title: NDRG1 overexpressing gliomas are characterized by reduced tumor vascularization and resistance to antiangiogenic treatment.
abstract: Hypoxia-regulated molecules play an important role in vascular resistance to antiangiogenic treatment. N-myc downstream-regulated-gene 1 (NDRG1) is significantly upregulated during hypoxia in glioma. It was the aim of the present study to analyze the role of NDRG1 on glioma angiogenesis and on antiangiogenic treatment. Orthotopically implanted NDRG1 glioma showed reduced tumor growth and vessel density compared to controls. RT-PCR gene array analysis revealed a 30-fold TNFSF15 increase in NDRG1 tumors. Consequently, the supernatant from NDRG1 transfected U87MG glioma cells resulted in reduced HUVEC proliferation, migration and angiogenic response in tube formation assays in vitro. This effect was provoked by increased TNFSF15 promoter activity in NDRG1 cells. Mutations in NF-κB and AP-1 promoter response elements suppressed TNFSF15 promoter activity. Moreover, U87MG glioma NDRG1 knockdown supernatant contained multiple proangiogenic proteins and increased HUVEC spheroid sprouting. Sunitinib treatment of orhotopically implanted mice reduced tumor volume and vessel density in controls; in NDRG1 overexpressing cells no reduction of tumor volume or vessel density was observed. NDRG1 overexpression leads to reduced tumor growth and angiogenesis in experimental glioma via upregulation of TNFSF15. In NDRG1 overexpressing glioma antiangiogenic treatment does not yield a therapeutic response.
authors: Department of Neurosurgery, Neurochirurgische Klinik - Universitätsmedizin Charite, Augustenburger Platz 1, 13353 Berlin, Germany.
authors: Thomas
authors: T
authors: Broggini
authors: Department of Neurosurgery, Neurochirurgische Klinik - Universitätsmedizin Charite, Augustenburger Platz 1, 13353 Berlin, Germany.
authors: Marie
authors: M
authors: Wüstner
authors: Department of Experimental Neurology, Universitätsmedizin Charite, Berlin, Germany.
authors: Christoph
authors: C
authors: Harms
authors: Department of Neurosurgery, Neurochirurgische Klinik - Universitätsmedizin Charite, Augustenburger Platz 1, 13353 Berlin, Germany.
authors: Lena
authors: L
authors: Stange
authors: Department of Neurooncology, Neurology Clinic and National Center for Tumor Diseases, Clinical Cooperation Unit Neurooncology, German Cancer Research Center (DKFZ), University of Heidelberg and German Cancer Consortium (DKTK), Germany.
authors: Jonas
authors: J
authors: Blaes
authors: Department of Neurooncology, Neurology Clinic and National Center for Tumor Diseases, Clinical Cooperation Unit Neurooncology, German Cancer Research Center (DKFZ), University of Heidelberg and German Cancer Consortium (DKTK), Germany.
authors: Carina
authors: C
authors: Thomé
authors: Department of Neurology, Universitätsmedizin Charite, Berlin, Germany.
authors: Ulrike
authors: U
authors: Harms
authors: Department of Neurology, Universitätsmedizin Charite, Berlin, Germany.
authors: Susanne
authors: S
authors: Mueller
authors: Department of Neurooncology, Neurology Clinic and National Center for Tumor Diseases, Clinical Cooperation Unit Neurooncology, German Cancer Research Center (DKFZ), University of Heidelberg and German Cancer Consortium (DKTK), Germany.
authors: Markus
authors: M
authors: Weiler
authors: Department of Neurooncology, Neurology Clinic and National Center for Tumor Diseases, Clinical Cooperation Unit Neurooncology, German Cancer Research Center (DKFZ), University of Heidelberg and German Cancer Consortium (DKTK), Germany.
authors: Wolfgang
authors: W
authors: Wick
authors: Department of Neurosurgery, Neurochirurgische Klinik - Universitätsmedizin Charite, Augustenburger Platz 1, 13353 Berlin, Germany.
authors: Peter
authors: P
authors: Vajkoczy
authors: Department of Neurosurgery, Neurochirurgische Klinik - Universitätsmedizin Charite, Augustenburger Platz 1, 13353 Berlin, Germany. Electronic address: marcus.czabanka@charite.de.
authors: Marcus
authors: M
authors: Czabanka
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D001932:Brain Neoplasms / Q000098:blood supply* / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D017077:Culture Media, Conditioned; D019008:Drug Resistance, Neoplasm; D015972:Gene Expression Regulation, Neoplastic; D005910:Glioma / Q000098:blood supply / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009154:Mutation; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D009389:Neovascularization, Pathologic; D018919:Neovascularization, Physiologic; D011401:Promoter Regions, Genetic; D011758:Pyrroles / Q000494:pharmacology*; D034622:RNA Interference; D015398:Signal Transduction; D000077210:Sunitinib; D013997:Time Factors; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D047368:Tumor Burden / Q000187:drug effects; D053380:Tumor Necrosis Factor Ligand Superfamily Member 15 / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation; D000099259:N-myc Downstream-Regulated Gene 1 Protein
chemical_list: D020533:Angiogenesis Inhibitors; D018797:Cell Cycle Proteins; D017077:Culture Media, Conditioned; D007211:Indoles; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; D011758:Pyrroles; D000077210:Sunitinib; D018808:Transcription Factor AP-1; D053380:Tumor Necrosis Factor Ligand Superfamily Member 15; D000099259:N-myc Downstream-Regulated Gene 1 Protein; C117026:TNFSF15 protein, human
keywords: Antiangiogenic treatment; Glioma angiogenesis; Glioma microcirculation; NDRG1; Resistance to antiangiogenesis; TNFSF15