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The Smo/Smo Model: Hedgehog-Induced Medulloblastoma with 90% Incidence and Leptomeningeal Spread

¹ Clinical Research Division and ² Animal Health Shared Resources, Fred Hutchinson Cancer Research Center; ³ Graduate Program in Molecular and Cellular Biology and ⁴ Department of Radiology, University of Washington; ⁵ Division of Pediatric Oncology and ⁶ Department of Laboratory Medicine, University of Washington/Children's Hospital, Seattle, Washington; ⁷ Department of Pathology, Johns Hopkins University, Baltimore, Maryland; and ⁸ Department of Pediatrics and Child Health, University of Queensland, Brisbane, Australia

Requests for reprints: James M. Olson, 1100 Fairview Avenue North, Mailstop D4-100, P.O. Box 19024, Seattle, WA 98109. Phone: 206-667-7955; Fax: 206-667-2917; E-mail: jolson{at}fhcrc.org.

Key Words: medulloblastoma • leptomeningeal spread • Sonic hedgehog • cerebellum • mouse cancer models

Toward the goal of generating a mouse medulloblastoma model with increased tumor incidence, we developed a homozygous version of our ND2:SmoA1 model. Medulloblastomas form in 94% of homozygous Smo/Smo mice by 2 months of age. Tumor formation is, thus, predictable by age, before the symptomatic appearance of larger lesions. This high incidence and early onset of tumors is ideal for preclinical studies because mice can be enrolled before symptom onset and with a greater latency period before late-stage disease. Smo/Smo tumors also display leptomeningeal dissemination of neoplastic cells to the brain and spine, which occurs in many human cases. Despite an extended proliferation of granule neuron precursors (GNP) in the postnatal external granular layer (EGL), the internal granular layer formed normally in Smo/Smo mice and tumor formation occurred only in localized foci on the superficial surface of the molecular layer. Thus, tumor formation is not simply the result of over proliferation of GNPs within the EGL. Moreover, Smo/Smo medulloblastomas were transplantable and serially passaged in vivo, demonstrating the aggressiveness of tumor cells and their transformation beyond a hyperplastic state. The Smo/Smo model is the first mouse medulloblastoma model to show leptomeningeal spread. The adherence to human pathology, high incidence, and early onset of tumors thus make Smo/Smo mice an efficient model for preclinical studies. [Cancer Res 2008;68(6):1768–76]