title: The Smo/Smo model: hedgehog-induced medulloblastoma with 90% incidence and leptomeningeal spread.
abstract: 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.
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, University of Washington, Seattle, Washington, USA.
authors.forename: Beryl A
authors.initials: BA
authors.lastname: Hatton
authors.forename: Elisabeth H
authors.initials: EH
authors.lastname: Villavicencio
authors.forename: Karen D
authors.initials: KD
authors.lastname: Tsuchiya
authors.forename: Joel I
authors.initials: JI
authors.lastname: Pritchard
authors.forename: Sally
authors.initials: S
authors.lastname: Ditzler
authors.forename: Barbara
authors.initials: B
authors.lastname: Pullar
authors.forename: Stacey
authors.initials: S
authors.lastname: Hansen
authors.forename: Sue E
authors.initials: SE
authors.lastname: Knoblaugh
authors.forename: Donghoon
authors.initials: D
authors.lastname: Lee
authors.forename: Charles G
authors.initials: CG
authors.lastname: Eberhart
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Hallahan
authors.forename: James M
authors.initials: JM
authors.lastname: Olson
mesh_terms: D000818:Animals; D002528:Cerebellar Neoplasms / Q000235:genetics* / Q000473:pathology*; D004195:Disease Models, Animal; D053823:Hedgehog Proteins / Q000235:genetics*; D008527:Medulloblastoma / Q000235:genetics* / Q000473:pathology*; D008577:Meningeal Neoplasms / Q000235:genetics / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D008822:Mice, Transgenic; D043562:Receptors, G-Protein-Coupled / Q000235:genetics*; D000072086:Smoothened Receptor; D019076:Transgenes
chemical_list: D053823:Hedgehog Proteins; D043562:Receptors, G-Protein-Coupled; C491022:Smo protein, mouse; D000072086:Smoothened Receptor