGFRB locus at chromosome 5q31~33 in adult patients with myelodysplastic syndrome/myeloproliferative disease (MDS/MPD). The PDGFRB gene encodes a cell surface receptor tyrosine kinase that upon activation stimulates mesenchymal cell division. Rearrangement of PDGFRB has been demonstrated by classical cytogenetic analysis in an exceedingly small fraction of MDS/MPD patients (~1%), usually cases with a clinical phenotype of chronic myelomonocytic leukemia (CMML). In particular, these patients harbor a t(5:12)(q31;p12) translocation involving the PDGFRB and ETV6 genes.
    [Show full text]
  • Synchronous Overexpression of Epidermal Growth Factor Receptor and HER2-Neu Protein Is a Predictor of Poor Outcome in Patients with Stage I Non-Small Cell Lung Cancer
    136 Vol. 10, 136–143, January 1, 2004 Clinical Cancer Research Synchronous Overexpression of Epidermal Growth Factor Receptor and HER2-neu Protein Is a Predictor of Poor Outcome in Patients with Stage I Non-Small Cell Lung Cancer ؍ Amir Onn,1,2 Arlene M. Correa,3 nocarcinomas than in squamous cell carcinomas (P Michael Gilcrease,4 Takeshi Isobe,2 0.035). Synchronous overexpression of EGFR and HER2- 1 2 neu was found in 11 tumors (9.9%). Patients with these ؍ ,Erminia Massarelli, Corazon D. Bucana 2,5 1 tumors had a significantly shorter time to recurrence (P ؍ Michael S. O’Reilly, Waun K. Hong, 0.006) and a trend toward shorter overall survival (P 2 3 Isaiah J. Fidler, Joe B. Putnam, and 0.093). Phosphorylated EGFR and transforming growth fac- Roy S. Herbst1,2 tor ␣ were detected but were not related to prognosis. Departments of 1Thoracic/Head and Neck Medical Oncology, 2Cancer Conclusions: Synchronous overexpression of EGFR Biology, 3Thoracic and Cardiovascular Surgery, 4Pathology, and and HER2-neu at the protein level predicts increased recur- 5 Radiation Oncology, The University of Texas M. D. Anderson rence risk and may predict decreased survival in patients Cancer Center, Houston, Texas with stage I NSCLC. This suggests that important interac- tions take place among the different members of the ErbB ABSTRACT family during tumor development and suggests a method for choosing targeted therapy. A prospective study is planned. Purpose: Despite maximal therapy, surgically treated patients with stage I non-small cell lung cancer (NSCLC) are at risk for developing metastatic disease. Histopathologic INTRODUCTION findings cannot adequately predict disease progression, so The overall 5-year survival rate in patients with lung cancer there is a need to identify molecular factors that serve this is Ͻ15% (1).
    [Show full text]