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
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.