α1-antitrypsin inhibits angiogenesis and tumor growth

Hanhua Huang, Steven C. Campbell, Thomas Nelius, Dhugal F. Bedford, Dorina Veliceasa, Noel P. Bouck, Olga V. Volpert*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

44 Scopus citations

Abstract

Disturbances of the ratio between angiogenic inducers and inhibitors in tumor microenvironment are the driving force behind angiogenic switch critical for tumor progression. Angiogenic inhibitors may vary depending on organismal age and the tissue of origin. We showed that α1-antitrypsin (AAT), a serine protease inhibitor (serpin) is an inhibitor of angiogenesis, which induced apoptosis and inhibited chemotaxis of endothelial cells. S- and Z-type mutations that cause abnormal folding and defective serpin activity abrogated AAT antiangiogenic activity. Removal of the C-terminal reactive site loop had no effect on its angiostatic activity. Both native AAT and AAT truncated on C-terminus (AATΔ) inhibited neovascularization in the rat cornea and delayed the growth of subcutaneous tumors in mice. Treatment with native AAT and truncated AATΔ, but not control vehicle reduced tumor microvessel density, while increasing apoptosis within tumor endothelium. Comparative analysis of the human tumors and normal tissues of origin showed correlation between reduced local α1-antitrypsin expression and more aggressive tumor growth.

Original languageEnglish (US)
Pages (from-to)1042-1048
Number of pages7
JournalInternational Journal of Cancer
Volume112
Issue number6
DOIs
StatePublished - Dec 20 2004

Keywords

  • Angiogenesis
  • Apoptosis
  • Reactive site loop
  • Tumor growth
  • α-antitrypsin

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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