title: Inhibitory potential of postnatal treatment with cyclopamine, a hedgehog signaling inhibitor, on medulloblastoma development in Ptch1 heterozygous mice.
abstract: Medulloblastomas (MBs) are thought to be derived from granular cell precursors in the external granular layer (EGL) of the developing cerebellum. Heterozygous patched1 (Ptch1) knockout mice develop MBs that resemble those in humans when the sonic hedgehog (Shh) signaling pathway is activated. The present study was conducted to evaluate postnatal effects of a Shh signaling inhibitor, cyclopamine, on the development of MBs in Ptch1 mice. Ptch1 and wild-type mice were treated daily with subcutaneous cyclopamine at 40 mg/kg or vehicle from postnatal day (PND) 1 to PND14, and the subsequent development of MBs and preneoplastic lesions was examined up to week 12 (W12). Proliferative lesions in the cerebellum, MBs, and preneoplastic lesions were only detected in Ptch1 mice. Cyclopamine treatment resulted in a statistically significant reduction in the incidence and/or area of proliferative lesions at PND14 and 21. The trend of decreasing preneoplastic lesions persisted up to W12. At PND7, cyclopamine treatment reduced the width and proliferation of the EGL regardless of genotype. These results indicate that inhibition of Shh signaling during cerebellar development has prolonged inhibitory potential on MB development in Ptch1 mice. This inhibitory potential might be related to inhibition of EGL proliferation, including preneoplastic MB cells.
authors.affiliation: Division of Pathology, National Institute of Health Sciences, Tokyo, Japan Pathogenetic Veterinary Science, United Graduate School of Veterinary Sciences, Gifu University, Gifu, Japan.
authors.forename: Saori
authors.initials: S
authors.lastname: Matsuo
authors.affiliation: Division of Pathology, National Institute of Health Sciences, Tokyo, Japan.
authors.forename: Miwa
authors.initials: M
authors.lastname: Takahashi
authors.affiliation: Division of Pathology, National Institute of Health Sciences, Tokyo, Japan.
authors.forename: Kaoru
authors.initials: K
authors.lastname: Inoue
authors.affiliation: Division of Pathology, National Institute of Health Sciences, Tokyo, Japan.
authors.forename: Kei
authors.initials: K
authors.lastname: Tamura
authors.affiliation: Division of Pathology, National Institute of Health Sciences, Tokyo, Japan.
authors.forename: Kaoru
authors.initials: K
authors.lastname: Irie
authors.affiliation: Division of Toxicology, National Institute of Health Sciences, Tokyo, Japan.
authors.forename: Yukio
authors.initials: Y
authors.lastname: Kodama
authors.affiliation: Pathogenetic Veterinary Science, United Graduate School of Veterinary Sciences, Gifu University, Gifu, Japan Biological Safety Research Center, National Institute of Health Sciences, Tokyo, Japan.
authors.forename: Akiyoshi
authors.initials: A
authors.lastname: Nishikawa
authors.affiliation: Division of Pathology, National Institute of Health Sciences, Tokyo, Japan midoriy@nihs.go.jp.
authors.forename: Midori
authors.initials: M
authors.lastname: Yoshida
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D002531:Cerebellum / Q000737:chemistry / Q000187:drug effects* / Q000254:growth & development / Q000473:pathology; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors*; D008527:Medulloblastoma / Q000737:chemistry / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D014704:Veratrum Alkaloids / Q000494:pharmacology*
chemical_list: D053823:Hedgehog Proteins; C000606236:PTCH1 protein, human; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; C000606240:Ptch1 protein, mouse; D011956:Receptors, Cell Surface; D014704:Veratrum Alkaloids; C000541:cyclopamine
keywords: cerebellum; cyclopamine; medulloblastoma; patched1; preneoplastic lesion; smoothened inhibitor; sonic hedgehog inhibitor.