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α 1 ‐antitrypsin inhibits angiogenesis and tumor growth
Author(s) -
Huang Hanhua,
Campbell Steven C.,
Nelius Thomas,
Bedford Dhugal F.,
Veliceasa Dorina,
Bouck Noel P.,
Volpert Olga V.
Publication year - 2004
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.20494
Subject(s) - serpin , angiogenesis , neovascularization , biology , cancer research , apoptosis , microvessel , serine proteinase inhibitors , angiostatin , serine protease , microbiology and biotechnology , immunology , protease , enzyme , biochemistry , gene
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 α 1 ‐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 α 1 ‐antitrypsin expression and more aggressive tumor growth. © 2004 Wiley‐Liss, Inc.