Adenovirus-mediated expression of antisense urokinase plasminogen activator receptor and antisense cathepsin B inhibits tumor growth, invasion, and angiogenesis in gliomas.

TitleAdenovirus-mediated expression of antisense urokinase plasminogen activator receptor and antisense cathepsin B inhibits tumor growth, invasion, and angiogenesis in gliomas.
Publication TypeJournal Article
Year of Publication2004
AuthorsGondi CS, Lakka SS, Yanamandra N, Olivero WC, Dinh DH, Gujrati M, Tung CH, Weissleder R, Rao JS
JournalCancer Res
Volume64
Issue12
Pagination4069-77
Date Published2004 Jun 15
ISSN0008-5472
KeywordsAdenoviridae, Animals, Cathepsin B, Cell Division, Cell Movement, DNA, Antisense, Female, Genetic Therapy, Glioblastoma, Humans, Male, Mice, Mice, Nude, Neoplasm Invasiveness, Neovascularization, Pathologic, Receptors, Cell Surface, Receptors, Urokinase Plasminogen Activator, Spheroids, Cellular, Xenograft Model Antitumor Assays
Abstract

We have shown previously that urokinase plasminogen activator receptor (uPAR) and cathepsin B are overexpressed during glioma progression, particularly at the leading edge of the tumor. In the present study, we simultaneously down-regulated uPAR and cathepsin B in SNB19 glioma cell monolayer or SNB19 spheroids using an adenoviral vector carrying antisense uPAR and antisense cathepsin B and a combination of these genes as determined by Western blot analysis. The Ad-uPAR-Cath B-infected cells revealed a marked reduction in tumor growth and invasiveness as compared with the parental and vector controls. In vitro and in vivo angiogenic assays demonstrated inhibition of capillary-like structure formation and microvessel formation after Ad-uPAR-Cath B infection of SNB19 cells when compared with Ad-cytomegalovirus (CMV)-infected or mock-infected controls. Furthermore, using a near infrared fluorescence probe, in vivo imaging for cathepsin B indicated low/undetectable levels of fluorescence after injection of the Ad-uPAR-Cath B construct into pre-established s.c. tumors as compared with Ad-CMV-treated and untreated tumors. The effect with bicistronic construct (Ad-uPAR-Cath B) was much higher than with single (Ad-uPAR/Ad-Cath B) constructs. These results indicate that the down-regulation of cathepsin B and uPAR plays a significant role in inhibiting tumor growth, invasion, and angiogenesis. Hence, the targeting of these two proteases may be a potential therapy for brain tumors and other cancers.

DOI10.1158/0008-5472.CAN-04-1243
Alternate JournalCancer Res
PubMed ID15205313
Grant ListCA 75557 / CA / NCI NIH HHS / United States
CA 76350 / CA / NCI NIH HHS / United States
CA 85216 / CA / NCI NIH HHS / United States
CA 92393 / CA / NCI NIH HHS / United States
Related Institute: 
Molecular Imaging Innovations Institute (MI3)

Weill Cornell Medicine
Department of Radiology
525 East 68th Street New York, NY 10065