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

C. Isogai, W. E. Laug, H. Shimada, P. J. Declerck, Monique Stins, D. L. Durden, A. Erdreich-Epstein, Y. A. DeClerck

Research output: Contribution to journalArticle

Abstract

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 αvβ3 integrin in blood vessels of primary neuroblastoma tumors, suggesting that PAI-1 plays a role in angiogenesis. Using human brain microvascular endothelial cells (HBMECs), we found that PAI-1 inhibits αvβ3 integrin-mediated cell adhesion to vitronectin but promotes α5β1-mediated migration from vitronectin toward fibronectin. Inhibition of vitronectin adhesion by PAI-1 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.

Original languageEnglish (US)
Pages (from-to)5587-5594
Number of pages8
JournalCancer Research
Volume61
Issue number14
StatePublished - Jul 15 2001
Externally publishedYes

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Plasminogen Activator Inhibitor 1
Fibronectins
Cell Movement
Vitronectin
Endothelial Cells
Neoplasms
Neuroblastoma
Cell Adhesion
Integrins
Brain
Blood Vessels
Apoptosis

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Isogai, C., Laug, W. E., Shimada, H., Declerck, P. J., Stins, M., Durden, D. L., ... DeClerck, Y. A. (2001). Plasminogen activator inhibitor-1 promotes angiogenesis by stimulating endothelial cell migration toward fibronectin. Cancer Research, 61(14), 5587-5594.

Plasminogen activator inhibitor-1 promotes angiogenesis by stimulating endothelial cell migration toward fibronectin. / Isogai, C.; Laug, W. E.; Shimada, H.; Declerck, P. J.; Stins, Monique; Durden, D. L.; Erdreich-Epstein, A.; DeClerck, Y. A.

In: Cancer Research, Vol. 61, No. 14, 15.07.2001, p. 5587-5594.

Research output: Contribution to journalArticle

Isogai, C, Laug, WE, Shimada, H, Declerck, PJ, Stins, M, Durden, DL, Erdreich-Epstein, A & DeClerck, YA 2001, 'Plasminogen activator inhibitor-1 promotes angiogenesis by stimulating endothelial cell migration toward fibronectin', Cancer Research, vol. 61, no. 14, pp. 5587-5594.
Isogai, C. ; Laug, W. E. ; Shimada, H. ; Declerck, P. J. ; Stins, Monique ; Durden, D. L. ; Erdreich-Epstein, A. ; DeClerck, Y. A. / Plasminogen activator inhibitor-1 promotes angiogenesis by stimulating endothelial cell migration toward fibronectin. In: Cancer Research. 2001 ; Vol. 61, No. 14. pp. 5587-5594.
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