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[Cancer Research 64, 7794-7800, November 1, 2004]
© 2004 American Association for Cancer Research

Regular Articles

The SmoA1 Mouse Model Reveals That Notch Signaling Is Critical for the Growth and Survival of Sonic Hedgehog-Induced Medulloblastomas

Andrew R. Hallahan1,2, Joel I. Pritchard1, Stacey Hansen1, Mark Benson1, Jennifer Stoeck1, Beryl A. Hatton1, Thomas L. Russell1, Richard G. Ellenbogen3, Irwin D. Bernstein1,2, Phillip A. Beachy4 and James M. Olson1,2

1 Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington; 2 Division of Pediatric Oncology and 3 Department of Neurosurgery, University of Washington/Children’s Hospital, Seattle, Washington; and 4 Departments of Molecular Biology and Genetics and Howard Hughes Medical Institute, Johns Hopkins University, Baltimore, Maryland

To develop a genetically faithful model of medulloblastoma with increased tumor incidence compared with the current best model we activated the Sonic Hedgehog (Shh) pathway by transgenically expressing a constitutively active form of Smoothened in mouse cerebellar granule neuron precursors (ND2:SmoA1 mice). This resulted in early cerebellar granule cell hyper-proliferation and a 48% incidence of medulloblastoma formation. Gene expression studies showed an increase in the known Shh targets Gli1 and Nmyc that correlated with increasing hyperplasia and tumor formation. Notch2 and the Notch target gene, HES5, were also significantly elevated in Smoothened-induced tumors showing that Shh pathway activation is sufficient to induce Notch pathway signaling. In human medulloblastomas reverse transcription-PCR for Shh and Notch targets revealed activation of both of these pathways in most tumors when compared with normal cerebellum. Notch pathway inhibition with soluble Delta ligand or {gamma} secretase inhibitors resulted in a marked reduction of viable cell numbers in medulloblastoma cell lines and primary tumor cultures. Treatment of mice with D283 medulloblastoma xenografts with a {gamma} secretase inhibitor resulted in decreased proliferation and increased apoptosis, confirming that Notch signaling contributes to human medulloblastoma proliferation and survival. Medulloblastomas in ND2:SmoA1 mice and humans have concomitant increase in Shh and Notch pathway activities, both of which contribute to tumor survival.




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