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N-ethyl-N-nitrosourea (ENU)-Induced Meningiomatosis and Meningioma in p16^INK4a/p19^ARF Tumor Suppressor Gene-Deficient Mice

¹ Charles River Laboratories, Pathology Associates, Durham, North Carolina 27703
² Drug Safety Research Laboratory, Daiichi Pharmaceutical Co., Ltd., Tokyo, 134-8630 Japan
³ Laboratory of Experimental Pathology
⁴ Environmental Toxicology Program
⁵ Biostatistics Branch, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, USA

Correspondence: Address correspondence to: Dr. David E. Malarkey, Laboratory Experimental Pathology, National Institute of Environmental Health Sciences, P. O. Box 12233, MD-B3-06, 111 Alexander Drive, Research Triangle Park, NC 27709; e-mail:malarkey{at}niehs.nih.gov

The cyclin-dependent kinase (CDK) inhibitor p16^INK4a and the MDM2 ubiquitin ligase inhibitor p19^ARF are critical to the regulation of cell cycle progression. Their loss by deletion, mutation or epigenetic silencing is a common molecular alteration in many human cancers. To investigate the role of p16^INK4a/p19^ARF deficiency in CNS tumor pathogenesis, pregnant mice bearing p16^–/–/p19^–/–, p16^+/–/p19^+/–, and p16^+/+/p19^+/+ embryos were exposed transplacentally on gestation day 14 to a single dose of the potent carcinogen, ethylnitrosourea (ENU). p16^+/–/p19^+/– male mice treated with ENU developed meningial proliferative lesions with a high incidence (5/10). The incidence was lower in other ENU-treated animals of both sexes and none occurred in saline-treated control animals. The lesions ranged from widespread meningeal proliferation and plaque-like thickening by neoplastic spindle cells consistent with meningiomatosis to a larger discrete mass consistent with a meningioma. Ultrastructural analysis revealed the presence of intercellular junctions between cells, supporting a meningothelial histogenesis. Spontaneous meningiomas occur rarely in wild-type mice but are a common neoplasm afflicting humans, accounting for between 13 and 26% of primary intracranial neoplasms. This ENU inducible meningeal lesion in p16^+/–/p19^+/– mice may provide additional insight into the pathogenesis of meningeal neoplasia and aid the development of therapeutics.

Key Words: Animal model • central nervous system • meningioma • meningiomatosis • mouse • tumor suppressor gene deficiency • ethylnitrosourea

Abbreviations: CDK, cyclin-dependent kinase • CNS, central nervous system • ENU, N-ethyl-N-nitrosourea (ethylnitrosourea)

Toxicologic Pathology, Vol. 35, No. 6, 838-845 (2007)
DOI: 10.1080/01926230701584130


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