Recombinant adenoviral vectors expressing
u-PA, t-PA,
PAI-1 and
PAI-2 were employed to correlate the expression of components of the fibrinolytic system with the invasiveness of HT 1080
tumor cells. Migration through Transwell inserts in vitro in the presence of
plasminogen was increased up to 22% by 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% with
PAI-1 and 29% with
PAI-2. Two routes of gene transfer were used to alter
metastasis of subcutaneously implanted HT 1080 cells expressing
firefly luciferase in nude mice.
Infection of cultured tumor cells with adenovirus expressing either
PAI-1 or
PAI-2 before implantation significantly reduced the incidence of lung
metastasis by 60% compared with control virus. However, only
PAI-2 reduced the incidence of lung and brain
metastasis following liver gene transfer. Although PAI gene transfer by either route reduced primary
tumor size, it had little effect on
tumor vascularization or host survival. The migratory and metastatic phenotype of HT 1080
tumor cells is thus directly dependent on
u-PA expression levels and can be altered by gene transfer of
u-PA or
plasminogen activator inhibitors.