IGF1R as a Key Target in High Risk, Metastatic Medulloblastoma
| Autor: | Matthew N. Svalina, Michael C. Young, Darell D. Bigner, Sarah Green, Jennifer L. Peckham, Brian Hernandez, Jinu Abraham, Joel E. Michalek, Randall L. Woltjer, Noah E. Berlow, Kellie J. Nazemi, Atiya Mansoor, Christopher L. Corless, Charles Keller, Melanie A. Jackson, Ken Kikuchi, Yoon Jae Cho, Monika A. Davare, Teagan P. Settelmeyer, Sangeet Lal, Daniel J. Guillaume, Nathan R. Selden, Brian P. Rubin, Sakir H. Gultekin |
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| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Male Pathology IGFBP3 Gene Expression Metastasis Receptor IGF Type 1 0302 clinical medicine Cell Movement Meningeal Neoplasms Molecular Targeted Therapy Insulin-Like Growth Factor I Child Multidisciplinary 3. Good health CXCL3 Matrix Metalloproteinase 9 030220 oncology & carcinogenesis Female medicine.medical_specialty Proteases Adolescent Context (language use) Antineoplastic Agents Biology Article 03 medical and health sciences Inhibitory Concentration 50 Cell Line Tumor Plasminogen Activator Inhibitor 1 medicine Biomarkers Tumor Cell Adhesion Humans Cerebellar Neoplasms neoplasms Insulin-like growth factor 1 receptor Cell Proliferation Medulloblastoma Tissue Inhibitor of Metalloproteinase-1 Cell growth Receptors Somatomedin medicine.disease nervous system diseases stomatognathic diseases 030104 developmental biology Insulin-Like Growth Factor Binding Protein 3 Case-Control Studies Cancer research Drug Screening Assays Antitumor |
| Zdroj: | Scientific Reports |
| ISSN: | 2045-2322 |
| Popis: | Risk or presence of metastasis in medulloblastoma causes substantial treatment-related morbidity and overall mortality. Through the comparison of cytokines and growth factors in the cerebrospinal fluid (CSF) of metastatic medulloblastoma patients with factors also in conditioned media of metastatic MYC amplified medulloblastoma or leptomeningeal cells, we were led to explore the bioactivity of IGF1 in medulloblastoma by elevated CSF levels of IGF1, IGF-sequestering IGFBP3, IGFBP3-cleaving proteases (MMP and tPA) and protease modulators (TIMP1 and PAI-1). IGF1 led not only to receptor phosphorylation but also accelerated migration/adhesion in MYC amplified medulloblastoma cells in the context of appropriate matrix or meningothelial cells. Clinical correlation suggests a peri-/sub-meningothelial source of IGF-liberating proteases that could facilitate leptomeningeal metastasis. In parallel, studies of key factors responsible for cell autonomous growth in MYC amplified medulloblastoma prioritized IGF1R inhibitors. Together, our studies identify IGF1R as a high value target for clinical trials in high risk medulloblastoma. |
| Databáze: | OpenAIRE |
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