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Activation of the IGF-IR system contributes to malignant growth of human and mouse medulloblastomas

Oncogene volume 20, pages 3857–3868 (2001)Cite this article

Abstract

Insulin-like growth factor I receptor (IGF-IR) has been implicated in the normal and malignant growth of many cell types including cells from the central nervous system. In the cerebellar cortex IGF-IR mRNA is found in granular cells and IGF-I stimulation is mitogenic and protects cells from low-potassium-induced apoptosis. Since primitive neuroectodermal tumors/medulloblastomas (PNETs/medulloblastomas) are suspected to originate from the external cerebellar granular layer, it is reasonable to postulate that IGF-IR and/or its signaling molecules may contribute to the transformation of these poorly differentiated cells. To study activation of the IGF-IR system in medulloblastomas, we have utilized an antibody (anti-pY1316) that specifically recognizes the phosphorylated (active) form of the IGF-IR. Medulloblastoma biopsy specimens were positive when examined immunohistochemically with anti-Y1316 antibody. Further analysis of the IGF-IR system was performed in three human (Daoy, TE-671, D283 Med) and four mouse (BsB8, BsB13, Bs-1b, Bs-1c) medulloblastoma cell lines. All the murine cell lines examined express IGF-IR and PI3-kinase at relatively normal levels, and grossly overexpress IRS-1, when compared with normal mouse cerebellum. Within 15 min following IGF-I stimulation both mouse and human cell lines phosphorylate the β subunit of the IGF-IR, IRS-1, Akt, and MAP kinases. They respond with cell proliferation when stimulated solely with IGF-I and are strongly inhibited when challenged with a dominant negative mutant of the IGF-IR (486/STOP), or with antisense oligonucleotides against the IGF-IR mRNA.

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Acknowledgements

Samples of frozen human cerebellum were kindly provided by Dr Mary Herman and Dr Joel E Kleinman from Neuropathology Section-CBDB NIMH, Bethesda, MD, USA. This work is supported by grant NIH PO-1 NS 36466. Reiss K, Tu X, Romano G, Wang J, Baserga R. Mechanism of action of a dominant-negative mutant of the IGF-I receptor (submitted for publication).

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Authors and Affiliations

  1. Center for Neurovirology and Cancer Biology, College of Science and Technology, Temple University, 1900 North 12th Street, Biology Life Science Building, Room 238, Philadelphia, 19122, Pennsylvania, PA, USA

    Jin Ying Wang, Luis Del Valle, Jennifer Gordon, Sidney Croul, Kamel Khalili & Krzysztof Reiss

  2. Kimmel Cancer Center, Thomas Jefferson University, 233 S 10th Street, 624 BLSB, Philadelphia, 19107, Pennsylvania, PA, USA

    Gaetano Romano & Francesca Peruzzi

  3. Universita 'Degli Studi di Ferrara Dipartimento di Medicina Sperimentale e Diagnostica, Via L. Borsari, Ferrara, 46-44100, Italy

    Michele Rubini

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Wang, J., Del Valle, L., Gordon, J. et al. Activation of the IGF-IR system contributes to malignant growth of human and mouse medulloblastomas. Oncogene 20, 3857–3868 (2001). https://doi.org/10.1038/sj.onc.1204532

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