Elevation of osteopontin levels in brain tumor cells reduces burden and promotes survival through the inhibition of cell dispersal.
Osteopontin (OPN) is a pleotrophic molecule that has been associated with multiple disorders of the central nervous system (CNS). Its roles in CNS malignancy are unclear but suggest that higher levels of OPN expression correlate with increased tumor grade and increased migratory capacity of tumor cells. In this study OPN cDNA was cloned into a retroviral vector and used to infect F98 Fischer rat-derived glioma cells and U87 human-derived glioblastoma multiforme (GBM) cells in vitro. Cells expressing high levels of OPN migrated less distance than control cells in vitro. This effect was not RGD mediated, but was reversed in the presence of c-Jun N-terminal kinase (JNK) inhibitor suggesting that JNK1 is an essential component of a negative feedback loop affecting OPN activated signaling cascades. Implantation of tumor cells expressing high levels of OPN into adult Fischer rats and nude rats resulted in morphologically distinct tumors and prolonged host survival relative to controls. We propose that local produced, high level OPN expression limits the malignant character of glioma cells and that the downstream mechanisms involved represent pathways that may have therapeutic value in the treatment of human CNS malignancy.
Selkirk
Stephen M
SM
Department of Neurology, University Hospital of Cleveland, Hanna House 5, 11100 Euclid Avenue, Cleveland, OH 44106, USA. stephen_selkirk@hotmail.com
Morrow
Jay
J
Barone
Tara A
TA
Hoffer
Alan
A
Lock
Jeffrey
J
DeChant
Anne
A
Mangla
Saisho
S
Plunkett
Robert J
RJ
Miller
Robert H
RH
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001932:Brain Neoplasms / Q000378:metabolism / Q000401:mortality / Q000503:physiopathology; D001973:Bromodeoxyuridine / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology*; D049109:Cell Proliferation; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics / Q000502:physiology; D005909:Glioblastoma / Q000378:metabolism / Q000401:mortality / Q000503:physiopathology; D005910:Glioma / Q000378:metabolism / Q000401:mortality / Q000503:physiopathology; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D020287:In Situ Nick-End Labeling; D053495:Osteopontin / Q000235:genetics / Q000378:metabolism*; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D051381:Rats; D016019:Survival Analysis; D013997:Time Factors; D014162:Transfection; D019737:Transplants
D019408:Platelet Endothelial Cell Adhesion Molecule-1; D053495:Osteopontin; D049452:Green Fluorescent Proteins; D001973:Bromodeoxyuridine