title: Inhibition of intracerebral glioblastoma growth by targeting the insulin-like growth factor 1 receptor involves different context-dependent mechanisms.
abstract: BACKGROUND
  Signaling by insulin-like growth factor 1 receptor (IGF-1R) can contribute to the formation and progression of many diverse tumor types, including glioblastoma. We investigated the effect of the IGF-1R blocking antibody IMC-A12 on glioblastoma growth in different in vivo models.
  
  
  METHODS
  U87 cells were chosen to establish rapidly growing, angiogenesis-dependent tumors in the brains of nude mice, and the GS-12 cell line was used to generate highly invasive tumors. IMC-A12 was administered using convection-enhanced local delivery. Tumor parameters were quantified histologically, and the functional relevance of IGF-1R activation was analyzed in vitro.
  
  
  RESULTS
  IMC-A12 treatment inhibited the growth of U87 and GS-12 tumors by 75% and 50%, respectively. In GS-12 tumors, the invasive tumor extension and proliferation rate were significantly reduced by IMC-A12 treatment, while apoptosis was increased. In IMC-A12-treated U87 tumors, intratumoral vascularization was markedly decreased, and tumor cell proliferation was moderately reduced. Flow cytometry showed that <2% of U87 cells but >85% of GS-12 cells expressed IGF-1R. Activation of IGF-1R by IGF-1 and IGF-2 in GS-12 cells was blocked by IMC-A12. Both ligands stimulated GS-12 cell proliferation, and IGF-2 also stimulated migration. IMC-A12 inhibited these stimulatory effects and increased apoptosis. In U87 cells, stimulation with either ligand had no functional effect.
  
  
  CONCLUSIONS
  IGF-1R blockade can inhibit glioblastoma growth by different mechanisms, including direct effects on the tumor cells as well as indirect anti-angiogenic effects. Hence, blocking IGF-1R may be useful to target both the highly proliferative, angiogenesis-dependent glioblastoma core component as well as the infiltrative periphery.
authors.affiliation: Department of Neurosurgery (M.Z., T.M., H.S.G., A.K., A.S., R.P., M.W., K.L.) and Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (J.M.).
authors.forename: Martin
authors.initials: M
authors.lastname: Zamykal
authors.affiliation: Department of Neurosurgery (M.Z., T.M., H.S.G., A.K., A.S., R.P., M.W., K.L.) and Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (J.M.).
authors.forename: Tobias
authors.initials: T
authors.lastname: Martens
authors.affiliation: Department of Neurosurgery (M.Z., T.M., H.S.G., A.K., A.S., R.P., M.W., K.L.) and Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (J.M.).
authors.forename: Jakob
authors.initials: J
authors.lastname: Matschke
authors.affiliation: Department of Neurosurgery (M.Z., T.M., H.S.G., A.K., A.S., R.P., M.W., K.L.) and Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (J.M.).
authors.forename: Hauke S
authors.initials: HS
authors.lastname: Günther
authors.affiliation: Department of Neurosurgery (M.Z., T.M., H.S.G., A.K., A.S., R.P., M.W., K.L.) and Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (J.M.).
authors.forename: Annegret
authors.initials: A
authors.lastname: Kathagen
authors.affiliation: Department of Neurosurgery (M.Z., T.M., H.S.G., A.K., A.S., R.P., M.W., K.L.) and Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (J.M.).
authors.forename: Alexander
authors.initials: A
authors.lastname: Schulte
authors.affiliation: Department of Neurosurgery (M.Z., T.M., H.S.G., A.K., A.S., R.P., M.W., K.L.) and Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (J.M.).
authors.forename: Regina
authors.initials: R
authors.lastname: Peters
authors.affiliation: Department of Neurosurgery (M.Z., T.M., H.S.G., A.K., A.S., R.P., M.W., K.L.) and Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (J.M.).
authors.forename: Manfred
authors.initials: M
authors.lastname: Westphal
authors.affiliation: Department of Neurosurgery (M.Z., T.M., H.S.G., A.K., A.S., R.P., M.W., K.L.) and Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (J.M.).
authors.forename: Katrin
authors.initials: K
authors.lastname: Lamszus
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D061067:Antibodies, Monoclonal, Humanized; D017209:Apoptosis / Q000187:drug effects; D001932:Brain Neoplasms / Q000473:pathology* / Q000503:physiopathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005909:Glioblastoma / Q000473:pathology* / Q000503:physiopathology; D006801:Humans; D018970:Insulin-Like Growth Factor Binding Protein 1 / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000502:physiology; D051379:Mice; D009389:Neovascularization, Pathologic; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D018970:Insulin-Like Growth Factor Binding Protein 1; C557414:cixutumumab
keywords: IGF-1R; angiogenesis; convection-enhanced delivery; glioma; invasion