title: Osteopontin expression in intratumoral astrocytes marks tumor progression in gliomas induced by prenatal exposure to N-ethyl-N-nitrosourea.
abstract: To better study early events in glioma genesis, markers that reliably denote landmarks in glioma development are needed. In the present study, we used microarray analysis to compare the gene expression patterns of magnetic resonance imaging (MRI)-localized N-ethyl-N-nitrosourea (ENU)-induced tumors in rat brains with those of uninvolved contralateral side and normal brains. Our analysis identified osteopontin (OPN) as the most up-regulated gene in glioma. Using immunohistochemistry we then confirmed OPN expression in every tumor examined (n = 17), including those with diameters as small as 300 mum. By contrast, no OPN immunostaining was seen in normal brain or in brains removed from ENU-exposed rats before the development of glioma. Further studies confirmed that OPN was co-localized exclusively in intratumoral glial fibrillary acidic protein-expressing cells and was notably absent from nestin-expressing ones. In conjunction with this, we confirmed that both normal neurosphere cells and ENU-im-mortalized subventricular zone/striatal cells produced negligible amounts of OPN compared to the established rat glioma cell line C6. Furthermore, inducing OPN expression in an immortalized cell line increased cell proliferation. Based on these findings, we conclude that OPN overexpression in ENU-induced gliomas occurs within a specific subset of intratumoral glial fibrillary acidic protein-positive cells and becomes evident at the stage of tumor progression.
authors.affiliation: Department of Neurology and Clinical Neurosciences, Stanford University Medical School, Stanford, California 94305-5487, USA.
authors.forename: Taichang
authors.initials: T
authors.lastname: Jang
authors.forename: Todd
authors.initials: T
authors.lastname: Savarese
authors.forename: Hoi Pang
authors.initials: HP
authors.lastname: Low
authors.forename: Sunchin
authors.initials: S
authors.lastname: Kim
authors.forename: Hannes
authors.initials: H
authors.lastname: Vogel
authors.forename: David
authors.initials: D
authors.lastname: Lapointe
authors.forename: Timothy
authors.initials: T
authors.lastname: Duong
authors.forename: N Scott
authors.initials: NS
authors.lastname: Litofsky
authors.forename: James M
authors.initials: JM
authors.lastname: Weimann
authors.forename: Alonzo H
authors.initials: AH
authors.lastname: Ross
authors.forename: Lawrence
authors.initials: L
authors.lastname: Recht
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism* / Q000473:pathology; D014408:Biomarkers, Tumor / Q000032:analysis*; D002540:Cerebral Cortex / Q000473:pathology; D004195:Disease Models, Animal; D018450:Disease Progression; D005038:Ethylnitrosourea; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D005910:Glioma / Q000139:chemically induced / Q000235:genetics*; D007150:Immunohistochemistry; D007381:Intermediate Filament Proteins / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D064231:Nestin; D053495:Osteopontin; D011247:Pregnancy; D011270:Pregnancy, Animal; D011297:Prenatal Exposure Delayed Effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D012795:Sialoglycoproteins / Q000378:metabolism*; D013997:Time Factors; D014162:Transfection
chemical_list: D014408:Biomarkers, Tumor; D007381:Intermediate Filament Proteins; D009419:Nerve Tissue Proteins; C577486:Nes protein, rat; D064231:Nestin; D012795:Sialoglycoproteins; C506897:Spp1 protein, rat; D053495:Osteopontin; D005038:Ethylnitrosourea