Inhibition of intracerebral glioblastoma growth by targeting the insulin-like growth factor 1 receptor involves different context-dependent mechanisms.
Neuro Oncol, 2015/8;17(8):1076-85.
Zamykal M[1], Martens T[1], Matschke J[1], Günther HS[1], Kathagen A[1], Schulte A[1], Peters R[1], Westphal M[1], Lamszus K[1]
Affiliations
PMID: 25543125DOI: 10.1093/neuonc/nou344
Impact factor: 13.029
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.
Keywords: IGF-1R; angiogenesis; convection-enhanced delivery; glioma; invasion
MeSH terms
Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Apoptosis; Brain Neoplasms; Cell Line, Tumor; Cell Proliferation; Glioblastoma; Humans; Insulin-Like Growth Factor Binding Protein 1; Mice; Neovascularization, Pathologic; Xenograft Model Antitumor Assays
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