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

Insulin-like growth factor I receptor (IGF-IR) has been implicated in the n ormal and malignant growth of many cell types including cells from the cent ral nervous system. In the cerebellar cortex ICF-IR mRNA is found in granul ar cells and IGF-I stimulation is mitogenic and protects cells from low-pot assium-induced apoptosis, Since primitive neuroectodermal tumers/medullobla stomas (PNETs/medulloblastomas) are suspected to originate from the externa l cerebellar granular layer, it is reasonable to postulate that IGF-IR and/ or its signaling molecules may contribute to the transformation of these po orly differentiated cells. To study activation of the IGF-IR system in medu lloblastomas, 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 ant i-Y1316 antibody. Further analysis of the IGF-IR system was performed in th ree human (Daoy, TE-671, D283 Med) and four mouse (BsB8, BsB13, Bs-lb, Bs-l c) medulloblastoma cell lines. All the murine cell lines examined express I GF-IR and PI3-kinase at relatively normal levels, and grossly overexpress I RS-I, when compared with normal mouse cerebellum. Within 15 min following I GF-I stimulation both mouse and human cell lines phosphorylate the P subuni t of the IGF-IR, IRS-1, Akt, and MAP kinases, They respond with cell prolif eration when stimulated solely with IGF-I and are strongly inhibited when c hallenged with a dominant negative mutant of the IGF-IR (486/STOP), or with antisense oligonucleotides against the IGF-IR mRNA.