Isogai, C × Laug, WE Shimada, H Declerck, Paul Stins, MF Durden, DL Erdreich-Epstein, A DeClerck, YA #
Amer assoc cancer research
Cancer Research vol:61 issue:14 pages:5587-5594
Increased expression of plasminogen activator inhibitor-1 (PAI-1) in cancer patients is associated with unfavorable outcome, and the reason for this paradox has been poorly understood. We have previously reported elevated levels 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 coexpressed with the angiogenesis marker cu,p, integrin in blood vessels of primary neuroblastoma tumors, suggesting that PAI-I plays a role in angiogenesis, Using human brain microvascular endothelial cells (HBMECs), we found that PAI-1 inhibits alpha (v)beta (3) integrin-mediated cell adhesion to vitronectin but promotes alpha (5)beta (1)-mediated migration from vitronectin toward fibronectin, Inhibition of vitronectin adhesion by PAI-I did not induce HBMEC apoptosis, PAI-1 also inhibited endothelial tube formation on Matrigel in the presence of vitronectin but had a stimulatory effect in the presence of fibronectin, This effect of PAI-1 on microvascular endothelial cells is primarily related to the ability of PAI-1 to bind to vitronectin via its NH2-terminal domain and to interfere with cell adhesion to vitronectin, We propose that PAI-1 acts as a positive switch for angiogenesis by promoting endothelial cell migration away from their vitronectin-containing perivascular space toward fibronectin-rich tumor tissue. These observations provide a novel explanation for the enhancing effect of PAI-1 in cancer progression.