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: Saori Matsuo, Miwa Takahashi, Kaoru Inoue, Kei Tamura, Kaoru Irie, Yukio Kodama, Akiyoshi Nishikawa, Midori Yoshida
• Journal: Toxicologic pathology (Toxicol Pathol) Vol. 42 Issue 8 Pg. 1174-87 (Dec 2014) ISSN: 1533-1601 [Electronic] United States
• PMID: 24862798 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2014 by The Author(s).

Chemical References

• Hedgehog Proteins
• PTCH1 protein, human
• Patched Receptors
• Patched-1 Receptor
• Ptch1 protein, mouse
• Receptors, Cell Surface
• Veratrum Alkaloids
• cyclopamine

Topics

• Animals
• Cell Proliferation (drug effects)
• Cerebellum (chemistry, drug effects, growth & development, pathology)
• Hedgehog Proteins (antagonists & inhibitors)
• Medulloblastoma (chemistry, metabolism, pathology)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Patched Receptors
• Patched-1 Receptor
• Receptors, Cell Surface (genetics, metabolism)
• Veratrum Alkaloids (pharmacology)