C. Isogai et al., Plasminogen activator inhibitor-1 promotes angiogenesis by stimulating endothelial cell migration toward fibronectin, CANCER RES, 61(14), 2001, pp. 5587-5594
Increased expression of plasminogen activator inhibitor-1 (PAI-1) in cancer
patients is associated with unfavorable outcome, and the reason for this p
aradox has been poorly understood. We have previously reported elevated lev
els of PAI-1 in primary tumors of advanced neuroblastomas (Y. Sugiura et al
., Cancer Res., 59: 1327-1336, 1999), Here we demonstrate that PAI-1 is coe
xpressed with the angiogenesis marker cu,p, integrin in blood vessels of pr
imary neuroblastoma tumors, suggesting that PAI-I plays a role in angiogene
sis, Using human brain microvascular endothelial cells (HBMECs), we found t
hat PAI-1 inhibits alpha (v)beta (3) integrin-mediated cell adhesion to vit
ronectin but promotes alpha (5)beta (1)-mediated migration from vitronectin
toward fibronectin, Inhibition of vitronectin adhesion by PAI-I did not in
duce HBMEC apoptosis, PAI-1 also inhibited endothelial tube formation on Ma
trigel in the presence of vitronectin but had a stimulatory effect in the p
resence of fibronectin, This effect of PAI-1 on microvascular endothelial c
ells is primarily related to the ability of PAI-1 to bind to vitronectin vi
a its NH2-terminal domain and to interfere with cell adhesion to vitronecti
n, We propose that PAI-1 acts as a positive switch for angiogenesis by prom
oting endothelial cell migration away from their vitronectin-containing per
ivascular space toward fibronectin-rich tumor tissue. These observations pr
ovide a novel explanation for the enhancing effect of PAI-1 in cancer progr
ession.