Reduction of tumor cell migration and metastasis by adenoviral gene transfer of plasminogen activator inhibitors

Citation
M. Praus et al., Reduction of tumor cell migration and metastasis by adenoviral gene transfer of plasminogen activator inhibitors, GENE THER, 6(2), 1999, pp. 227-236
Citations number
42
Categorie Soggetti
Molecular Biology & Genetics
Journal title
GENE THERAPY
ISSN journal
09697128 → ACNP
Volume
6
Issue
2
Year of publication
1999
Pages
227 - 236
Database
ISI
SICI code
0969-7128(199902)6:2<227:ROTCMA>2.0.ZU;2-2
Abstract
Recombinant adenoviral vectors expressing u-PA, t-PA, PAI-1 and PAI-2 were employed to correlate the expression of components of the fibrinolytic syst em with the invasiveness of HT 1080 tumor cells. Migration through Transwel l inserts in vitro in the presence of plasminogen was increased up to 22% b y overexpression of u-PA, whereas t-PA had no effect. Gene transfer of PAI- 1 or PAI-2 both reduced migration in a dose-dependent manner by up to 43% w ith PAI-1 and 29% with PAI-2. Two routes of gene transfer were used to alte r metastasis of subcutaneously implanted HT 1080 cells expressing firefly l uciferase in nude mice. Infection of cultured tumor cells with adenovirus e xpressing either PAI-I or PAI-2 before implantation significantly reduced t he incidence of lung metastasis by 60% compared with control virus. However , only PAI-2 reduced the incidence of lung and brain metastasis following l iver gene transfer Although PAI gene transfer by either route reduced prima ry tumor size, it had little effect an tumor vascularization or host surviv al The migratory and metastatic phenotype of HT 1080 tumor cells is thus di rectly dependent on u-PA expression levels and can be altered by gene trans fer of u-PA or plasminogen activator inhibitors.