Medulloblastomas (MB) represent the most frequent malignant brain tumors of childhood. Cerebellar granule cell progenitors (GCP) of the external granule cell layer are thought to represent the progenitor cells of at least one subtype, the desmoplastic variant (DMB). Activating genetic alterations of the Sonic Hedgehog (Shh)-Patched signaling pathway have been identified particularly in this subtype. It has previously been shown that Insulin-like growth factor-II (IGF-II) mRNA is expressed at higher levels in DMB than in the classic variant (CMB). Using a quantitative RT-PCR assay, we screened a panel of 16 classic and 10 desmoplastic MB for mRNA expression of Insulin-like growth factor binding protein 5 (IGFBP5). While IGFBP5 has previously been characterized as a negatively regulated target in Hedgehog signaling, we found that expression of IGFBP5 was significantly higher in DMB than in CMB. In search of the regulatory background of this finding, we performed in vitro experiments with murine GCP prepared at day P8. Treatment with recombinant murine (rm)Shh lead to a significant decrease in IGFBP5 mRNA expression. In contrast, stimulation with rmIGF-II resulted in a 5.3-fold transcriptional induction of IGFBP5. Using luciferase reporter assays, we found that IGF-II also induces IGFBP5 transcriptional activity in human MB cells. To elucidate the impact of IGFBP5 on cell proliferation, we treated murine GCP and human MB cells with appropriate levels of IGF-II and IGFBP5. 3H-thymidine uptake assays revealed that, in MB cells and GCP alike, IGFBP5 and IGF-II act synergistically to regulate cellular proliferative activity. In conclusion, our data suggest that IGF-II mediated upregulation of IGFBP5 results in synergistic growth promotion in MB. Furthermore, they imply that the Hedgehog and IGF signaling pathways converge in the molecular pathogenesis of medulloblastoma.

[Proc Amer Assoc Cancer Res, Volume 46, 2005]