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Sonic hedgehog and insulin-like growth factor signaling synergize to induce medulloblastoma formation from nestin-expressing neural progenitors in mice

Abstract

Medulloblastoma (MB) is a malignant brain tumor that arises in the cerebellum of children. Activation of the Sonic hedgehog/Patched (Shh/Ptc) signaling pathway in neural progenitor cells of the cerebellum induces MBs in mice. The incomplete penetrance of tumor formation in mice, coupled with the low frequency of mutations in Shh/Ptc pathway genes in human tumors, suggests that other signaling molecules cooperate with Shh to enhance MB formation. We modeled the ability of insulin-like growth factor (IGF) signaling to induce MB using the RCAS/tv-a system, which allows postnatal gene transfer and expression in a cell-type-specific manner. We used RCAS retroviral vectors to target expression of Shh, IGF2, and activated Akt to nestin-expressing neural progenitors in the cerebella of newborn mice. The incidence of Shh-induced tumor formation (15%) was enhanced by coexpression with IGF2 (39%) and Akt (48%). Neither IGF2 nor Akt caused tumors when expressed independently. The induced tumors showed upregulated expression of insulin receptor substrate 1 and phosphorylated forms of IGF1 receptor and Akt, mimicking activated IGF signaling found in human MBs. These results indicate that combined activation of the Shh/Ptc and IGF signaling pathways is an important mechanism in MB pathogenesis.

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Acknowledgements

This work was supported by a grant from The Brain Tumor Society. We thank Dr Peter Vogt (The Scripps Research Institute) for RCAS-Akt-Myr-Δ11-60, Dr Peter Rotwein (Oregon Health Sciences University) for IGF2 cDNA, and Erin Fults for skillful assistance.

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Correspondence to Daniel W Fults.

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Rao, G., Pedone, C., Valle, L. et al. Sonic hedgehog and insulin-like growth factor signaling synergize to induce medulloblastoma formation from nestin-expressing neural progenitors in mice. Oncogene 23, 6156–6162 (2004). https://doi.org/10.1038/sj.onc.1207818

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