N-ethyl-N-nitrosourea (ENU)-induced meningiomatosis and meningioma in p16(INK4a)/p19(ARF) tumor suppressor gene-deficient mice.
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.
Morrison
James P
JP
Charles River Laboratories, Pathology Associates, Durham, North Carolina 27703, USA.
Satoh
Hiroshi
H
Foley
Julie
J
Horton
John L
JL
Dunnick
June K
JK
Kissling
Grace E
GE
Malarkey
David E
DE
D000818:Animals; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000502:physiology*; D005038:Ethylnitrosourea / Q000633:toxicity*; D005260:Female; D005333:Fetus / Q000187:drug effects; D016147:Genes, Tumor Suppressor; D019942:Genes, p16 / Q000502:physiology*; D008297:Male; D008577:Meningeal Neoplasms / Q000139:chemically induced* / Q000473:pathology; D008579:Meningioma / Q000139:chemically induced* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D011247:Pregnancy
C417743:Cdkn2a protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; D005038:Ethylnitrosourea