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(American Journal of Pathology. 2006;168:1676-1685.)
© 2006 American Society for Investigative Pathology

Osteopontin Expression in Intratumoral Astrocytes Marks Tumor Progression in Gliomas Induced by Prenatal Exposure to N-Ethyl-N-Nitrosourea

Taichang Jang*, Todd Savarese{dagger}, Hoi Pang Low{ddagger}, Sunchin Kim*, Hannes Vogel§, David Lapointe, Timothy Duong||, N. Scott Litofsky**, James M. Weimann*, Alonzo H. Ross{dagger}{dagger} and Lawrence Recht*

From the Departments of Neurology and Clinical Neurosciences* and Pathology,§ Stanford University Medical School, Stanford, California; the Departments of Cancer Biology,{dagger} Neurology,{ddagger} Cell Biology, Psychiatry,|| and Biochemistry and Molecular Pharmacology,{dagger}{dagger} University of Massachusetts Medical School, Worcester, Massachusetts; and the Division of Neurological Surgery,** University of Missouri–Columbia School of Medicine, Columbia, Missouri

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 µm. 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.






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Copyright © 2006 by the American Society for Investigative Pathology.