Insulin-like growth factor I receptor activity in human medulloblastomas.
Medulloblastomas represent about 25% of all pediatric intracranial neoplasms. These highly malignant tumors arise from the cerebellum affecting mainly children between ages 5 and 15. Although the etiology of medulloblastomas has not yet been elucidated, several reports suggest that insulin-like growth factor I (IGF-I) may contribute to the development of these tumors. Results of this study show that the majority of cases examined were characterized by the abundant presence of the receptor for IGF-I (IGF-IR) protein (16 of 20 cases), and its major signaling molecule, insulin receptor substrate 1 (IRS-1; 15 of 20). Protein levels for IGF-IR and IRS-1, determined by Western blot and immunohistochemistry, were significantly higher in medulloblastoma biopsies than in control cerebellar tissue. By immunohistochemistry, 10 of 17 biopsies examined were also positive for the anti-pY1316 antibody staining that specifically recognizes the phosphorylated (active) form of the IGF-IR. These findings correlate with the fact that phosphorylated forms of the downstream-signaling molecules Erk-1, Erk-2, and Akt/protein kinase B were found in medulloblastoma biopsies but not in control cerebellar tissue. Importantly, there is a strong inverse correlation between biopsies that are positive for anti-pY1316 and for anti-Trk-C immunoreactivity. These observations direct our attention to the IGF-IR system as a potential therapeutic target in medulloblastomas and suggest a possibility of using the anti-pY1316 antibody as a potential prognostic marker for medulloblastomas.
Del Valle
Luis
L
Center for Neurovirology and Cancer Biology, Temple University, 1900 North 12th Street, Philadelphia, PA 19122, USA.
Enam
Sahnila
S
Lassak
Adam
A
Wang
Jin Yiang
JY
Croul
Sidney
S
Khalili
Kamel
K
Reiss
Krzysztof
K
D000293:Adolescent; D000818:Animals; D001706:Biopsy; D015153:Blotting, Western; D002455:Cell Division / Q000502:physiology; D002528:Cerebellar Neoplasms / Q000378:metabolism* / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D015536:Down-Regulation; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D007124:Immunoenzyme Techniques; D007223:Infant; D055504:Insulin Receptor Substrate Proteins; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D008297:Male; D008527:Medulloblastoma / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016612:Paraffin Embedding; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D017526:Receptor, IGF Type 1 / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D014407:Tumor Cells, Cultured
D055504:Insulin Receptor Substrate Proteins; D007334:Insulin-Like Growth Factor I; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D019869:Phosphatidylinositol 3-Kinases; D010750:Phosphoproteins; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D017526:Receptor, IGF Type 1; C526292:IRS1 protein, human; C526295:Irs1 protein, mouse; C494918:AKT1 protein, human