Plasminogen activator inhibitor-1 promotes angiogenesis by stimulating endothelial cell migration toward fibronectin

Citation
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
Citations number
29
Categorie Soggetti
Oncology,"Onconogenesis & Cancer Research
Journal title
CANCER RESEARCH
ISSN journal
00085472 → ACNP
Volume
61
Issue
14
Year of publication
2001
Pages
5587 - 5594
Database
ISI
SICI code
0008-5472(20010715)61:14<5587:PAIPAB>2.0.ZU;2-E
Abstract
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.