Expression of antisense uPAR and antisense uPA from a bicistronic adenoviral construct inhibits glioma cell invasion, tumor growth, and angiogenesis.
Urokinase-type plasminogen activator (uPA) and its receptor (uPAR) play an important role in the invasiveness of gliomas and other infiltrative tumors. In glioma cell lines and tumors, high grade correlates with increased expression of uPAR and uPA. We report here the downregulation of uPAR and uPA by delivery of antisense sequences of uPAR and uPA in a single adenoviral vector, Ad-uPAR-uPA (Ad, adenovirus). The bicistronic construct (Ad-uPAR-uPA) infected glioblastoma cell line had significantly reduced levels of uPAR, uPA enzymatic activity and immunoreactivity for these proteins when compared to controls. The Ad-uPAR-uPA infected cells showed a markedly lower level of invasion in the Matrigel invasion assays, and their spheroids failed to invade the fetal rat brain aggregates in the coculture system. Intracranial injection of SNB19 cells with the Ad-uPAR-uPA antisense bicistronic construct showed inhibited invasiveness and tumorigenicity. Subcutaneous injections of bicistronic antisense constructs into established tumors (U87 MG) caused regression of those tumors. Our results support the therapeutic potential of targeting the individual components of the uPAR-uPA system by using a single adenovirus construct for the treatment of glioma and other invasive cancers.
Gondi
Christopher S
CS
Division of Cancer Biology, Department of Biomedical and Therapeutic Sciences, University of Illinois, Peoria, IL, USA.
Lakka
Sajani S
SS
Yanamandra
Niranjan
N
Siddique
Khawar
K
Dinh
Dzung H
DH
Olivero
William C
WC
Gujrati
Meena
M
Rao
Jasti S
JS
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D015197:Carcinogenicity Tests; D002465:Cell Movement; D016543:Central Nervous System Neoplasms / Q000098:blood supply / Q000235:genetics* / Q000473:pathology / Q000628:therapy*; D016373:DNA, Antisense / Q000008:administration & dosage / Q000235:genetics; D015870:Gene Expression; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors / Q000235:genetics; D005910:Glioma / Q000098:blood supply / Q000235:genetics* / Q000473:pathology / Q000628:therapy*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000628:therapy*; D011956:Receptors, Cell Surface / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D055293:Receptors, Urokinase Plasminogen Activator; D014407:Tumor Cells, Cultured; D014568:Urokinase-Type Plasminogen Activator / Q000235:genetics* / Q000276:immunology / Q000378:metabolism
D016373:DNA, Antisense; C524898:PLAUR protein, human; C524899:Plaur protein, mouse; C524900:Plaur protein, rat; D011956:Receptors, Cell Surface; D055293:Receptors, Urokinase Plasminogen Activator; D014568:Urokinase-Type Plasminogen Activator